{ "branches": [ { "id": "foundations", "family": "trunk", "approach": "behind", "label": "Foundations", "status": "done", "verdict": "Lewy bodies and dopamine loss define what any cure must protect or restore." }, { "id": "synuclein-spread", "family": "synuclein", "approach": "clear", "label": "Synuclein misfolding & spread", "status": "active", "verdict": "Cinpanemab and minzasolmin failed; prasinezumab Phase 3 PARAISO runs to 2029; exidavnemab and UB-312 have safety data only." }, { "id": "synuclein-dosage", "family": "synuclein", "approach": "clear", "label": "Synuclein lowering", "status": "active", "verdict": "Too much normal synuclein causes disease; the dedicated lowering drugs (antisense and siRNA) are all Phase 1 with no efficacy data; buntanetap, a translation inhibitor, missed its Phase 3 primary measure." }, { "id": "gut-brain", "family": "synuclein", "approach": "body", "label": "Gut–brain origin", "status": "open", "verdict": "Mouse spread, registry data and body-first/brain-first subtypes are suggestive; faecal-transplant trials gave mixed results." }, { "id": "mitochondria", "family": "housekeeping", "approach": "rubbish", "label": "Mitochondria & energy", "status": "narrowed", "verdict": "CoQ10, creatine, MitoQ and nicotinamide riboside (NOPARK, worse than placebo) all failed; UDCA hit its target; the first USP30 mitophagy drug is in patients." }, { "id": "oxidative-stress", "family": "housekeeping", "approach": "rubbish", "label": "Oxidative stress", "status": "pruned", "verdict": "MAO-B inhibitors, urate and iron removal all failed to slow the disease." }, { "id": "lysosome-gba", "family": "housekeeping", "approach": "rubbish", "label": "Lysosome & GBA", "status": "active", "verdict": "Venglustat, BIA 28-6156 and ambroxol in GBA carriers (AMBITIOUS, no cognitive benefit, preprint) failed; the ambroxol Phase 3 (ASPro-PD, reads out ~2029) and PR001 gene therapy continue." }, { "id": "lrrk2", "family": "housekeeping", "approach": "genes", "label": "LRRK2", "status": "narrowed", "verdict": "Raised LRRK2 activity in ordinary Parkinson's justified LUMA, which failed; lung findings proved reversible; BEACON (carriers) and NEU-411 read out in 2027." }, { "id": "vulnerability", "family": "housekeeping", "approach": "protect", "label": "Selective vulnerability", "status": "open", "verdict": "Calcium load, giant axons and a named subtype explain why; isradipine failed; Nurr1 activators are preclinical." }, { "id": "cell-survival", "family": "housekeeping", "approach": "protect", "label": "Cell survival & anti-apoptosis", "status": "narrowed", "verdict": "Blocking cell-death signals failed (CEP-1347, TCH346, nilotinib); c-Abl inhibitors keep going but vodobatinib (PROSEEK) was no better than placebo and was stopped, risvodetinib missed its 12-week measure, and radotinib (primary follow-up complete Sept 2026) reports in 2027." }, { "id": "inflammation", "family": "body", "approach": "body", "label": "Inflammation & immunity", "status": "open", "verdict": "Azathioprine (AZA-PD) failed; NLRP3 drugs are in patients (DAPA-PD due 2027); adalimumab is being tested for prevention in REM sleep disorder (PRISMS, 2029)." }, { "id": "metabolic-repurposing", "family": "body", "approach": "body", "label": "Metabolic drug repurposing", "status": "narrowed", "verdict": "Exenatide Phase 3 (now under a Lancet expression of concern), NLY01, pioglitazone and simvastatin failed; lixisenatide Phase 2 was positive." }, { "id": "environment", "family": "body", "approach": "body", "label": "Environment & lifestyle", "status": "open", "verdict": "Toxins and head injury raise risk; nicotine failed; exercise (SPARX3) is being tested." }, { "id": "genetics", "family": "genetics", "approach": "genes", "label": "Genetic architecture", "status": "enabler", "verdict": "Risk genes feed every other branch; most are tagged in the branch they opened." }, { "id": "cell-replacement", "family": "restoration", "approach": "replace", "label": "Cell replacement", "status": "active", "verdict": "Strongest branch: conditional approval in Japan; bemdaneprocel Phase 3 (exPDite-2) reads out ~2027; fetal and Spheramine grafts failed; does not stop the disease." }, { "id": "growth-factors", "family": "restoration", "approach": "replace", "label": "Growth factors", "status": "revived", "verdict": "GDNF infusions, neurturin gene therapy and fosgonimeton failed; AB-1005 (REGENERATE-PD, readout ~2028) and CDNF keep it alive." }, { "id": "gene-delivery", "family": "restoration", "approach": "replace", "label": "Gene therapy & delivery", "status": "active", "verdict": "Dopamine-making gene therapies ended; brain-crossing capsids advance delivery for other branches." }, { "id": "biomarkers", "family": "enabler", "approach": "behind", "label": "Biomarkers", "status": "enabler", "verdict": "The seed test shows who has the disease, not how fast it progresses." }, { "id": "trial-methods", "family": "enabler", "approach": "behind", "label": "Trial methods & regulation", "status": "enabler", "verdict": "Washout, delayed-start and imaging designs never proved slowing; prodromal criteria and REM sleep disorder cohorts now allow prevention trials (PRISMS, due 2029)." }, { "id": "infrastructure", "family": "enabler", "approach": "behind", "label": "Infrastructure & funding", "status": "enabler", "verdict": "Open cohorts and funders underpin most modern work." }, { "id": "models", "family": "enabler", "approach": "behind", "label": "Models", "status": "enabler", "verdict": "Patient-derived neurons and organoids not tied to one hypothesis." } ], "nodes": [ { "id": 21, "title": "Lewy bodies described; tied to the substantia nigra", "oneline": "Three early researchers gave the field the physical signature of Parkinson's (the inclusion body) and the place where the damage is concentrated (the substantia nigra).", "years": [ 1912, 1919 ], "kind": "discovery", "branch": [ "foundations" ], "outcome": "advanced", "file": "21-lewy-bodies-and-the-nigra-1912-1919.md", "unverified": 2 }, { "id": 22, "title": "Carlsson: dopamine is a brain transmitter", "oneline": "Arvid Carlsson showed dopamine is a signalling chemical in the brain, and that a drug-induced loss of movement can be reversed with L-DOPA.", "years": [ 1957, 1958 ], "kind": "discovery", "branch": [ "foundations" ], "outcome": "advanced", "file": "22-carlsson-dopamine-1957-1958.md", "unverified": 3 }, { "id": 1, "title": "Dopamine is missing from the Parkinson's brain", "oneline": "Autopsy measurements showed the brain's movement hub is starved of dopamine, naming the system that any cure must protect or restore.", "years": [ 1960, 1960 ], "kind": "discovery", "branch": [ "foundations" ], "outcome": "advanced", "file": "01-dopamine-missing-1960.md", "unverified": 2 }, { "id": 285, "title": "Levodopa becomes standard treatment", "oneline": "Intravenous levodopa produced a striking short-term improvement in 1961, and a 1967 regimen of high oral doses made it a usable daily drug, proving that replacing the missing dopamine helps while leaving the loss of neurons untouched.", "years": [ 1961, 1967 ], "kind": "discovery", "branch": [ "foundations" ], "outcome": "advanced", "file": "285-levodopa-becomes-standard-treatment-1961-1967.md", "unverified": 4 }, { "id": 284, "title": "Hoehn and Yahr staging scale", "oneline": "A five-stage severity scale from a 1967 paper on onset, progression and mortality became the field's shorthand for how advanced the disease is, and is still used to describe trial groups, though rating scales have replaced it for measuring change.", "years": [ 1967, 1967 ], "kind": "tool", "branch": [ "trial-methods" ], "outcome": "superseded", "file": "284-hoehn-yahr-staging-scale-1967.md", "unverified": 3 }, { "id": 339, "title": "Manganese parkinsonism in welders and miners", "oneline": "Heavy exposure to manganese in mines and welding gives a movement disorder that looks like Parkinson's, but differs in scans and pathology, so it shows how a metal can damage dopamine circuits without proving it causes the common disease.", "years": [ 1967, 2013 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "339-manganese-parkinsonism-welders-miners-1967-2013.md", "unverified": 4 }, { "id": 23, "title": "6-OHDA model and first rat dopamine grafts", "oneline": "A toxin that selectively destroys dopamine neurons gave the field its standard rat model, and in 1979 grafting new neurons into lesioned rats first showed that replacing lost cells can repair the circuit.", "years": [ 1968, 1979 ], "kind": "model", "branch": [ "cell-replacement", "foundations", "models" ], "outcome": "advanced", "file": "23-6ohda-model-and-first-grafts-1968-1979.md", "unverified": 5 }, { "id": 2, "title": "MPTP: a chemical that causes Parkinson's", "oneline": "A contaminated street drug caused Parkinson's-like disease, proving a chemical can selectively kill the right neurons and giving researchers a model to test protective drugs.", "years": [ 1983, 1983 ], "kind": "discovery", "branch": [ "environment", "mitochondria", "models" ], "outcome": "advanced", "file": "02-mptp-1983.md", "unverified": 4 }, { "id": 274, "title": "Fluorodopa PET", "oneline": "Garnett, Firnau and Nahmias used a radioactive form of L-dopa, [18F]fluorodopa, to image the dopamine pathways of living volunteers, which opened the way to measuring dopamine loss in Parkinson's.", "years": [ 1983, 1983 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "274-fluorodopa-pet-1983.md", "unverified": 3 }, { "id": 277, "title": "Parkinson Study Group founded", "oneline": "A network of North American clinics set up in the mid-1980s gave Parkinson's research the shared protocols and patient access needed for large placebo-controlled trials, starting with DATATOP (800 people).", "years": [ 1985, 1985 ], "kind": "infrastructure", "branch": [ "infrastructure" ], "outcome": "advanced", "file": "277-parkinson-study-group-founded-1985.md", "unverified": 6 }, { "id": 3, "title": "First fetal dopamine-cell transplants", "oneline": "The first open-label grafts of fetal dopamine cells showed that replacement neurons can survive and make dopamine in a human brain; sham-controlled trials then failed to confirm a clear benefit, and the approach gave way to stem-cell-derived neurons.", "years": [ 1987, 1990 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "superseded", "file": "03-fetal-transplants-1987-2025.md", "unverified": 4 }, { "id": 61, "title": "DATATOP: deprenyl", "oneline": "The first large trial of a possible brain-protecting drug found that deprenyl halved the risk of needing levodopa, but critics argued the delay came from symptom relief, so the question stayed open.", "years": [ 1987, 1993 ], "kind": "trial", "branch": [ "oxidative-stress", "trial-methods" ], "outcome": "superseded", "file": "61-datatop-deprenyl-1989-1993.md", "unverified": 4, "n": 800 }, { "id": 52, "title": "Inflammation in the Parkinson's nigra", "oneline": "Postmortem work found activated microglia, the brain's resident immune cells, in the region where Parkinson's kills neurons, first suggesting that inflammation takes part in the disease.", "years": [ 1988, 1988 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "52-microglia-in-nigra-1988.md", "unverified": 2 }, { "id": 128, "title": "Iron and neuromelanin in the nigra", "oneline": "The Parkinson's nigra holds more iron, and a rat model with human-like neuromelanin suggests the pigment's build-up with age can set a threshold for cell death.", "years": [ 1988, 2019 ], "kind": "discovery", "branch": [ "oxidative-stress", "vulnerability" ], "outcome": "open", "file": "128-neuromelanin-and-iron-in-the-nigra-1988-2019.md", "unverified": 4 }, { "id": 257, "title": "Lewy bodies in the gut's nerve plexuses", "oneline": "A Japanese autopsy study found Lewy bodies, the clumps that mark Parkinson's, in the nerve networks of the gut wall in all seven patients examined, an early pathology finding that the disease reaches the gut.", "years": [ 1988, 1988 ], "kind": "discovery", "branch": [ "gut-brain" ], "outcome": "advanced", "file": "257-lewy-bodies-in-gut-nerve-plexuses-1988.md", "unverified": 4 }, { "id": 11, "title": "Complex I deficiency in the Parkinson's brain", "oneline": "The first human evidence that the cell's energy machinery fails in Parkinson's, opening the mitochondrial line of research.", "years": [ 1989, 1990 ], "kind": "discovery", "branch": [ "mitochondria" ], "outcome": "advanced", "file": "11-complex-i-deficiency-1989.md", "unverified": 3 }, { "id": 343, "title": "Calbindin dopamine neurons spared", "oneline": "Two post-mortem studies found that midbrain dopamine neurons containing the calcium-binding protein calbindin were relatively spared, and that the neighbouring ventral tegmental area lost fewer cells than the nigra, giving the first molecular clue to why some dopamine cells survive.", "years": [ 1990, 1992 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "343-calbindin-neurons-spared-ventral-tegmental-1990-1992.md", "unverified": 3 }, { "id": 267, "title": "Nigral cell loss pattern differs from ageing", "oneline": "Counting pigmented cells in brains from 36 controls and 20 people with Parkinson's, Fearnley and Lees showed that the disease hits the lateral ventral tier of the substantia nigra hardest, the reverse of normal ageing, with 68% of that tier gone when symptoms start.", "years": [ 1991, 1991 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "advanced", "file": "267-nigral-ventrolateral-tier-loss-1991.md", "unverified": 3 }, { "id": 136, "title": "UK Brain Bank diagnostic criteria", "oneline": "Checking 100 diagnoses against autopsy showed only 76% were really Parkinson's, and a written set of criteria lifted accuracy to 82%, giving trials a common entry standard.", "years": [ 1992, 1992 ], "kind": "tool", "branch": [ "trial-methods" ], "outcome": "advanced", "file": "136-uk-brain-bank-criteria-1992.md", "unverified": 2 }, { "id": 342, "title": "Locus coeruleus loss alongside the nigra", "oneline": "The locus coeruleus, a small brainstem nucleus that makes noradrenaline, loses roughly 60% of its cells in Parkinson's, as severe as the nigra, and Braak's ascending staging has Lewy pathology in the lower brainstem before the nigra, so dopamine loss may not be where the disease starts.", "years": [ 1992, 2007 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "342-locus-coeruleus-loss-parkinsons-1992-2007.md", "unverified": 2 }, { "id": 213, "title": "GDNF discovered", "oneline": "Researchers at Synergen purified and cloned glial cell line-derived neurotrophic factor (GDNF), a protein that raised survival of dopamine neurons in dish cultures, the origin of every GDNF treatment since.", "years": [ 1993, 1993 ], "kind": "discovery", "branch": [ "growth-factors" ], "outcome": "advanced", "file": "213-gdnf-discovery-1993.md", "unverified": 3 }, { "id": 129, "title": "Glutathione loss in the nigra", "oneline": "Post-mortem brains showed about 40% less of the cell's main antioxidant, glutathione, in the Parkinson's nigra and nowhere else, early evidence that oxidative stress is part of the disease.", "years": [ 1994, 1994 ], "kind": "discovery", "branch": [ "oxidative-stress" ], "outcome": "open", "file": "129-glutathione-loss-nigra-1994.md", "unverified": 2 }, { "id": 340, "title": "Dieldrin and organochlorines in Parkinson's brains", "oneline": "Small autopsy and blood studies found the banned insecticide dieldrin, and related chemicals, more often in people with Parkinson's, and mouse work showed dieldrin harms the dopamine system.", "years": [ 1994, 2009 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "340-dieldrin-organochlorines-in-parkinsons-brains-1994-2009.md", "unverified": 3 }, { "id": 221, "title": "REM sleep behaviour disorder becomes Parkinson's", "oneline": "People who act out their dreams with no other cause (isolated REM sleep behaviour disorder, iRBD) turn out to be in the early stage of a synuclein disease. A 24-centre study of 1,280 people measured how fast, which makes iRBD the best-defined group for prevention trials.", "years": [ 1996, 2019 ], "kind": "discovery", "branch": [ "biomarkers", "trial-methods" ], "outcome": "advanced", "file": "221-rbd-converts-to-synucleinopathy-1996-2019.md", "unverified": 2 }, { "id": 4, "title": "First Parkinson's gene: SNCA", "oneline": "A single amino-acid change in alpha-synuclein caused inherited Parkinson's, proving the disease can be genetic and pointing to the protein now at the centre of slowing-the-disease research.", "years": [ 1997, 1997 ], "kind": "discovery", "branch": [ "synuclein-spread", "synuclein-dosage", "genetics" ], "outcome": "advanced", "file": "04-snca-gene-1997.md", "unverified": 4 }, { "id": 5, "title": "Alpha-synuclein is what Lewy bodies are made of", "oneline": "The protein clumps that define Parkinson's are made mainly of alpha-synuclein, tying the rare inherited form to the common disease through one protein.", "years": [ 1997, 1997 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "advanced", "file": "05-synuclein-in-lewy-bodies-1997.md", "unverified": 2 }, { "id": 176, "title": "Nurr1 (NR4A2) discovery", "oneline": "Mice without the Nurr1 gene never make midbrain dopamine neurons, and rare Nurr1 variants were found in families with Parkinson's, making it a target for drugs that protect those neurons.", "years": [ 1997, 2003 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "advanced", "file": "176-nurr1-nr4a2-discovery-1997-2003.md", "unverified": 2 }, { "id": 12, "title": "Parkin mutations cause juvenile parkinsonism", "oneline": "The first recessive Parkinson's gene showed that losing a protein-disposal function can kill dopamine neurons.", "years": [ 1998, 1998 ], "kind": "discovery", "branch": [ "mitochondria", "genetics" ], "outcome": "advanced", "file": "12-parkin-gene-1998.md", "unverified": 2 }, { "id": 44, "title": "Further SNCA point mutations", "oneline": "Four further single-letter changes in the synuclein gene cause inherited Parkinson's, and each gives a slightly different disease, from classic Parkinson's to a blend with multiple system atrophy.", "years": [ 1998, 2013 ], "kind": "discovery", "branch": [ "synuclein-spread", "genetics" ], "outcome": "advanced", "file": "44-snca-point-mutations-1998-2013.md", "unverified": 5 }, { "id": 191, "title": "UCHL1 I93M (PARK5)", "oneline": "A single German sibling pair carrying a change in UCHL1, an enzyme of the cell's ubiquitin protein-disposal system, was reported as a Parkinson's gene, but no other family has confirmed it.", "years": [ 1998, 1998 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "dead-end", "file": "191-uchl1-park5-1998.md", "unverified": 3 }, { "id": 238, "title": "Twin study: genes matter little after age 50", "oneline": "Identical twins were no more likely than fraternal twins to share Parkinson's when it began after age 50, which pushed the field to look hard at environment before the genome-wide scans of the 2000s.", "years": [ 1999, 1999 ], "kind": "discovery", "branch": [ "genetics", "environment" ], "outcome": "advanced", "file": "238-twin-study-low-heritability-1999.md", "unverified": 2 }, { "id": 13, "title": "Rotenone reproduces Parkinson's features in rats", "oneline": "A pesticide that blocks mitochondrial Complex I produced Parkinson's-like neuron loss and alpha-synuclein-containing inclusions in rats.", "years": [ 2000, 2000 ], "kind": "model", "branch": [ "mitochondria", "environment", "models" ], "outcome": "advanced", "file": "13-rotenone-model-2000.md", "unverified": 3 }, { "id": 77, "title": "Michael J. Fox Foundation founded", "oneline": "An actor with Parkinson's and a former banker created a research-only funder that became the world's largest non-profit funder of Parkinson's science and a backer of many landmarks in this catalogue.", "years": [ 2000, 2000 ], "kind": "infrastructure", "branch": [ "infrastructure" ], "outcome": "advanced", "file": "77-michael-j-fox-foundation-2000.md", "unverified": 2 }, { "id": 82, "title": "Smoking and coffee: protective associations", "oneline": "One of the most replicated findings in Parkinson's epidemiology is lower risk in smokers and coffee drinkers; genetic analysis supports the smoking link, but a nicotine-patch trial found no benefit.", "years": [ 2000, 2023 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "dead-end", "file": "82-smoking-and-coffee-protective-association-2000-2023.md", "unverified": 2 }, { "id": 125, "title": "MAPT (tau) H1 haplotype", "oneline": "A common version of the tau gene region (MAPT, haplotype H1) raises Parkinson's risk modestly, tying the disease to a protein better known from Alzheimer's and other tauopathies.", "years": [ 2000, 2009 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "125-mapt-tau-risk-locus-2009.md", "unverified": 3 }, { "id": 201, "title": "Synuclein knockout mice are viable", "oneline": "Mice engineered to lack alpha-synuclein developed normally and lived, with only small changes in how dopamine neurons release dopamine, an early sign that lowering synuclein might be safe.", "years": [ 2000, 2000 ], "kind": "preclinical", "branch": [ "synuclein-dosage" ], "outcome": "advanced", "file": "201-snca-knockout-mice-viable-2000.md", "unverified": 3 }, { "id": 205, "title": "Drosophila synuclein model", "oneline": "Fruit flies given the human synuclein gene lost dopamine neurons with age and formed clumps, giving a fast, cheap model for genetic screens.", "years": [ 2000, 2000 ], "kind": "model", "branch": [ "synuclein-spread", "models" ], "outcome": "advanced", "file": "205-drosophila-synuclein-model-2000.md", "unverified": 3 }, { "id": 345, "title": "DaTscan approved in the EU and US", "oneline": "The first dopamine-transporter brain scan to reach clinics, ioflupane (123I), was authorised in the EU on 27 July 2000 and by the US FDA in January 2011, putting a dopamine-loss measurement into routine care and later into trial screening.", "years": [ 2000, 2011 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "345-datscan-eu-and-fda-approvals-2000-2011.md", "unverified": 3 }, { "id": 258, "title": "Constipation precedes Parkinson's", "oneline": "In 6,790 men in the Honolulu Heart Program followed for 24 years, those with fewer than one bowel movement a day had a 2.7-fold higher risk of later Parkinson's, showing gut symptoms come first.", "years": [ 2001, 2001 ], "kind": "discovery", "branch": [ "gut-brain" ], "outcome": "advanced", "file": "258-constipation-precedes-parkinsons-2001.md", "unverified": 4 }, { "id": 283, "title": "Placebo releases dopamine", "oneline": "Brain scans showed that patients who expected to be treated released real dopamine in the striatum, a release similar in size to that from an active dopamine drug, so a placebo response in Parkinson's is biological and can look like benefit.", "years": [ 2001, 2001 ], "kind": "discovery", "branch": [ "trial-methods" ], "outcome": "advanced", "file": "283-placebo-dopamine-release-2001.md", "unverified": 4 }, { "id": 317, "title": "Freed: sham-controlled fetal grafts", "oneline": "In 40 people with severe Parkinson's, fetal dopamine-cell grafts did not beat sham surgery on the main measure, helped only patients aged 60 or under, and left 15% with dystonia and dyskinesias.", "years": [ 2001, 2001 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "dead-end", "file": "317-freed-sham-fetal-grafts-2001.md", "unverified": 6, "phase": 2, "n": 40 }, { "id": 31, "title": "A53T alpha-synuclein mice", "oneline": "Mice carrying the human alpha-synuclein gene with the Parkinson's-causing A53T mutation developed protein clumps, severe movement problems, paralysis and early death, showing in a living animal that the mutant protein alone can drive disease, though without the classic loss of nigral dopamine neurons.", "years": [ 2002, 2002 ], "kind": "model", "branch": [ "synuclein-spread", "models" ], "outcome": "advanced", "file": "31-a53t-synuclein-mice-2002.md", "unverified": 5 }, { "id": 41, "title": "Virus-driven synuclein rat and marmoset models", "oneline": "Using a harmless virus to make dopamine neurons produce extra human alpha-synuclein killed a large share of them in rats and marmosets, giving early synuclein-driven nigral cell-loss models in adult animals, including a monkey.", "years": [ 2002, 2003 ], "kind": "model", "branch": [ "synuclein-dosage", "models" ], "outcome": "advanced", "file": "41-aav-synuclein-rat-and-marmoset-models-2002-2003.md", "unverified": 4 }, { "id": 94, "title": "Synuclein Ser129 phosphorylation", "oneline": "Alpha-synuclein in Lewy-body diseases is heavily tagged with a phosphate group at serine 129, a signature that became the standard way to spot pathology, though whether the tag causes harm or protects is still argued.", "years": [ 2002, 2002 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "94-synuclein-ser129-phosphorylation-2002.md", "unverified": 3 }, { "id": 102, "title": "Coenzyme Q10 Phase 2", "oneline": "An 80-person dose-finding trial found the highest dose of coenzyme Q10 slowed functional decline in early Parkinson's, which justified the 600-person QE3 trial that found no benefit in 2014.", "years": [ 2002, 2002 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "superseded", "file": "102-coq10-phase2-2002.md", "unverified": 4, "phase": 2, "n": 80 }, { "id": 162, "title": "TEMPO: rasagiline delayed start", "oneline": "In 404 people with early Parkinson's, starting rasagiline right away left people better off than starting it six months later, a gap that lasted 6.5 years, but the design could not prove protection.", "years": [ 2002, 2009 ], "kind": "trial", "branch": [ "oxidative-stress", "trial-methods" ], "outcome": "superseded", "file": "162-tempo-rasagiline-2002-2009.md", "unverified": 2, "phase": 3, "n": 404 }, { "id": 163, "title": "CALM-PD β-CIT and REAL-PET", "oneline": "Two trials found that starting with pramipexole or ropinirole instead of levodopa slowed the loss of dopamine signal on brain scans, but neither showed that people were clinically protected.", "years": [ 2002, 2003 ], "kind": "trial", "branch": [ "trial-methods", "biomarkers" ], "outcome": "superseded", "file": "163-calm-pd-real-pet-imaging-2002-2003.md", "unverified": 3, "n": 268 }, { "id": 170, "title": "TCH346 (GAPDH binder)", "oneline": "TCH346 (CGP 3466), a drug that binds the enzyme GAPDH to stop a cell-death pathway, did not differ from placebo in 301 people with early Parkinson's.", "years": [ 2002, 2006 ], "kind": "trial", "branch": [ "cell-survival", "mitochondria" ], "outcome": "dead-end", "file": "170-tch346-2002-2006.md", "unverified": 2, "phase": 2, "n": 301 }, { "id": 6, "title": "Braak staging: the disease spreads in order", "oneline": "Autopsy mapping showed Lewy pathology climbing the brain in a predictable order, reframing Parkinson's as a spreading disease that might be intercepted early.", "years": [ 2003, 2003 ], "kind": "discovery", "branch": [ "synuclein-spread", "gut-brain" ], "outcome": "open", "file": "06-braak-staging-2003.md", "unverified": 2 }, { "id": 14, "title": "Extra copies of the synuclein gene cause Parkinson's", "oneline": "Simply having too much normal alpha-synuclein is enough to cause Parkinson's, the main reason for trying to lower it.", "years": [ 2003, 2003 ], "kind": "discovery", "branch": [ "synuclein-dosage", "genetics" ], "outcome": "advanced", "file": "14-snca-triplication-2003.md", "unverified": 5 }, { "id": 33, "title": "DJ-1 mutations cause early-onset parkinsonism", "oneline": "Two families with inherited early-onset Parkinson's had faults in a gene called DJ-1 (PARK7), a protein thought to protect cells from oxidative stress; the gene is real but rare, and exactly what the protein does is still debated.", "years": [ 2003, 2003 ], "kind": "discovery", "branch": [ "mitochondria", "genetics" ], "outcome": "open", "file": "33-dj1-gene-2003.md", "unverified": 3 }, { "id": 39, "title": "GDNF: the growth-factor idea, from infusions to gene therapy", "oneline": "The growth factor GDNF looked like a way to rescue dopamine neurons, but infusing it into the brain failed in controlled trials, so the idea is now tested as a gene therapy that makes the brain produce GDNF.", "years": [ 2003, 2026 ], "kind": "discovery", "branch": [ "growth-factors", "gene-delivery" ], "outcome": "open", "file": "39-gdnf-gene-therapy-2003-2026.md", "unverified": 4 }, { "id": 264, "title": "Ibuprofen and lower Parkinson's risk", "oneline": "Large US cohorts found that people who regularly took ibuprofen had about 38% lower risk of later Parkinson's, but aspirin and other painkillers showed no link and no trial has tested it.", "years": [ 2003, 2011 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "264-ibuprofen-nsaids-lower-parkinsons-risk-2003-2011.md", "unverified": 3 }, { "id": 270, "title": "Yeast synuclein models", "oneline": "Baker's yeast engineered to make human alpha-synuclein formed inclusions and died, and genome-wide screens found that the earliest defect was a block in transport from the endoplasmic reticulum to the Golgi, which the protein Rab1 rescued in animal models.", "years": [ 2003, 2006 ], "kind": "model", "branch": [ "models" ], "outcome": "advanced", "file": "270-yeast-synuclein-models-2003-2006.md", "unverified": 4 }, { "id": 271, "title": "Knockout mice keep their neurons", "oneline": "Gene-knockout mice for three recessive Parkinson's genes showed subtle dopamine-signalling changes but normal numbers of nigral neurons, so the most direct genetic models did not reproduce the disease's defining cell loss.", "years": [ 2003, 2007 ], "kind": "model", "branch": [ "models" ], "outcome": "open", "file": "271-knockout-mice-keep-dopamine-neurons-2003-2007.md", "unverified": 4 }, { "id": 318, "title": "Olanow: sham-controlled fetal grafts", "oneline": "In 34 people with advanced Parkinson's, fetal grafts did not significantly beat a placebo operation at 24 months, and 56% of grafted patients had dyskinesias that continued off medication.", "years": [ 2003, 2003 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "dead-end", "file": "318-olanow-sham-fetal-grafts-2003.md", "unverified": 4, "phase": 2, "n": 34 }, { "id": 7, "title": "The LRRK2 gene: the first gene-based drug target", "oneline": "Two groups found that mutations in LRRK2 are the most common known genetic cause of Parkinson's, which gave the field its first gene-based drug target.", "years": [ 2004, 2004 ], "kind": "discovery", "branch": [ "lrrk2", "genetics" ], "outcome": "open", "file": "07-lrrk2-2004.md", "unverified": 0 }, { "id": 15, "title": "PINK1 and the mitophagy pathway", "oneline": "A second recessive gene tied the genetics to the cell's quality control for failing mitochondria, giving concrete drug targets.", "years": [ 2004, 2004 ], "kind": "discovery", "branch": [ "mitochondria", "genetics" ], "outcome": "open", "file": "15-pink1-and-mitophagy-2004.md", "unverified": 4 }, { "id": 59, "title": "Chaperone-mediated autophagy", "oneline": "Normal synuclein is cleared through chaperone-mediated autophagy (CMA), a lysosomal pathway, and the two mutant forms that cause inherited Parkinson's clog that pathway, hinting that failed clearance lets synuclein build up.", "years": [ 2004, 2004 ], "kind": "discovery", "branch": [ "lysosome-gba", "synuclein-spread" ], "outcome": "open", "file": "59-chaperone-mediated-autophagy-2004.md", "unverified": 3 }, { "id": 112, "title": "AAV-AADC gene therapy", "oneline": "Injecting a virus carrying the AADC gene into the putamen raised dopamine-making in the brain and helped symptoms in two small open-label trials (10 and 15 people); the later Voyager phase 1b and sham-controlled trial, and the end of the Parkinson's programme in 2021, are in [landmark 305](305-voyager-vy-aadc-phase-1b-restore-1-2017-2021.md).", "years": [ 2004, 2019 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "112-aav-aadc-gene-therapy-2009-2024.md", "unverified": 2 }, { "id": 132, "title": "Sex differences in risk", "oneline": "A pooled analysis found Parkinson's about 1.5 times more common in men, hinting at hormonal, genetic or exposure-related drivers, none of which is proven.", "years": [ 2004, 2004 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "132-sex-differences-risk-2004.md", "unverified": 4 }, { "id": 161, "title": "ELLDOPA: levodopa and progression", "oneline": "In 361 people with early Parkinson's, levodopa kept scores better than placebo even after a two-week washout, but dopamine-transporter scans looked worse, so the trial could not say whether the drug protects or harms.", "years": [ 2004, 2004 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "superseded", "file": "161-elldopa-levodopa-2004.md", "unverified": 3, "phase": 3, "n": 361 }, { "id": 239, "title": "POLG mutations cause parkinsonism", "oneline": "Families with a mitochondrial eye-muscle disease and POLG mutations also developed parkinsonism, an inherited cause of parkinsonism in a mitochondrial protein, with the authors noting that none had been characterised before.", "years": [ 2004, 2004 ], "kind": "discovery", "branch": [ "genetics", "mitochondria" ], "outcome": "open", "file": "239-polg-mutations-parkinsonism-2004.md", "unverified": 3 }, { "id": 286, "title": "Smell loss predicts Parkinson's", "oneline": "Two prospective studies showed that otherwise unexplained poor smell raised the risk of later Parkinson's (at least 10% in relatives over 2 years; a fivefold higher risk in elderly men), making smell loss an established early marker.", "years": [ 2004, 2008 ], "kind": "discovery", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "286-smell-loss-predicts-parkinsons-2004-2008.md", "unverified": 3 }, { "id": 335, "title": "SNCA duplications: ordinary-looking Parkinson's, partial penetrance", "oneline": "Two 2004 reports found SNCA duplications (three gene copies instead of two) in families with late-onset Parkinson's that resembled the ordinary disease; a 2009 Japanese study put lifetime penetrance at 43.8%.", "years": [ 2004, 2009 ], "kind": "discovery", "branch": [ "synuclein-dosage", "genetics" ], "outcome": "advanced", "file": "335-snca-duplications-penetrance-2004-2009.md", "unverified": 5 }, { "id": 103, "title": "Vaccinating mice against synuclein", "oneline": "Mouse work in 2005 suggested that immunising against alpha-synuclein could clear it; the human vaccine trials that followed are in [landmark 324](324-pd01a-affiris-synuclein-vaccine-2012-2020.md) (PD01A) and [landmark 325](325-aci-7104-vacsyn-phase2-2023-2028.md) (ACI-7104).", "years": [ 2005, 2005 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "advanced", "file": "103-synuclein-vaccines-2005-2026.md", "unverified": 3 }, { "id": 253, "title": "MRI-guided convection-enhanced delivery", "oneline": "Krystof Bankiewicz's UCSF group showed in monkeys that infusions into the putamen could be tracked live on MRI and placed within about 1 mm, the method later used for AAV-AADC and GDNF gene therapy in people.", "years": [ 2005, 2011 ], "kind": "tool", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "253-mri-guided-convection-enhanced-delivery-2005-2011.md", "unverified": 5 }, { "id": 327, "title": "HTRA2/Omi (PARK13) did not hold up", "oneline": "A 2005 screen of German patients linked a mitochondrial protease gene, *HTRA2*, to Parkinson's; a 15,000-person association study in 2011 and a 5,800-person sequencing study in 2021 found no effect, so the claim is treated as unproven.", "years": [ 2005, 2021 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "dead-end", "file": "327-htra2-omi-park13-2005-2021.md", "unverified": 4 }, { "id": 32, "title": "iPSC reprogramming (Yamanaka)", "oneline": "Four genes were enough to turn ordinary skin cells back into stem cells, first in mice (2006) and then in humans (2007), the tool behind both patient-derived Parkinson's cell models and the stem-cell grafts now in trials.", "years": [ 2006, 2007 ], "kind": "tool", "branch": [ "cell-replacement", "models" ], "outcome": "advanced", "file": "32-ipsc-reprogramming-2006-2007.md", "unverified": 4 }, { "id": 45, "title": "ATP13A2 and Kufor-Rakeb syndrome", "oneline": "Loss of a lysosomal \"pump\" protein, ATP13A2, causes a rare early-onset recessive parkinsonism with dementia, and in 2020 the pump turned out to export polyamines (small molecules) from lysosomes.", "years": [ 2006, 2006 ], "kind": "discovery", "branch": [ "lysosome-gba", "genetics" ], "outcome": "open", "file": "45-atp13a2-kufor-rakeb-2006.md", "unverified": 3 }, { "id": 81, "title": "Mitochondrial DNA deletions in nigral neurons", "oneline": "Two papers in the same issue showed that the dopamine neurons of the substantia nigra accumulate large amounts of damaged mitochondrial DNA with age, enough in many cells to disable their energy production, offering a link between ageing and Parkinson's.", "years": [ 2006, 2006 ], "kind": "discovery", "branch": [ "mitochondria", "vulnerability" ], "outcome": "open", "file": "81-mtdna-deletions-nigral-neurons-2006.md", "unverified": 5 }, { "id": 146, "title": "GDNF infusion trials (Amgen, Bristol)", "oneline": "Two placebo-controlled trials (34 and 35 people) pumped the growth factor GDNF into the putamen; neither improved symptoms, though the Bristol trial showed more dopamine activity on PET scans.", "years": [ 2006, 2019 ], "kind": "trial", "branch": [ "growth-factors" ], "outcome": "dead-end", "file": "146-gdnf-infusion-trials-2006-2019.md", "unverified": 3, "phase": 2, "n": 69 }, { "id": 164, "title": "NET-PD futility screens FS-1 and FS-2", "oneline": "The US NET-PD programme tested four drugs (minocycline, creatine, GPI-1485, CoQ10) against a \"futility\" bar; none was ruled out, but the method was criticised and later Phase 3 trials found no benefit.", "years": [ 2006, 2007 ], "kind": "trial", "branch": [ "trial-methods", "mitochondria" ], "outcome": "advanced", "file": "164-net-pd-futility-screens-2006-2007.md", "unverified": 3, "phase": 2 }, { "id": 168, "title": "Vanderbilt early-DBS pilot", "oneline": "A 30-person randomised pilot found that deep brain stimulation (DBS) begun early, plus best drugs, left people with less tremor worsening and fewer medicines at 5 years, and led the FDA to approve a larger pivotal trial.", "years": [ 2006, 2020 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "open", "file": "168-early-dbs-vanderbilt-pilot-2006-2020.md", "unverified": 3, "n": 30 }, { "id": 194, "title": "LRRK2 G2385R and R1628P", "oneline": "Two changes in the LRRK2 gene, G2385R and R1628P, are common in Chinese and other East Asian people and raise Parkinson's risk by about 1.8-fold (R1628P) to 2.4-fold (G2385R, first reported in 2006), making LRRK2 relevant beyond rare family mutations.", "years": [ 2006, 2008 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "194-lrrk2-asian-risk-variants-2007-2008.md", "unverified": 3 }, { "id": 206, "title": "PINK1 and parkin share a pathway (flies)", "oneline": "Three papers showed fly mutants lacking PINK1 have damaged mitochondria, and that adding parkin repairs them, so the two recessive genes act in a single quality-control pathway.", "years": [ 2006, 2006 ], "kind": "model", "branch": [ "mitochondria", "models" ], "outcome": "advanced", "file": "206-pink1-parkin-fly-pathway-2006.md", "unverified": 3 }, { "id": 265, "title": "PET shows microglial activation in life", "oneline": "A PET study of 18 people with Parkinson's found a marker of immune activation raised across the brain, and unchanged over two years, so inflammation could be measured in life.", "years": [ 2006, 2006 ], "kind": "tool", "branch": [ "inflammation" ], "outcome": "open", "file": "265-pet-microglial-activation-in-living-patients-2006.md", "unverified": 3 }, { "id": 276, "title": "Neuromelanin MRI and nigrosome sign", "oneline": "Neuromelanin-sensitive MRI (Sasaki 2006) showed lost signal in the Parkinson's nigra, and a 3T iron-sensitive scan (Schwarz 2014) showed the healthy nigrosome-1 \"swallow tail\", which was lost in PD, with 96% accuracy in one small retrospective study.", "years": [ 2006, 2014 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "276-neuromelanin-mri-nigrosome-sign-2006-2014.md", "unverified": 2 }, { "id": 334, "title": "SNCA Rep1 promoter variant raises risk", "oneline": "A pooled analysis of 2,692 patients and 2,652 controls showed that a length variant in the SNCA promoter, called REP1, gave an odds ratio of 1.43 for genotypes defined by the 263-base-pair allele, a pointer to how slightly higher synuclein output might raise the risk of ordinary Parkinson's.", "years": [ 2006, 2006 ], "kind": "discovery", "branch": [ "synuclein-dosage", "genetics" ], "outcome": "advanced", "file": "334-snca-rep1-promoter-risk-2006.md", "unverified": 2 }, { "id": 42, "title": "MitoPark mouse", "oneline": "Switching off a mitochondrial maintenance gene only in dopamine neurons made mice develop slowly progressive, levodopa-responsive parkinsonism, testing whether failing mitochondria alone can drive the disease.", "years": [ 2007, 2007 ], "kind": "model", "branch": [ "mitochondria", "models" ], "outcome": "open", "file": "42-mitopark-mouse-2007.md", "unverified": 1 }, { "id": 57, "title": "Calcium channels and vulnerable neurons", "oneline": "Dopamine neurons of the substantia nigra rely on a calcium channel (Cav1.3) to keep firing, which may stress them; the blood-pressure drug isradipine, a channel blocker, protected them in mice.", "years": [ 2007, 2007 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "57-cav13-calcium-pacemaking-2007.md", "unverified": 2 }, { "id": 131, "title": "Urate epidemiology", "oneline": "Two studies found that people with higher blood urate (a natural antioxidant) were less likely to get Parkinson's and declined more slowly, which launched the urate-raising trials that later failed.", "years": [ 2007, 2008 ], "kind": "discovery", "branch": [ "oxidative-stress" ], "outcome": "dead-end", "file": "131-urate-epidemiology-2007-2008.md", "unverified": 2 }, { "id": 169, "title": "PRECEPT: CEP-1347", "oneline": "An anti-apoptotic drug that protected nerve cells in mouse and cell models did nothing in 806 people with early Parkinson's; the trial was stopped when an interim look showed it could not succeed.", "years": [ 2007, 2007 ], "kind": "trial", "branch": [ "cell-survival", "mitochondria" ], "outcome": "dead-end", "file": "169-precept-cep-1347-2007.md", "unverified": 3, "phase": 2, "n": 806 }, { "id": 268, "title": "VMAT2 and dopamine storage", "oneline": "Mice with about 5% of normal VMAT2 slowly lose nigral neurons, while mice with twice the normal amount resist the toxin MPTP, so how well a cell stores dopamine helps decide whether it survives.", "years": [ 2007, 2014 ], "kind": "preclinical", "branch": [ "vulnerability" ], "outcome": "open", "file": "268-vmat2-dopamine-storage-2007-2014.md", "unverified": 4 }, { "id": 8, "title": "Lewy bodies in grafts: prion-like spread", "oneline": "Healthy transplanted neurons developed Lewy bodies years later, and injected fibrils spread through mouse brains, suggesting misfolded alpha-synuclein passes from cell to cell like a prion.", "years": [ 2008, 2008 ], "kind": "discovery", "branch": [ "synuclein-spread", "cell-replacement" ], "outcome": "open", "file": "08-lewy-pathology-in-grafts-2008.md", "unverified": 3 }, { "id": 46, "title": "How often LRRK2 G2019S carriers get Parkinson's", "oneline": "A 21-centre study put numbers on the commonest known Parkinson's gene change: it explains about 1% of sporadic cases, and carriers face a risk that rises with age but is far from certain.", "years": [ 2008, 2008 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "46-lrrk2-g2019s-penetrance-2008.md", "unverified": 3 }, { "id": 114, "title": "MDS-UPDRS", "oneline": "The Movement Disorder Society's 2008 revision of the Unified Parkinson's Disease Rating Scale became the common yardstick by which most disease-modification trials since then have measured whether patients got worse or better.", "years": [ 2008, 2008 ], "kind": "tool", "branch": [ "trial-methods" ], "outcome": "advanced", "file": "114-mds-updrs-2008.md", "unverified": 4 }, { "id": 118, "title": "EMA two-step rule for 'disease-modifying'", "oneline": "The European Medicines Agency's guideline set a two-step bar for any \"disease-modifying\" claim; in 2025 it opened a revision to cover biomarkers, targeted drugs and digital measures.", "years": [ 2008, 2025 ], "kind": "infrastructure", "branch": [ "trial-methods" ], "outcome": "open", "file": "118-ema-pd-guideline-two-step-2008-2025.md", "unverified": 3 }, { "id": 121, "title": "FBXO7 (PARK15) and PLA2G6 (PARK14)", "oneline": "Two further recessive genes, FBXO7 and PLA2G6, cause early-onset parkinsonism, and FBXO7 was shown in 2013 to work with PINK1 and parkin in clearing damaged mitochondria.", "years": [ 2008, 2013 ], "kind": "discovery", "branch": [ "genetics", "mitochondria" ], "outcome": "advanced", "file": "121-fbxo7-pla2g6-recessive-parkinsonism-2008-2013.md", "unverified": 4 }, { "id": 147, "title": "CERE-120 (AAV2-neurturin)", "oneline": "A gene therapy that made neurons produce neurturin, a GDNF relative, failed to beat sham surgery in 58 people (putamen only) and then in 51 people (putamen plus substantia nigra).", "years": [ 2008, 2015 ], "kind": "trial", "branch": [ "growth-factors", "gene-delivery" ], "outcome": "dead-end", "file": "147-cere-120-neurturin-2010-2015.md", "unverified": 4, "phase": 2, "n": 109 }, { "id": 175, "title": "Spheramine (STEPS)", "oneline": "Retinal pigment cells stuck to tiny gelatin beads and placed in the putamen did not improve movement more than a fake operation in 71 people with advanced Parkinson's.", "years": [ 2008, 2011 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "dead-end", "file": "175-spheramine-steps-2008-2011.md", "unverified": 3, "phase": 2, "n": 71 }, { "id": 192, "title": "GIGYF2 and EIF4G1: disputed genes", "oneline": "Two papers named GIGYF2 (2008) and EIF4G1 (2011) as causes of inherited Parkinson's, but larger screens found the same changes in healthy people and the claims are now treated as unproven or refuted.", "years": [ 2008, 2015 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "dead-end", "file": "192-gigyf2-eif4g1-disputed-genes-2008-2011.md", "unverified": 2 }, { "id": 245, "title": "Critiques of Braak staging", "oneline": "Autopsy studies and reviews found that 6–43% of brains do not follow Braak's bottom-up order, and that about half of people with widespread Lewy pathology had no clinical signs, which weakens the case that early Lewy pathology always becomes Parkinson's.", "years": [ 2008, 2009 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "245-braak-staging-critiques-2008-2009.md", "unverified": 3 }, { "id": 252, "title": "AAV2-GAD sham-controlled Phase 2", "oneline": "Injecting a virus carrying the GAD gene into both subthalamic nuclei lowered motor scores 8.1 points versus 4.7 for sham surgery in 45 people (2011), and MeiraGTx revived the programme with a 14-person sham-controlled study in 2022–24.", "years": [ 2008, 2025 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "252-aav2-gad-sham-controlled-phase-2-2008-2025.md", "unverified": 4, "phase": 2, "n": 45 }, { "id": 16, "title": "GBA mutations: commonest genetic risk factor", "oneline": "Mutations in the Gaucher-disease gene GBA raise Parkinson's risk about fivefold, tying the disease to the cell's recycling system and giving a defined group for targeted trials.", "years": [ 2009, 2009 ], "kind": "discovery", "branch": [ "lysosome-gba", "genetics" ], "outcome": "advanced", "file": "16-gba-risk-factor-2009.md", "unverified": 3 }, { "id": 40, "title": "Ambroxol: cough medicine to first Parkinson's trials", "oneline": "A cheap cough medicine that boosts the GBA enzyme GCase reached the brain in a small uncontrolled 2020 trial; it did not help cognition in Parkinson's dementia in 2025, and the controlled Parkinson's trials are now in their own files.", "years": [ 2009, 2025 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "open", "file": "40-ambroxol-2020-2026.md", "unverified": 4 }, { "id": 62, "title": "ADAGIO: rasagiline", "oneline": "A delayed-start trial of rasagiline hinted at slower progression on the 1 mg dose, but the 2 mg dose showed nothing and an FDA panel voted 17-0 that slowing was not proven.", "years": [ 2009, 2009 ], "kind": "trial", "branch": [ "oxidative-stress", "trial-methods" ], "outcome": "dead-end", "file": "62-adagio-rasagiline-2009.md", "unverified": 5, "phase": 3, "n": 1176 }, { "id": 224, "title": "Free-water MRI", "oneline": "A diffusion MRI measure, the fraction of free water in the back of the substantia nigra, rises over time in Parkinson's, including in the PPMI cohort across four years, and was proposed as an endpoint for slowing trials.", "years": [ 2009, 2017 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "224-free-water-mri-progression-marker-2009-2017.md", "unverified": 4 }, { "id": 237, "title": "First GWAS: SNCA, MAPT, then 24 loci", "oneline": "Two scans in 2009 showed that common DNA variants near SNCA (and, in Europeans, MAPT) raise risk of ordinary Parkinson's, and a 2014 pooled analysis of 13,708 cases found 24 risk loci, six of them new.", "years": [ 2009, 2014 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "advanced", "file": "237-first-gwas-snca-mapt-and-24-loci-2009-2014.md", "unverified": 2 }, { "id": 251, "title": "PDGF-BB into the ventricles", "oneline": "A second growth factor, PDGF-BB, was infused for 12 days into the ventricles of 12 people with Parkinson's; it was well tolerated, symptom scores did not change, and a dopamine-transporter scan hinted at a rise in one area.", "years": [ 2009, 2015 ], "kind": "trial", "branch": [ "growth-factors" ], "outcome": "open", "file": "251-pdgf-bb-intraventricular-phase-1-2009-2015.md", "unverified": 4, "phase": 1, "n": 12 }, { "id": 269, "title": "Cytosolic dopamine, calcium and synuclein", "oneline": "Direct measurements in cultured mouse neurons showed that L-DOPA raises free dopamine 2 to 3 times higher in vulnerable nigral cells than in spared neighbouring cells, via calcium channels, and that cells without alpha-synuclein resist the damage.", "years": [ 2009, 2009 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "269-cytosolic-dopamine-calcium-2009.md", "unverified": 3 }, { "id": 304, "title": "Intravenous AAV9 reaches the brain", "oneline": "Foust and colleagues showed that a virus called AAV9, injected into a vein, can get past the blood-brain barrier: in newborn mice it reached neurons across the brain and spinal cord, and in adult mice mostly astrocytes.", "years": [ 2009, 2009 ], "kind": "discovery", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "304-aav9-crosses-blood-brain-barrier-foust-2009.md", "unverified": 0 }, { "id": 331, "title": "DCTN1 mutations cause Perry syndrome", "oneline": "Mutations in *DCTN1*, a gene for a transport-motor protein, were found in eight families with Perry syndrome, linking a disease of early parkinsonism, depression, weight loss and breathing failure to axon transport.", "years": [ 2009, 2009 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "advanced", "file": "331-dctn1-perry-syndrome-2009.md", "unverified": 3 }, { "id": 24, "title": "PPMI launches", "oneline": "An open, standardised patient cohort created the shared dataset that let the field validate the seed assay and define biological stages of the disease.", "years": [ 2010, 2010 ], "kind": "infrastructure", "branch": [ "infrastructure", "biomarkers" ], "outcome": "advanced", "file": "24-ppmi-launch-2010.md", "unverified": 3 }, { "id": 34, "title": "Synuclein helps assemble synapse machinery", "oneline": "Burré, Südhof and colleagues showed that alpha-synuclein acts as a helper (a \"chaperone\") that builds the SNARE complexes neurons use to release chemical signals, suggesting the protein's everyday job matters for any plan to remove it.", "years": [ 2010, 2010 ], "kind": "discovery", "branch": [ "synuclein-dosage" ], "outcome": "open", "file": "34-synuclein-snare-chaperone-2010.md", "unverified": 5 }, { "id": 95, "title": "Synuclein travels in vesicles", "oneline": "Neurons were shown to export alpha-synuclein inside exosomes (small membrane bubbles), oligomers riding on them proved more toxic and easily absorbed, and exosomes from patients' spinal fluid could seed new clumps.", "years": [ 2010, 2010 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "95-synuclein-extracellular-vesicles-2010.md", "unverified": 5 }, { "id": 171, "title": "MitoQ (PROTECT)", "oneline": "A pill designed to sit inside mitochondria and mop up damaging oxygen molecules did nothing to slow progression in 128 newly diagnosed people over 12 months.", "years": [ 2010, 2010 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "dead-end", "file": "171-mitoq-protect-2010.md", "unverified": 2, "phase": 2, "n": 128 }, { "id": 195, "title": "HLA-DR region GWAS signal", "oneline": "A scan of 2,000 patients and 1,986 controls found that common variation in the HLA region, which controls how immune cells present protein fragments, is linked to late-onset Parkinson's.", "years": [ 2010, 2010 ], "kind": "discovery", "branch": [ "inflammation", "genetics" ], "outcome": "open", "file": "195-hla-region-gwas-2010.md", "unverified": 3 }, { "id": 211, "title": "c-Abl switches off parkin in Parkinson's brain", "oneline": "Two papers showed that stress activates the enzyme c-Abl, which attaches a phosphate tag to parkin and switches it off, and that c-Abl is active in the brains of people with ordinary (non-inherited) Parkinson's.", "years": [ 2010, 2011 ], "kind": "discovery", "branch": [ "cell-survival" ], "outcome": "advanced", "file": "211-c-abl-inactivates-parkin-2010.md", "unverified": 3 }, { "id": 215, "title": "Serotonin neurons cause graft dyskinesias", "oneline": "Brain scans of two people with fetal grafts showed excess serotonin neurons in the graft, and the serotonin-drug buspirone cut their involuntary movements, so future grafts should be nearly pure dopamine neurons.", "years": [ 2010, 2010 ], "kind": "discovery", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "215-graft-induced-dyskinesias-serotonin-2010.md", "unverified": 2 }, { "id": 231, "title": "Target-engagement markers for LRRK2 drugs", "oneline": "Blood phosphorylation of LRRK2 itself (pS935), phosphorylation of its Rab targets (pRab10) and a urine lipid called BMP gave trials a way to tell whether a LRRK2 drug reached its target.", "years": [ 2010, 2023 ], "kind": "tool", "branch": [ "biomarkers", "lrrk2" ], "outcome": "advanced", "file": "231-lrrk2-target-engagement-markers-2010-2023.md", "unverified": 5 }, { "id": 244, "title": "Too little synuclein harms neurons", "oneline": "Strong knockdown of synuclein in adult rat nigra killed dopamine neurons, while a milder cut of about 35% did not, so how much synuclein to remove may decide whether lowering it is safe.", "years": [ 2010, 2018 ], "kind": "discovery", "branch": [ "synuclein-dosage" ], "outcome": "open", "file": "244-too-little-synuclein-harms-neurons-2010-2018.md", "unverified": 3 }, { "id": 319, "title": "TRANSEURO fetal grafts", "oneline": "Only 11 people could be grafted because fetal tissue was scarce, and 3 years later the group showed no overall clinical gain, which argued for a stem-cell source of dopamine neurons.", "years": [ 2010, 2026 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "dead-end", "file": "319-transeuro-fetal-grafts-2010-2026.md", "unverified": 3, "n": 11 }, { "id": 17, "title": "Stem cells to transplantable dopamine neurons", "oneline": "A recipe for growing real midbrain dopamine neurons from human embryonic stem cells made replacement therapy scalable, the step that made [landmark 10](10-stem-cell-dopamine-neurons-2025.md) possible.", "years": [ 2011, 2011 ], "kind": "tool", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "17-floor-plate-dopamine-neurons-2011.md", "unverified": 3 }, { "id": 25, "title": "Pesticides and solvents linked to Parkinson's", "oneline": "Studies of people who used paraquat and rotenone, or drank solvent-contaminated water, found roughly doubled or higher Parkinson's risk, supporting \"genes plus environment\" as the cause of most cases.", "years": [ 2011, 2023 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "25-pesticides-and-solvents-2011.md", "unverified": 4 }, { "id": 35, "title": "GCase and synuclein feed each other", "oneline": "Mazzulli, Krainc and colleagues proposed that too little of the Gaucher enzyme GCase lets alpha-synuclein build up, and that built-up synuclein in turn blocks GCase from reaching the cell's recycling compartment, a self-reinforcing loop.", "years": [ 2011, 2011 ], "kind": "discovery", "branch": [ "lysosome-gba" ], "outcome": "open", "file": "35-gcase-synuclein-loop-2011.md", "unverified": 4 }, { "id": 36, "title": "VPS35 mutation and the retromer", "oneline": "Two groups independently found the same single-letter change in VPS35 (a core part of the \"retromer\", a protein-recycling complex) in families with inherited late-onset Parkinson's; years later it was tied to the LRRK2 drug target.", "years": [ 2011, 2011 ], "kind": "discovery", "branch": [ "lrrk2", "genetics" ], "outcome": "open", "file": "36-vps35-retromer-2011.md", "unverified": 3 }, { "id": 43, "title": "Fibril-seeding (PFF) models", "oneline": "Lab-made synuclein fibrils added to normal neurons, then injected into normal mice, set off Lewy-body-like clumps and slow dopamine-neuron loss, giving a model that does not need a mutant gene.", "years": [ 2011, 2012 ], "kind": "model", "branch": [ "synuclein-spread", "models" ], "outcome": "advanced", "file": "43-pff-seeding-models-2011-2012.md", "unverified": 4 }, { "id": 47, "title": "Patient-derived dopamine neurons", "oneline": "Skin cells from patients with LRRK2 or triplicated-SNCA Parkinson's were turned into dopamine neurons in a dish, which accumulated synuclein and were unusually fragile under stress; GBA lines followed in 2014.", "years": [ 2011, 2011 ], "kind": "model", "branch": [ "models", "genetics" ], "outcome": "advanced", "file": "47-patient-ipsc-dopamine-neurons-2011.md", "unverified": 3 }, { "id": 92, "title": "Synuclein oligomers are toxic", "oneline": "Engineered alpha-synuclein variants that favour small clusters (\"oligomers\") killed far more dopamine neurons in rats than a variant that rapidly forms fibrils, shifting suspicion from the visible clumps to their smaller precursors.", "years": [ 2011, 2011 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "92-synuclein-oligomers-toxic-2011.md", "unverified": 4 }, { "id": 179, "title": "Neurturin autopsies (Bartus)", "oneline": "Brains of CERE-120 patients showed the growth factor made in the putamen but rarely reached the dying nigra cells, offering a likely reason the gene-therapy trials failed.", "years": [ 2011, 2011 ], "kind": "discovery", "branch": [ "growth-factors" ], "outcome": "advanced", "file": "179-neurturin-autopsy-bartus-2011.md", "unverified": 2 }, { "id": 204, "title": "9E4 antibody in mice (paper retracted 2024)", "oneline": "A mouse antibody against the tail of alpha-synuclein, given to synuclein-overproducing mice, was reported to reduce protein build-up and memory deficits and became prasinezumab, but the paper was retracted in November 2024 over image concerns.", "years": [ 2011, 2011 ], "kind": "preclinical", "branch": [ "synuclein-spread" ], "outcome": "dead-end", "file": "204-9e4-antibody-mice-2011.md", "unverified": 2 }, { "id": 212, "title": "PARIS builds up when parkin fails", "oneline": "A newly found parkin target, PARIS (ZNF746), accumulates when parkin is lost, represses PGC-1α (a master gene for building mitochondria) and kills dopamine neurons, a possible route from parkin failure to cell death.", "years": [ 2011, 2011 ], "kind": "discovery", "branch": [ "cell-survival", "mitochondria" ], "outcome": "open", "file": "212-paris-zn746-pgc1a-2011.md", "unverified": 4 }, { "id": 214, "title": "Skin cells to dopamine neurons, no stem-cell stage", "oneline": "Two groups converted human skin fibroblasts directly into dopamine-making neurons using a few genes, skipping the stem-cell step and its tumour risk.", "years": [ 2011, 2011 ], "kind": "tool", "branch": [ "cell-replacement" ], "outcome": "open", "file": "214-direct-reprogramming-dopamine-neurons-2011.md", "unverified": 4 }, { "id": 216, "title": "Type 2 diabetes raises Parkinson's risk", "oneline": "Large population studies found type 2 diabetes goes with a 30–40% higher chance of later Parkinson's, the main reason diabetes drugs were tried against it.", "years": [ 2011, 2018 ], "kind": "discovery", "branch": [ "metabolic-repurposing" ], "outcome": "advanced", "file": "216-type-2-diabetes-parkinsons-risk-2011-2018.md", "unverified": 3 }, { "id": 272, "title": "Isogenic patient stem-cell lines", "oneline": "Soldner and Jaenisch used zinc finger nucleases to correct or insert two alpha-synuclein point mutations in human stem cells, creating sets of cells that differ only at the disease mutation.", "years": [ 2011, 2011 ], "kind": "tool", "branch": [ "models" ], "outcome": "advanced", "file": "272-isogenic-ipsc-soldner-2011.md", "unverified": 4 }, { "id": 275, "title": "CSF total synuclein", "oneline": "Measuring total alpha-synuclein in spinal fluid by ELISA showed lower levels in Parkinson's, but the groups overlapped so much that the test could not diagnose individuals, and seed amplification later replaced it.", "years": [ 2011, 2013 ], "kind": "discovery", "branch": [ "biomarkers" ], "outcome": "superseded", "file": "275-csf-total-synuclein-too-overlapping-2011-2013.md", "unverified": 3 }, { "id": 50, "title": "DNAJC6 and SYNJ1: juvenile parkinsonism", "oneline": "Mutations in two genes that recycle synaptic vesicles (the nerve ending's neurotransmitter packages), DNAJC6 and SYNJ1, were found to cause early-onset recessive parkinsonism, pointing to the synapse as a site of failure.", "years": [ 2012, 2013 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "50-juvenile-parkinsonism-dnajc6-synj1-2012-2013.md", "unverified": 3 }, { "id": 51, "title": "One injection of fibrils spreads pathology", "oneline": "A single injection of lab-made alpha-synuclein fibrils into healthy mice triggered clumps that spread along connected brain circuits, killed dopamine neurons and impaired movement, giving the field its standard \"spreading\" model.", "years": [ 2012, 2012 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "advanced", "file": "51-synuclein-fibril-seeding-2012.md", "unverified": 2 }, { "id": 72, "title": "Lund's embryonic-stem-cell dopamine recipe", "oneline": "Lund researchers showed how to steer embryonic stem cells into midbrain dopamine neurons, then found gene markers that predict which batches will work after grafting, the basis for a clinical-grade product.", "years": [ 2012, 2017 ], "kind": "tool", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "72-lund-hesc-dopamine-recipe-2012-2017.md", "unverified": 2 }, { "id": 107, "title": "GM1 ganglioside", "oneline": "A 77-person trial of GM1, a fat-like molecule found in nerve membranes, suggested slower progression over two years, but it was small, from one centre, and no larger confirmation has been run.", "years": [ 2012, 2012 ], "kind": "trial", "branch": [ "growth-factors" ], "outcome": "open", "file": "107-gm1-ganglioside-2012.md", "unverified": 2, "phase": 2, "n": 77 }, { "id": 126, "title": "Mitochondrial-derived vesicles", "oneline": "Parkin and PINK1 also control small packages budded off mitochondria, and without them those packages can trigger an immune response, a possible link between inherited Parkinson's and inflammation.", "years": [ 2012, 2016 ], "kind": "discovery", "branch": [ "mitochondria", "inflammation" ], "outcome": "open", "file": "126-mitochondrial-derived-vesicles-2012-2016.md", "unverified": 3 }, { "id": 135, "title": "PDBP and BioFIND", "oneline": "Two US programmes created shared banks of clinical data and blood, spinal fluid and other samples, so any lab could hunt for Parkinson's biomarkers.", "years": [ 2012, 2016 ], "kind": "infrastructure", "branch": [ "infrastructure" ], "outcome": "advanced", "file": "135-pdbp-biofind-2012-2016.md", "unverified": 2 }, { "id": 196, "title": "GCase low in sporadic Parkinson's brains", "oneline": "Autopsy brains from people with ordinary Parkinson's and no GBA mutation had low activity of the GBA enzyme (GCase), so boosting it could help more people than the 5-10% who carry a GBA variant.", "years": [ 2012, 2014 ], "kind": "discovery", "branch": [ "lysosome-gba" ], "outcome": "open", "file": "196-gcase-low-sporadic-pd-2012-2014.md", "unverified": 2 }, { "id": 242, "title": "Ferroptosis in dopamine neurons", "oneline": "A cell-death route that needs iron and ends in fat oxidation was defined in 2012, and in 2016 it was shown to kill dopamine neurons in cells, slices and MPTP mice, giving iron a mechanism beyond \"toxic metal\".", "years": [ 2012, 2016 ], "kind": "discovery", "branch": [ "cell-survival", "oxidative-stress" ], "outcome": "open", "file": "242-ferroptosis-dopamine-neurons-2012-2016.md", "unverified": 4 }, { "id": 261, "title": "Gut biopsies for synuclein", "oneline": "A 2012 pilot found synuclein in gut biopsies from all nine early Parkinson's patients and no controls, but 2015 and 2016 studies found it in healthy people too, so the test was dropped.", "years": [ 2012, 2016 ], "kind": "discovery", "branch": [ "gut-brain", "biomarkers" ], "outcome": "superseded", "file": "261-gut-biopsy-synuclein-poor-specificity-2012-2016.md", "unverified": 3 }, { "id": 324, "title": "PD01A synuclein vaccine (AFFiRiS)", "oneline": "A short synthetic peptide that trains the immune system against alpha-synuclein was safe in 24 people with early Parkinson's and raised antibodies, but the trial was too small and open to say if it slows the disease.", "years": [ 2012, 2020 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "advanced", "file": "324-pd01a-affiris-synuclein-vaccine-2012-2020.md", "unverified": 3, "phase": 1, "n": 32 }, { "id": 93, "title": "The cost of a giant axon", "oneline": "Mapping and modelling showed that each substantia nigra dopamine neuron sprawls across the striatum, and the energy needed to power such an arbor may explain why these cells, and not their neighbours, are lost.", "years": [ 2013, 2013 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "93-axon-arbor-energy-cost-2013.md", "unverified": 3 }, { "id": 97, "title": "Striatal terminals are lost first", "oneline": "Postmortem counts showed that dopamine markers in the putamen (the striatal region that controls movement) vanish far faster than the nigral cell bodies that feed it, supporting a \"dying-back\" picture in which the nerve endings fail first.", "years": [ 2013, 2013 ], "kind": "discovery", "branch": [ "vulnerability", "growth-factors" ], "outcome": "open", "file": "97-striatal-terminals-lost-first-2013.md", "unverified": 3 }, { "id": 100, "title": "TFEB, the lysosome master switch", "oneline": "Synuclein was found to impair TFEB, the transcription factor that builds lysosomes and autophagy machinery, and boosting TFEB cleared synuclein and spared neurons in a rat model.", "years": [ 2013, 2013 ], "kind": "discovery", "branch": [ "lysosome-gba" ], "outcome": "open", "file": "100-tfeb-lysosome-biogenesis-2013.md", "unverified": 3 }, { "id": 101, "title": "Exenatide pilot", "oneline": "A 44-patient trial with no placebo injections suggested the diabetes drug exenatide helped movement and thinking in Parkinson's, which launched the controlled trials in [landmark 20](20-glp1-story-2017-2025.md); the large Phase 3 later found no benefit.", "years": [ 2013, 2013 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "superseded", "file": "101-exenatide-pilot-2013.md", "unverified": 2 }, { "id": 119, "title": "Linked Clinical Trials", "oneline": "The Cure Parkinson's Trust's expert committee scored dozens of drugs approved for other conditions and prioritised a few for quick pilot trials, a process that fed exenatide, ambroxol and later platform trials.", "years": [ 2013, 2013 ], "kind": "infrastructure", "branch": [ "trial-methods", "infrastructure" ], "outcome": "advanced", "file": "119-linked-clinical-trials-2013.md", "unverified": 2 }, { "id": 140, "title": "EARLYSTIM early DBS", "oneline": "Stimulating the brain early improved quality of life and movement in 251 people, but EARLYSTIM did not test or show slowing of the disease.", "years": [ 2013, 2013 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "open", "file": "140-earlystim-2013.md", "unverified": 2, "phase": 4, "n": 251 }, { "id": 165, "title": "PROUD: pramipexole delayed start", "oneline": "In 535 people, starting pramipexole at once rather than 6–9 months later made no lasting difference to symptoms or to dopamine-transporter scans.", "years": [ 2013, 2013 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "dead-end", "file": "165-proud-pramipexole-2013.md", "unverified": 3, "phase": 3, "n": 535 }, { "id": 228, "title": "RAB29 recruits and activates LRRK2", "oneline": "A protein encoded at a Parkinson's risk locus, RAB29 (also called RAB7L1), was shown to pull LRRK2 onto the Golgi membrane and strongly raise its activity, linking two genetic signals into one pathway.", "years": [ 2013, 2018 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "228-rab29-activates-lrrk2-2013-2018.md", "unverified": 4 }, { "id": 311, "title": "Molecular hydrogen trials", "oneline": "Drinking hydrogen-rich water improved scores in a 17-person Japanese pilot, but the 178-person follow-up found no difference from placebo, and a US trial stopped after enrolling two people.", "years": [ 2013, 2021 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "dead-end", "file": "311-molecular-hydrogen-trials-2013-2021.md", "unverified": 3, "phase": 2, "n": 178 }, { "id": 26, "title": "QE3: coenzyme Q10 fails in Phase 3", "oneline": "A mitochondria-support supplement that looked promising in an earlier trial failed at scale, the cautionary tale that pushed the field to demand stronger evidence before Phase 3.", "years": [ 2014, 2014 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "dead-end", "file": "26-coq10-qe3-2014.md", "unverified": 2, "phase": 3, "n": 600 }, { "id": 68, "title": "The c-Abl idea: mouse studies and a 12-person pilot", "oneline": "Mouse studies of the cancer drug nilotinib and a 12-person uncontrolled Georgetown pilot led to controlled trials of c-Abl blockers, which did not slow Parkinson's ([322](322-nilotinib-nilo-pd-georgetown-2017-2021.md), [323](323-vodobatinib-proseek-2019-2026.md)).", "years": [ 2014, 2015 ], "kind": "discovery", "branch": [ "cell-survival", "mitochondria" ], "outcome": "superseded", "file": "68-nilotinib-c-abl-2014-2024.md", "unverified": 2 }, { "id": 87, "title": "TMEM175: a lysosome channel", "oneline": "A chromosome 4 risk signal from the 2014 genetic scan points to TMEM175, a channel in the lysosome (the cell's recycling compartment) whose loss raises synuclein clumping, though how it works is still disputed.", "years": [ 2014, 2026 ], "kind": "discovery", "branch": [ "lysosome-gba", "genetics" ], "outcome": "open", "file": "87-tmem175-lysosome-channel-2014-2026.md", "unverified": 4 }, { "id": 89, "title": "Mendelian randomisation: urate and BMI", "oneline": "Using inherited gene variants as a natural randomised experiment, researchers found that the apparent protection of high urate was probably not causal, helping explain why raising urate failed, while higher body mass index may weakly protect.", "years": [ 2014, 2021 ], "kind": "discovery", "branch": [ "oxidative-stress", "environment" ], "outcome": "dead-end", "file": "89-mendelian-randomisation-urate-bmi-2014-2021.md", "unverified": 1 }, { "id": 113, "title": "ProSavin and OXB-102", "oneline": "A lentiviral gene therapy delivering three dopamine-making enzymes looked safe in 15 people in 2014; its successor was stopped in 2022 after a sponsor collapse, with a small 2026 report showing mixed, unpowered results.", "years": [ 2014, 2026 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "dead-end", "file": "113-prosavin-oxb-102-lentiviral-gene-therapy-2014-2026.md", "unverified": 3 }, { "id": 122, "title": "RAB39B: X-linked parkinsonism", "oneline": "Loss of the RAB39B gene on the X chromosome causes early-onset parkinsonism with Lewy bodies, implicating a protein-trafficking pathway.", "years": [ 2014, 2015 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "122-rab39b-x-linked-parkinsonism-2014.md", "unverified": 3 }, { "id": 240, "title": "GCH1 variants raise risk", "oneline": "Carrying one faulty copy of GCH1, the gene that supplies a cofactor for dopamine synthesis, raised the odds of Parkinson's about 7.5-fold in an exome study of 1,318 cases.", "years": [ 2014, 2014 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "240-gch1-variants-parkinsons-risk-2014.md", "unverified": 4 }, { "id": 246, "title": "Patient Lewy body extracts harm mice and monkeys", "oneline": "Injecting Lewy body extract from Parkinson's brains into mouse and macaque nigra triggered slowly progressive loss of dopamine neurons, showing that real patient-derived synuclein, not only lab-made fibrils, is harmful.", "years": [ 2014, 2014 ], "kind": "discovery", "branch": [ "synuclein-spread", "models" ], "outcome": "advanced", "file": "246-lewy-body-extracts-mice-monkeys-2014.md", "unverified": 3 }, { "id": 259, "title": "Synuclein travels gut to brain in rats", "oneline": "Injecting human Parkinson's brain extract or lab-made synuclein into a rat's intestinal wall led it to travel up the vagus nerve into the brainstem, the first direct experimental test of Braak's gut-to-brain route.", "years": [ 2014, 2014 ], "kind": "discovery", "branch": [ "gut-brain", "synuclein-spread" ], "outcome": "open", "file": "259-synuclein-gut-to-brain-in-rats-2014.md", "unverified": 5 }, { "id": 315, "title": "N-acetylcysteine (Monti)", "oneline": "A Philadelphia group reports that intravenous plus oral NAC raised dopamine-transporter scan signal by 3% to 8% and improved symptoms in two small trials with no placebo, and a 50-person follow-up using a different PET scan finishes around January 2027.", "years": [ 2014, 2027 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "pending", "file": "315-nac-monti-trials-2014-2027.md", "unverified": 4, "expected": "2027-01", "phase": 2, "n": 50 }, { "id": 328, "title": "DNAJC13 and TMEM230: disputed genes", "oneline": "A 2014 paper named *DNAJC13* as a Parkinson's gene and a 2016 *Nature Genetics* paper named *TMEM230* from the same family, but replication failed for both and the second was challenged directly.", "years": [ 2014, 2021 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "dead-end", "file": "328-dnajc13-tmem230-disputed-genes-2014-2021.md", "unverified": 6 }, { "id": 60, "title": "Synuclein strains", "oneline": "Differently shaped forms (\"strains\") of the same synuclein protein produced different toxicity and pathology in rats, supporting the idea that strain differences may explain why synuclein diseases differ.", "years": [ 2015, 2015 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "60-synuclein-strains-2015.md", "unverified": 3 }, { "id": 70, "title": "NET-PD LS-1: creatine", "oneline": "After creatine cleared a government \"screen then confirm\" futility screen, a 1,741-person trial found no benefit and stopped early.", "years": [ 2015, 2015 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "dead-end", "file": "70-net-pd-creatine-2015.md", "unverified": 2, "phase": 3, "n": 1741 }, { "id": 79, "title": "DAT scans qualified for trials", "oneline": "The European Medicines Agency in 2018 qualified dopamine-transporter (DAT) brain scans as a way to screen out people without dopamine loss from early Parkinson's trials, the field's first regulator-endorsed biomarker.", "years": [ 2015, 2018 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "79-dat-imaging-regulatory-qualification-2015-2018.md", "unverified": 5 }, { "id": 83, "title": "Vagotomy and appendix studies", "oneline": "Large registry studies tested the idea that Parkinson's starts in the gut and climbs the vagus nerve; results were suggestive for one type of vagotomy and for appendix removal in a rural Swedish group, but other cohorts disagreed, and a 2025 meta-analysis of appendectomy found no association.", "years": [ 2015, 2018 ], "kind": "discovery", "branch": [ "gut-brain" ], "outcome": "open", "file": "83-vagotomy-and-appendix-studies-2015-2018.md", "unverified": 3 }, { "id": 86, "title": "GBA mutation severity", "oneline": "GBA mutations that cause severe Gaucher disease carry several times the Parkinson's risk of mild ones, and bring earlier onset, more dementia and a harder course, so GBA carriers are not one uniform group.", "years": [ 2015, 2016 ], "kind": "discovery", "branch": [ "lysosome-gba" ], "outcome": "advanced", "file": "86-gba-mutation-severity-2015-2016.md", "unverified": 2 }, { "id": 90, "title": "CHCHD2 (PARK22)", "oneline": "Mutations in CHCHD2, which encodes a small mitochondrial protein, cause dominantly inherited Parkinson's in a few Japanese families, but screens in Taiwan and Italy found none, so it is rare and its role outside East Asia is unclear.", "years": [ 2015, 2015 ], "kind": "discovery", "branch": [ "mitochondria", "genetics" ], "outcome": "open", "file": "90-chchd2-park22-2015.md", "unverified": 4 }, { "id": 105, "title": "Pioglitazone (FS-ZONE)", "oneline": "A 210-person NINDS \"futility\" trial found pioglitazone, a diabetes drug that protects neurons in animals, was unlikely to slow early Parkinson's at either dose tested.", "years": [ 2015, 2015 ], "kind": "trial", "branch": [ "metabolic-repurposing", "mitochondria" ], "outcome": "dead-end", "file": "105-pioglitazone-fs-zone-2015.md", "unverified": 3, "phase": 2, "n": 210 }, { "id": 149, "title": "Nurr1 (NR4A2) activators", "oneline": "Drugs that switch on Nurr1, a master gene-switch that keeps dopamine neurons healthy, protected neurons in rodents; the first such pill (HL192) passed a 76-person healthy-volunteer safety study in 2024, but no one with Parkinson's has been tested yet.", "years": [ 2015, 2024 ], "kind": "preclinical", "branch": [ "vulnerability", "growth-factors" ], "outcome": "open", "file": "149-nurr1-agonists-2015-2024.md", "unverified": 4 }, { "id": 154, "title": "Sargramostim boosts regulatory T cells", "oneline": "An approved white-cell growth drug raised regulatory T cells (immune \"brakes\") in 20 people with Parkinson's, and small open-label follow-ups of five people saw stable motor scores for up to 33 months; no placebo-controlled Phase 2 yet.", "years": [ 2015, 2021 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "open", "file": "154-sargramostim-gm-csf-2015-2021.md", "unverified": 3 }, { "id": 167, "title": "MDS clinical diagnostic criteria", "oneline": "The Movement Disorder Society replaced the 1992 UK Brain Bank rules with criteria that add non-motor signs and two levels of certainty, giving trials a more reproducible way to say who has Parkinson's.", "years": [ 2015, 2015 ], "kind": "infrastructure", "branch": [ "trial-methods" ], "outcome": "advanced", "file": "167-mds-diagnostic-criteria-2015.md", "unverified": 2 }, { "id": 181, "title": "Intranasal glutathione, Phase IIb", "oneline": "A nose-spray form of the brain's own antioxidant, glutathione, improved scores in all groups, including placebo, so the study could not show it works.", "years": [ 2015, 2017 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "open", "file": "181-intranasal-glutathione-2017.md", "unverified": 2, "phase": 2, "n": 45 }, { "id": 199, "title": "LRRK2 inhibitor lung findings", "oneline": "Blocking LRRK2 made lung type II cells swell with fat-containing bodies in macaques, a worry for drug safety, but the change was reversible and caused no measurable breathing deficit.", "years": [ 2015, 2020 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "199-lrrk2-inhibitor-lung-primates-2015-2020.md", "unverified": 3 }, { "id": 217, "title": "Gut microbiome differs in Parkinson's", "oneline": "A 144-person Finnish study in 2015, then a 724-person shotgun-sequencing study in 2022, found Parkinson's patients carry a different gut microbiome, though cause and effect are unproven.", "years": [ 2015, 2022 ], "kind": "discovery", "branch": [ "gut-brain" ], "outcome": "open", "file": "217-gut-microbiome-differs-in-pd-2015-2022.md", "unverified": 3 }, { "id": 222, "title": "MDS prodromal criteria", "oneline": "A scoring system turns age, risk factors and early signs into a probability that someone is in the pre-motor stage of Parkinson's, so people can be picked for prevention trials before they have a diagnosis.", "years": [ 2015, 2019 ], "kind": "tool", "branch": [ "trial-methods" ], "outcome": "advanced", "file": "222-mds-prodromal-criteria-2015-2019.md", "unverified": 2 }, { "id": 226, "title": "Critical Path for Parkinson's", "oneline": "A public-private consortium run by the Critical Path Institute pools patient-level data from studies and trials and builds regulator-recognised tools for trial design, of which the 2018 DAT-scan qualification is the best known.", "years": [ 2015, 2026 ], "kind": "infrastructure", "branch": [ "infrastructure" ], "outcome": "advanced", "file": "226-critical-path-for-parkinsons-2015.md", "unverified": 4 }, { "id": 263, "title": "Soroka faecal transplant pilot (Israel)", "oneline": "An Israeli pilot of faecal transplant in Parkinson's enrolled only 10 people between 2015 and 2020, and no results are public.", "years": [ 2015, 2020 ], "kind": "trial", "branch": [ "gut-brain" ], "outcome": "open", "file": "263-soroka-fmt-pilot-2015-2020.md", "unverified": 3, "phase": 2, "n": 10 }, { "id": 333, "title": "Polygenic risk scores and their limits", "oneline": "Adding up hundreds of small risk variants separates patients from controls (top quarter versus bottom quarter: odds ratio 3.7 to 6.3), but the score is too weak for screening and was built only in people of European ancestry.", "years": [ 2015, 2019 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "333-polygenic-risk-scores-2015-2019.md", "unverified": 4 }, { "id": 37, "title": "LRRK2 phosphorylates Rab proteins", "oneline": "Steger, Alessi, Mann and colleagues identified the real targets of the Parkinson's enzyme LRRK2, a family of Rab proteins that steer traffic inside cells, giving a way to measure whether a LRRK2 drug is working.", "years": [ 2016, 2016 ], "kind": "discovery", "branch": [ "lrrk2", "biomarkers" ], "outcome": "advanced", "file": "37-lrrk2-rab-proteins-2016.md", "unverified": 4 }, { "id": 48, "title": "Midbrain organoids", "oneline": "Stem cells grown into layered 3D midbrain-like clusters made working dopamine neurons plus neuromelanin-like pigment, opening a more human-like model for Parkinson's research.", "years": [ 2016, 2016 ], "kind": "model", "branch": [ "models" ], "outcome": "open", "file": "48-midbrain-organoids-2016.md", "unverified": 2 }, { "id": 49, "title": "A risk variant that regulates SNCA", "oneline": "CRISPR editing in human stem cells traced a common, non-coding Parkinson's risk variant to a switch (an \"enhancer\") that modestly raises how much synuclein is made, linking population genetics to the central protein.", "years": [ 2016, 2016 ], "kind": "discovery", "branch": [ "synuclein-dosage", "genetics" ], "outcome": "open", "file": "49-snca-enhancer-risk-variant-2016.md", "unverified": 2 }, { "id": 56, "title": "Gut microbes and synuclein mice", "oneline": "Mice engineered to overproduce synuclein stayed healthier without gut microbes, and microbes from Parkinson's patients made them worse than microbes from healthy people, tying the gut to brain disease.", "years": [ 2016, 2016 ], "kind": "discovery", "branch": [ "gut-brain", "inflammation" ], "outcome": "open", "file": "56-gut-microbiota-mice-2016.md", "unverified": 2 }, { "id": 71, "title": "RT-QuIC and PMCA: first synuclein amplification", "oneline": "Papers from 2016 to 2020 showed that tiny amounts of misfolded alpha-synuclein in spinal fluid can be amplified and detected, the groundwork for the 2023 test now used to select people for trials.", "years": [ 2016, 2020 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "71-rt-quic-and-pmca-origins-2016-2020.md", "unverified": 3 }, { "id": 111, "title": "AAV capsids that cross into the brain", "oneline": "Caltech and Broad Institute teams evolved harmless virus shells (AAV capsids) that carry genes from a vein injection into the whole mouse brain; the first (PHP.B) failed in primates, a 2023 Caltech capsid crosses in monkeys, and a 2024 Broad capsid was built to bind the human receptor.", "years": [ 2016, 2024 ], "kind": "tool", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "111-aav-php-b-brain-capsids-2016-2024.md", "unverified": 4 }, { "id": 123, "title": "VPS13C recessive parkinsonism", "oneline": "Loss of VPS13C causes a rapidly progressing recessive parkinsonism, and silencing it in cells damages mitochondria and raises PINK1/parkin-dependent mitophagy.", "years": [ 2016, 2016 ], "kind": "discovery", "branch": [ "genetics", "mitochondria" ], "outcome": "open", "file": "123-vps13c-recessive-parkinsonism-2016.md", "unverified": 2 }, { "id": 203, "title": "LAG3 as a synuclein-fibril receptor", "oneline": "A 2016 screen named the immune protein LAG3 as a neuronal docking site for synuclein fibrils, a possible way to block spread, but a 2021 study found no LAG3 in neurons.", "years": [ 2016, 2021 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "203-lag3-synuclein-receptor-2016.md", "unverified": 4 }, { "id": 256, "title": "Nusinersen: intrathecal antisense works", "oneline": "Nusinersen, injected into the spinal fluid every few months, improved movement in infants and children with spinal muscular atrophy and won US approval on 23 December 2016, proving that antisense drugs can reach the central nervous system in people.", "years": [ 2016, 2018 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "256-nusinersen-intrathecal-antisense-2016.md", "unverified": 4, "phase": 3 }, { "id": 312, "title": "EPI-589 Phase 2a", "oneline": "A 44-person, no-placebo Phase 2a trial of the redox drug EPI-589 found no safety problems and, as expected without a control group, no clear change in symptoms; no later Parkinson's trial exists.", "years": [ 2016, 2019 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "312-epi-589-phase2a-2016-2019.md", "unverified": 4, "phase": 2, "n": 44 }, { "id": 20, "title": "The GLP-1 idea: can diabetes drugs slow Parkinson's?", "oneline": "Two positive Phase 2 trials of diabetes-type GLP-1 drugs raised hopes of slowing Parkinson's; the first Phase 3 found no benefit, and the idea is still being tested with other drugs.", "years": [ 2017, 2025 ], "kind": "discovery", "branch": [ "metabolic-repurposing" ], "outcome": "open", "file": "20-glp1-story-2017-2025.md", "unverified": 2 }, { "id": 30, "title": "iPSC-derived neurons work in monkeys", "oneline": "Dopamine neurons grown from human induced stem cells survived, worked and could be tracked by scans in Parkinson's-model monkeys, the primate proof behind the Kyoto human trial.", "years": [ 2017, 2017 ], "kind": "preclinical", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "30-ipsc-neurons-in-monkeys-2017.md", "unverified": 2 }, { "id": 38, "title": "T cells recognise synuclein", "oneline": "Immune T cells from Parkinson's patients reacted to fragments of alpha-synuclein presented by certain immune-gene variants, raising the idea that part of the disease is an autoimmune attack.", "years": [ 2017, 2017 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "38-t-cells-synuclein-2017.md", "unverified": 3 }, { "id": 53, "title": "Microglia can turn astrocytes toxic", "oneline": "Activated microglia were shown to convert supportive astrocytes into neuron-killing \"A1\" cells, a chain a long-acting GLP-1 drug blocked in Parkinson's mice.", "years": [ 2017, 2018 ], "kind": "discovery", "branch": [ "inflammation", "metabolic-repurposing" ], "outcome": "open", "file": "53-toxic-astrocytes-2017-2018.md", "unverified": 2 }, { "id": 58, "title": "Dopamine oxidation damages the lysosome", "oneline": "In neurons grown from patients, mitochondrial stress oxidised dopamine, which disabled the lysosomal enzyme GCase and let synuclein pile up, a loop that may explain why dopamine cells are so fragile.", "years": [ 2017, 2017 ], "kind": "discovery", "branch": [ "lysosome-gba", "mitochondria", "oxidative-stress" ], "outcome": "open", "file": "58-dopamine-oxidation-2017.md", "unverified": 3 }, { "id": 104, "title": "Exercise: SPARX and SPARX3", "oneline": "A 128-person Phase 2 trial found high-intensity treadmill exercise kept motor scores close to flat over six months in new, unmedicated patients; SPARX3 (370 people, 12-month primary outcome) is fully enrolled and no results are due before about mid-2027.", "years": [ 2017, 2026 ], "kind": "trial", "branch": [ "environment" ], "outcome": "open", "file": "104-exercise-sparx-sparx3-2017-2026.md", "unverified": 2 }, { "id": 152, "title": "CDNF Phase 1/2", "oneline": "CDNF, a protein that protects dopamine cells in animals, was infused into the putamen of 17 people; it was safe enough but showed no significant symptom benefit, and its developer has since moved to a subcutaneous peptide copy, HER-096.", "years": [ 2017, 2023 ], "kind": "trial", "branch": [ "growth-factors" ], "outcome": "superseded", "file": "152-cdnf-phase1-2-2017-2023.md", "unverified": 3, "phase": "1/2", "n": 17 }, { "id": 202, "title": "β2 agonists lower SNCA", "oneline": "A common beta-2 agonist (salbutamol) switched down the SNCA gene in cells and was linked to a 34% lower Parkinson's rate in Norway, but later reviews found the salbutamol link weak.", "years": [ 2017, 2017 ], "kind": "discovery", "branch": [ "synuclein-dosage" ], "outcome": "open", "file": "202-beta2-agonists-lower-snca-2017.md", "unverified": 1 }, { "id": 233, "title": "Lysosomal storage disease genes as a group raise risk", "oneline": "Rare damaging variants across 54 lysosomal storage disease genes were more common in people with Parkinson's, even with GBA removed, pointing at the whole lysosome system, with SMPD1 among the genes.", "years": [ 2017, 2017 ], "kind": "discovery", "branch": [ "lysosome-gba", "genetics" ], "outcome": "advanced", "file": "233-lysosomal-storage-gene-burden-2017.md", "unverified": 3 }, { "id": 250, "title": "RET agonists: small-molecule GDNF mimics", "oneline": "Helsinki groups found drug-like molecules (BT13, BT44) that switch on RET, GDNF's receptor, and helped dopamine neurons in dishes and rats; no human trial has been found.", "years": [ 2017, 2021 ], "kind": "preclinical", "branch": [ "growth-factors" ], "outcome": "open", "file": "250-ret-agonists-small-gdnf-mimics-2017-2021.md", "unverified": 3 }, { "id": 280, "title": "Fox Insight online cohort", "oneline": "An internet-based study run by the Michael J. Fox Foundation collects regular questionnaires and optional genetic data from tens of thousands of people, so researchers can find and follow patients without clinic visits.", "years": [ 2017, 2020 ], "kind": "infrastructure", "branch": [ "infrastructure" ], "outcome": "advanced", "file": "280-fox-insight-online-cohort-2017.md", "unverified": 2 }, { "id": 305, "title": "VY-AADC Phase 1b and RESTORE-1", "oneline": "After a 15-person Phase 1, Voyager and Neurocrine ran a 16-person Phase 1b and then RESTORE-1, a sham-surgery-controlled trial of an AADC gene therapy; MRI abnormalities led to an FDA hold in December 2020 and Neurocrine ended the Parkinson's programme in 2021.", "years": [ 2017, 2021 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "dead-end", "file": "305-voyager-vy-aadc-phase-1b-restore-1-2017-2021.md", "unverified": 7, "phase": 2, "n": 14 }, { "id": 322, "title": "Nilotinib: Georgetown and NILO-PD", "oneline": "Two placebo-controlled Phase 2 trials of the leukaemia drug nilotinib ran in parallel; the first reported shifts in spinal-fluid markers, the second found almost no drug in the brain, no marker change and slightly worse motor scores, and advised against going further.", "years": [ 2017, 2021 ], "kind": "trial", "branch": [ "cell-survival" ], "outcome": "dead-end", "file": "322-nilotinib-nilo-pd-georgetown-2017-2021.md", "unverified": 3, "phase": 2, "n": 151 }, { "id": 350, "title": "One faulty copy of PINK1: risk not confirmed", "oneline": "A 2017 study found that carrying one copy of the PINK1 G411S variant raised Parkinson's risk nearly threefold, but two large later analyses (13,708 cases in one) found no robust risk from single broken PINK1 copies in general.", "years": [ 2017, 2022 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "350-single-pink1-copy-not-clear-risk-2017-2022.md", "unverified": 3 }, { "id": 27, "title": "Atomic structures of synuclein fibrils", "oneline": "Cryo-electron microscopy showed that alpha-synuclein clumps from patients have a different shape from lab-made ones, and differ between Parkinson's and multiple system atrophy, so drugs and tracers must be designed against the real disease fold.", "years": [ 2018, 2022 ], "kind": "discovery", "branch": [ "synuclein-spread", "biomarkers" ], "outcome": "advanced", "file": "27-synuclein-fibril-structures-2018-2022.md", "unverified": 4 }, { "id": 54, "title": "Parkin/PINK1–STING paper retracted", "oneline": "A high-profile *Nature* paper linked failed mitochondrial clean-up to inflammation through the STING pathway, but its authors retracted it in 2025 after finding unreliable and irreproducible data.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "inflammation", "mitochondria" ], "outcome": "dead-end", "file": "54-parkin-pink1-sting-retracted-2018.md", "unverified": 2 }, { "id": 55, "title": "NLRP3 inflammasome", "oneline": "Synuclein clumps switched on an inflammatory alarm complex (NLRP3) in microglia, and an oral drug that blocks it reduced synuclein build-up and dopamine-neuron loss in rodents; a first human safety trial of a related drug followed.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "55-nlrp3-inflammasome-2018.md", "unverified": 5 }, { "id": 84, "title": "IBD, anti-TNF drugs and LRRK2", "oneline": "People with inflammatory bowel disease (IBD) developed Parkinson's more often, anti-TNF drugs were linked to much lower rates, and LRRK2 variants influence both Crohn's disease and Parkinson's.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "inflammation", "lrrk2", "gut-brain" ], "outcome": "open", "file": "84-ibd-anti-tnf-and-lrrk2-2018.md", "unverified": 3 }, { "id": 85, "title": "Head injury raises Parkinson's risk", "oneline": "In US veterans, traumatic brain injury of any severity, including mild concussion, was followed by more Parkinson's, and diagnosed earlier, suggesting injury is a modifiable trigger.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "85-head-injury-and-parkinsons-2018.md", "unverified": 3 }, { "id": 96, "title": "LRRK2 and lysosome damage", "oneline": "Three papers showed that LRRK2, the most common inherited Parkinson's kinase (an enzyme that adds phosphate tags), moves onto stressed or leaking lysosomes and helps repair or sort them, hinting at its normal job.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "lrrk2", "lysosome-gba" ], "outcome": "open", "file": "96-lrrk2-lysosome-damage-response-2018.md", "unverified": 4 }, { "id": 117, "title": "Gene editing of SNCA", "oneline": "CRISPR-based tools have turned down or cut the synuclein gene (SNCA) in patient neurons and in rodents, protecting cells and movement in one rat model, but nothing has reached humans.", "years": [ 2018, 2023 ], "kind": "preclinical", "branch": [ "synuclein-dosage", "gene-delivery" ], "outcome": "open", "file": "117-snca-gene-editing-2018-2023.md", "unverified": 3 }, { "id": 151, "title": "Focused ultrasound opens the blood-brain barrier", "oneline": "Small safety trials showed that ultrasound plus injected microbubbles can open the blood-brain barrier in a chosen patch of a Parkinson's brain, safely and reversibly, and (in one trial) let an enzyme drug reach the putamen; no benefit has been shown.", "years": [ 2018, 2022 ], "kind": "trial", "branch": [ "gene-delivery" ], "outcome": "open", "file": "151-focused-ultrasound-bbb-opening-2018-2022.md", "unverified": 3 }, { "id": 193, "title": "LRP10", "oneline": "A Dutch-led team linked rare loss-of-function changes in LRP10 to inherited Parkinson's and dementia with Lewy bodies, but follow-up screens found variants in controls or no excess in patients.", "years": [ 2018, 2021 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "193-lrp10-2018.md", "unverified": 4 }, { "id": 198, "title": "LRRK2 overactive in idiopathic Parkinson's", "oneline": "Autopsy tissue showed LRRK2 kinase activity was higher in nigral dopamine neurons of people with ordinary Parkinson's and no LRRK2 mutation, justifying inhibitor trials in non-carriers.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "open", "file": "198-lrrk2-activity-idiopathic-pd-2018.md", "unverified": 2 }, { "id": 241, "title": "Basal mitophagy runs without PINK1", "oneline": "A fluorescent reporter mouse showed that routine removal of worn-out mitochondria in neurons and other tissues continues when PINK1 is deleted, so the PINK1 pathway is not the main route for everyday clean-up.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "mitochondria" ], "outcome": "open", "file": "241-basal-mitophagy-without-pink1-2018.md", "unverified": 2 }, { "id": 243, "title": "Synuclein fibrils kill via PARP1", "oneline": "In neurons and mice, synuclein fibrils activated the enzyme PARP1, whose product made the fibrils more toxic and drove a cell-death route called parthanatos; PARP inhibitors, which are cancer drugs, blocked it.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "cell-survival" ], "outcome": "open", "file": "243-parp1-parthanatos-synuclein-2018.md", "unverified": 3 }, { "id": 254, "title": "AAV-PHP.B fails in primates", "oneline": "The engineered virus shell that carried genes across the mouse blood-brain barrier gave no brain boost in monkeys, and two 2019 papers showed it relies on LY6A, a receptor that varies between mouse strains.", "years": [ 2018, 2019 ], "kind": "discovery", "branch": [ "gene-delivery" ], "outcome": "advanced", "file": "254-aav-php-b-fails-in-primates-ly6a-2018-2019.md", "unverified": 4 }, { "id": 260, "title": "ENT-01 (squalamine) KARMET", "oneline": "A pill that aims to loosen synuclein's grip on gut nerve cells improved constipation in Parkinson's, but the trial tested a symptom, not slowing of the disease.", "years": [ 2018, 2022 ], "kind": "trial", "branch": [ "gut-brain" ], "outcome": "open", "file": "260-ent-01-squalamine-karmet-2018-2021.md", "unverified": 4, "phase": 2, "n": 150 }, { "id": 279, "title": "AMP PD data platform", "oneline": "A public-private partnership launched in 2018 pooled whole-genome, RNA and clinical data from four cohorts (3,941 people in version 1) so any approved researcher can analyse them under one agreement.", "years": [ 2018, 2021 ], "kind": "infrastructure", "branch": [ "infrastructure", "genetics" ], "outcome": "advanced", "file": "279-amp-pd-data-platform-2018.md", "unverified": 2 }, { "id": 281, "title": "NAPS: prodromal synucleinopathy consortium", "oneline": "A nine-site consortium is following people with polysomnogram-confirmed REM sleep behaviour disorder and healthy controls to learn which measures best track the pre-motor stage, so a prevention trial can be sized and timed.", "years": [ 2018, 2028 ], "kind": "infrastructure", "branch": [ "infrastructure", "trial-methods" ], "outcome": "open", "file": "281-naps-prodromal-synucleinopathy-consortium-2018-2028.md", "unverified": 3 }, { "id": 300, "title": "Kyoto iPSC dopamine-cell trial", "oneline": "In a seven-person Phase 1/2 trial at Kyoto University Hospital, dopamine progenitors made from donor iPSCs survived for two years, raised dopamine-making by 44.7% on PET, and caused no serious adverse events; Japan gave the product conditional approval in March 2026.", "years": [ 2018, 2025 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "300-kyoto-ipsc-dopamine-cells-phase-1-2-2018-2025.md", "unverified": 4, "phase": 2, "n": 7 }, { "id": 307, "title": "GRF6021 plasma fraction", "oneline": "A 79-person Phase 2 safety trial of an infusion made from blood plasma found the product was tolerated but showed no clear cognitive benefit over placebo in its posted data, and no follow-on trial has been announced.", "years": [ 2018, 2021 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "open", "file": "307-grf6021-plasma-fraction-2018-2021.md", "unverified": 4, "phase": 2, "n": 79 }, { "id": 341, "title": "Global Burden of Disease 2016 for Parkinson's", "oneline": "A global modelled estimate showed 6.1 million people with Parkinson's in 2016, up from 2.5 million in 1990, and ageing alone did not explain all of it, which made the case for the urgency of prevention and slowing the disease.", "years": [ 2018, 2018 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "advanced", "file": "341-gbd-2016-parkinsons-burden-2018.md", "unverified": 2 }, { "id": 344, "title": "Necroptosis in Parkinson's models", "oneline": "Three labs found that necroptosis, a form of programmed cell death run by the enzymes RIPK1, RIPK3 and MLKL, kills dopamine neurons or their fibres in cell and mouse models, and that blocking it helped.", "years": [ 2018, 2020 ], "kind": "preclinical", "branch": [ "cell-survival" ], "outcome": "open", "file": "344-necroptosis-in-parkinsons-models-2018-2020.md", "unverified": 3 }, { "id": 18, "title": "Gut-to-brain spread in mice", "oneline": "In mice, misfolded alpha-synuclein placed in the gut wall travelled up the vagus nerve and killed dopamine neurons, experimental support for Braak's gut-first idea.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "gut-brain", "synuclein-spread" ], "outcome": "open", "file": "18-gut-to-brain-spread-2019.md", "unverified": 3 }, { "id": 19, "title": "90 genetic risk signals", "oneline": "The largest genetic map of Parkinson's risk showed the disease is polygenic and pointed to lysosomal, mitochondrial, immune and synuclein pathways.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "advanced", "file": "19-nalls-gwas-2019.md", "unverified": 1 }, { "id": 78, "title": "ASAP and GP2", "oneline": "A philanthropy-funded, open-data research network (ASAP) and its first resource, GP2, set out to genotype over 150,000 people worldwide to find the genes behind Parkinson's.", "years": [ 2019, 2021 ], "kind": "infrastructure", "branch": [ "infrastructure", "genetics" ], "outcome": "open", "file": "78-asap-and-gp2-2019-2021.md", "unverified": 6 }, { "id": 91, "title": "Lewy bodies are full of lipids and organelles", "oneline": "Electron microscopy of donated Parkinson's brains found that most Lewy bodies are packed with lipid membranes, vesicles and damaged mitochondria, with alpha-synuclein filaments in only a minority, challenging the idea that the clump is simply a fibril ball.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "91-lewy-body-lipids-organelles-2019.md", "unverified": 3 }, { "id": 130, "title": "Body-first vs brain-first Parkinson's", "oneline": "A hypothesis, backed by a small imaging study, says Parkinson's has two subtypes depending on whether synuclein pathology starts in the body (gut, heart) or in the brain.", "years": [ 2019, 2020 ], "kind": "discovery", "branch": [ "gut-brain" ], "outcome": "open", "file": "130-body-first-brain-first-subtypes-2019-2020.md", "unverified": 4 }, { "id": 133, "title": "Air pollution and Parkinson's", "oneline": "A meta-analysis found weak evidence linking traffic-related pollution to Parkinson's, and a 21.6-million-person US Medicare study found much higher risk where fine-particle pollution (PM2.5) was higher, but this is association, not proof.", "years": [ 2019, 2023 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "133-air-pollution-parkinsons-2019-2023.md", "unverified": 3 }, { "id": 137, "title": "23andMe and UK Biobank cohorts", "oneline": "Consumer genetics (23andMe) and a 500,000-person biobank gave Parkinson's genetics many times more people than clinics could recruit, and let researchers study risk before diagnosis.", "years": [ 2019, 2020 ], "kind": "infrastructure", "branch": [ "infrastructure", "genetics" ], "outcome": "advanced", "file": "137-23andme-ukbiobank-cohorts-2019-2020.md", "unverified": 3 }, { "id": 144, "title": "Isradipine (STEADY-PD III)", "oneline": "The blood-pressure drug isradipine, chosen to ease calcium stress on dopamine neurons, did not slow Parkinson's in 336 people over three years.", "years": [ 2019, 2020 ], "kind": "trial", "branch": [ "vulnerability" ], "outcome": "dead-end", "file": "144-isradipine-steady-pd3-2020.md", "unverified": 2, "phase": 3, "n": 336 }, { "id": 153, "title": "Anle138b (emrusolmin)", "oneline": "An oral drug that blocks the formation of toxic synuclein oligomers passed Phase 1 in healthy volunteers and a small Phase 1b in Parkinson's; its Phase 2 work is in multiple system atrophy, not Parkinson's.", "years": [ 2019, 2026 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "153-anle138b-oligomer-modulator-2019-2026.md", "unverified": 3, "phase": 1 }, { "id": 166, "title": "LEAP: early vs delayed levodopa", "oneline": "In 445 people, levodopa begun at once did no better after 80 weeks than levodopa begun after 40 weeks of placebo, so it does not slow the disease.", "years": [ 2019, 2019 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "dead-end", "file": "166-leap-levodopa-2019.md", "unverified": 2, "phase": 3, "n": 445 }, { "id": 173, "title": "CNM-Au8 (REPAIR-PD)", "oneline": "A tiny open-label imaging study of a drink of gold nanocrystals suggested a rise in brain NAD after 12 weeks, but it had no placebo group and no clinical readout.", "years": [ 2019, 2021 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "173-cnm-au8-repair-pd-2021.md", "unverified": 4, "phase": 2, "n": 13 }, { "id": 189, "title": "Semaglutide Phase 2 trials (Oslo, MOST-ABLE)", "oneline": "Two Phase 2 trials of semaglutide, a GLP-1 diabetes-type drug, are registered (Oslo and Osaka), but neither has a reported result; the two other post-Phase 3 exenatide trials now have their own files ([landmark 309](309-pt320-sustained-release-exenatide-2020-2021.md), [landmark 310](310-stockholm-exenatide-fdg-pet-2020-2025.md)).", "years": [ 2019, 2026 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "open", "file": "189-semaglutide-and-next-glp1-trials-2019-2026.md", "unverified": 3, "phase": 2 }, { "id": 197, "title": "LRRK2 lowers GCase", "oneline": "In dopamine neurons from patients, mutant LRRK2 reduced lysosomal GCase activity and a LRRK2 inhibitor raised it, joining the two best-known drug targets.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "lysosome-gba", "lrrk2" ], "outcome": "open", "file": "197-lrrk2-gcase-link-2019.md", "unverified": 3 }, { "id": 208, "title": "Terazosin and PGK1 glycolysis", "oneline": "A prostate drug that turns on the energy enzyme PGK1 protected neurons in animals and was linked to lower Parkinson's risk in some databases, but not all.", "years": [ 2019, 2021 ], "kind": "discovery", "branch": [ "mitochondria" ], "outcome": "open", "file": "208-terazosin-pgk1-glycolysis-2019.md", "unverified": 3 }, { "id": 248, "title": "Terazosin randomised pilot", "oneline": "In 13 people with Parkinson's, 12 weeks of terazosin 5 mg raised brain and blood ATP (cell fuel) compared with placebo, but three on the drug dropped out with dizziness, and it was too small to test slowing.", "years": [ 2019, 2021 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "248-terazosin-randomised-pilot-2019-2021.md", "unverified": 2, "phase": 2, "n": 13 }, { "id": 266, "title": "Gut infection in PINK1-knockout mice", "oneline": "Mice missing the PINK1 gene developed immune attacks on their own mitochondria and a levodopa-reversible movement problem after a bowel infection, a possible route from gene to gut to immune system to brain.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "inflammation", "mitochondria", "gut-brain" ], "outcome": "open", "file": "266-gut-infection-pink1-knockout-mice-2019.md", "unverified": 3 }, { "id": 278, "title": "PD GENEration: free genetic testing", "oneline": "The Parkinson's Foundation offers free gene testing and counselling; in its first 10,510 enrollees, 13% carried a variant in one of seven causal genes, so many people eligible for gene-targeted trials do not know it.", "years": [ 2019, 2024 ], "kind": "infrastructure", "branch": [ "infrastructure", "genetics" ], "outcome": "open", "file": "278-pd-generation-genetic-testing-2019-2024.md", "unverified": 3 }, { "id": 314, "title": "Low-dose lithium (Buffalo)", "oneline": "A Buffalo team is testing very low doses of lithium (a tenth of psychiatric doses) against blood and MRI markers in four small studies of 15 to 35 people each; the Phase 1 data are in and a randomised trial and its extension finish in late 2026.", "years": [ 2019, 2026 ], "kind": "trial", "branch": [ "cell-survival" ], "outcome": "pending", "file": "314-lithium-trials-2019-2026.md", "unverified": 3, "expected": "2026-11", "phase": 1, "n": 15 }, { "id": 323, "title": "Vodobatinib: PROSEEK Phase 2", "oneline": "A c-Abl blocker built to enter the brain, with spinal-fluid levels shown to be high enough, did no better than placebo on motor decline at 40 weeks and was stopped in April 2024.", "years": [ 2019, 2026 ], "kind": "trial", "branch": [ "cell-survival" ], "outcome": "dead-end", "file": "323-vodobatinib-proseek-2019-2026.md", "unverified": 3, "phase": 2, "n": 513 }, { "id": 332, "title": "Age-at-onset and progression GWAS", "oneline": "The first large scans of when Parkinson's starts and how fast it worsens found only a handful of signals, led by the risk genes *SNCA*, *TMEM175* and *GBA*, so progression genetics is still thin.", "years": [ 2019, 2023 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "332-age-at-onset-and-progression-gwas-2019-2023.md", "unverified": 4 }, { "id": 355, "title": "PPM1H reverses LRRK2's Rab tags", "oneline": "An siRNA screen of all human protein phosphatases found PPM1H, which removes the phosphate tags LRRK2 puts on Rab proteins, suggesting a second way to cut LRRK2 signalling.", "years": [ 2019, 2019 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "355-ppm1h-reverses-lrrk2-rab-phosphorylation-2019.md", "unverified": 3 }, { "id": 73, "title": "First graft of a patient's own iPSC neurons", "oneline": "A 69-year-old man received dopamine-neuron precursors grown from his own reprogrammed skin cells, without immunosuppressant drugs; scans suggested the cells survived, but one patient cannot show benefit.", "years": [ 2020, 2020 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "open", "file": "73-autologous-ipsc-graft-2020.md", "unverified": 4 }, { "id": 75, "title": "Turning astrocytes into neurons: a dispute", "oneline": "Two 2020 papers claimed that switching off one gene (PTBP1) turns astrocytes into dopamine neurons in Parkinson's mice, but later lineage-tracing work could not reproduce it.", "years": [ 2020, 2023 ], "kind": "preclinical", "branch": [ "cell-replacement" ], "outcome": "open", "file": "75-astrocyte-reprogramming-2020-2023.md", "unverified": 4 }, { "id": 109, "title": "GBA gene therapy (PR001)", "oneline": "A one-time brain-fluid injection of a working GBA1 gene (PR001, now Lilly's LY3884961) is in a Phase 1/2 trial in carriers of GBA1 mutations, with no efficacy results found.", "years": [ 2020, 2026 ], "kind": "trial", "branch": [ "lysosome-gba", "gene-delivery" ], "outcome": "open", "file": "109-gba-gene-therapy-pr001-2020-2026.md", "unverified": 3, "phase": "1/2" }, { "id": 115, "title": "Neurofilament light", "oneline": "A large study found that blood levels of neurofilament light, a protein released from damaged nerve fibres, rise over time in Parkinson's and track severity, though they are not specific to the disease.", "years": [ 2020, 2020 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "115-neurofilament-light-progression-2020.md", "unverified": 3 }, { "id": 120, "title": "Mobilise-D: sensor-measured walking", "oneline": "The EMA gave a letter of support in April 2020 for sensor-measured walking as a trial measure in Parkinson's, a first step toward replacing clinic-visit snapshots with continuous real-life data, but not as a primary endpoint.", "years": [ 2020, 2020 ], "kind": "tool", "branch": [ "trial-methods" ], "outcome": "open", "file": "120-mobilise-d-digital-mobility-2020.md", "unverified": 3 }, { "id": 155, "title": "AZA-PD azathioprine", "oneline": "The first trial of an immune-suppressing drug in early Parkinson's (66 people, 12 months) did not meet its primary measure (off-state gait and axial score at 12 months); exploratory analyses hinted at immune-marker effects.", "years": [ 2020, 2026 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "dead-end", "file": "155-azathioprine-aza-pd-2020-2026.md", "unverified": 4, "phase": 2, "n": 66 }, { "id": 172, "title": "NOPARK: nicotinamide riboside Phase 3", "oneline": "Boosting the cell's energy molecule NAD with a daily supplement did not help 410 people with early Parkinson's and left them slightly worse than placebo after a year.", "years": [ 2020, 2026 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "dead-end", "file": "172-nopark-nicotinamide-riboside-2026.md", "unverified": 3, "phase": 3, "n": 410 }, { "id": 190, "title": "LARGE-PD Latino GWAS", "oneline": "A Latin American consortium genotyped 1,497 people (807 with Parkinson's, 690 controls) from South America and confirmed that the SNCA gene matters there too, filling a gap left by European and East Asian studies.", "years": [ 2020, 2021 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "advanced", "file": "190-large-pd-latino-gwas-2020-2021.md", "unverified": 4 }, { "id": 227, "title": "People with one broken LRRK2 copy are healthy", "oneline": "Among 1,455 people who naturally carry a broken copy of the LRRK2 gene, no disease was strongly linked to it, which supported the idea that a drug could lower LRRK2 safely.", "years": [ 2020, 2020 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "227-lrrk2-loss-of-function-carriers-healthy-2020.md", "unverified": 5 }, { "id": 230, "title": "Detailed 3D structures of LRRK2", "oneline": "Three papers showed what the giant LRRK2 protein looks like, in cells and as a full-length purified molecule, at the best resolution then available, giving drug designers a map.", "years": [ 2020, 2021 ], "kind": "discovery", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "230-lrrk2-first-structures-2020-2021.md", "unverified": 2 }, { "id": 236, "title": "One faulty copy of PRKN is probably not a risk factor", "oneline": "Two large studies found that carrying one broken copy of the PRKN gene does not raise the chance of Parkinson's, while a third found a raised risk that depended on studies that had not ruled out a hidden second mutation.", "years": [ 2020, 2022 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "236-single-prkn-copy-not-clear-risk-2020-2022.md", "unverified": 3 }, { "id": 282, "title": "Idebenone in REM sleep behaviour disorder", "oneline": "A small randomised, placebo-controlled Chinese trial tests whether idebenone delays progression from REM sleep behaviour disorder to Parkinson's or a related disease; the registry shows 28 people enrolled against 142 planned, and no results.", "years": [ 2020, 2026 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "pending", "file": "282-idebenone-irbd-ruijin-2020-2026.md", "unverified": 6, "expected": "2026-11", "phase": 2, "n": 28 }, { "id": 308, "title": "AKST4290 (TEAL)", "oneline": "A 110-person, 12-week Phase 2 trial of a pill that blocks the immune receptor CCR3 found no advantage over placebo on its main motor measure.", "years": [ 2020, 2021 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "dead-end", "file": "308-akst4290-ccr3-teal-2020-2021.md", "unverified": 4, "phase": 2, "n": 110 }, { "id": 309, "title": "PT320 slow-release exenatide", "oneline": "A Korean Phase 2 trial of a long-acting exenatide (PT320) in early Parkinson's was registered in 2020 and has no result, status update or paper since April 2021.", "years": [ 2020, 2021 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "open", "file": "309-pt320-sustained-release-exenatide-2020-2021.md", "unverified": 4, "phase": 2, "n": 99 }, { "id": 310, "title": "Stockholm exenatide trial", "oneline": "A 59-person Swedish Phase 2 found exenatide shifted brain metabolic networks on PET scans but gave no movement benefit, matching the UK Phase 3.", "years": [ 2020, 2025 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "dead-end", "file": "310-stockholm-exenatide-fdg-pet-2020-2025.md", "unverified": 4, "phase": 2, "n": 59 }, { "id": 316, "title": "Australian Parkinson's Mission APM001", "oneline": "Australia's first platform trial gave alogliptin, albuterol, nilvadipine or placebo to 131 people (target 240) for 48 weeks; recruitment finished in February 2024, a lay summary was filed in August 2026, and I could not read any findings.", "years": [ 2020, 2026 ], "kind": "trial", "branch": [ "trial-methods" ], "outcome": "open", "file": "316-australian-parkinsons-mission-apm001-2020-2026.md", "unverified": 4, "phase": 2, "n": 131 }, { "id": 329, "title": "ATP10B loss-of-function raises risk", "oneline": "Belgian researchers found both copies of *ATP10B* damaged in about 1% of Parkinson's patients; the gene moves a fat that also builds up in GBA-linked disease, but follow-up cohorts have not confirmed the genetic link.", "years": [ 2020, 2025 ], "kind": "discovery", "branch": [ "genetics", "lysosome-gba" ], "outcome": "open", "file": "329-atp10b-lysosomal-lipid-flippase-2020-2025.md", "unverified": 3 }, { "id": 330, "title": "PSAP (prosaposin) variants", "oneline": "Three Japanese families with dominant Parkinson's carried changes in the saposin D region of the lysosomal gene *PSAP*, and common variants nearby were more frequent in patients, but other cohorts gave a mixed picture.", "years": [ 2020, 2021 ], "kind": "discovery", "branch": [ "genetics", "lysosome-gba" ], "outcome": "open", "file": "330-psap-saposin-d-variants-2020-2021.md", "unverified": 3 }, { "id": 336, "title": "Synuclein T cells highest near diagnosis", "oneline": "A follow-up to the 2017 T-cell finding saw synuclein-specific T-cell responses at their highest soon after motor diagnosis and declining afterwards, with one patient showing them about a decade before diagnosis.", "years": [ 2020, 2020 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "336-synuclein-t-cells-highest-near-diagnosis-2020.md", "unverified": 3 }, { "id": 349, "title": "Finnish faecal transplant trial", "oneline": "In a placebo-controlled trial of 48 Finnish patients whose gut bacteria were out of balance, one colonoscopic faecal transplant did not change the combined movement and daily-life score at six months, and caused more stomach side effects.", "years": [ 2020, 2024 ], "kind": "trial", "branch": [ "gut-brain" ], "outcome": "dead-end", "file": "349-finnish-fmt-trial-scheperjans-2020-2024.md", "unverified": 4, "phase": 2, "n": 48 }, { "id": 64, "title": "SPARK: cinpanemab", "oneline": "Biogen's anti-synuclein antibody cinpanemab did nothing on any dose in 357 people with early Parkinson's, so Biogen ended its development in February 2021.", "years": [ 2021, 2022 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "dead-end", "file": "64-spark-cinpanemab-2021-2022.md", "unverified": 3, "phase": 2, "n": 357 }, { "id": 66, "title": "SURE-PD3: inosine", "oneline": "A Phase 3 trial that deliberately raised blood urate, an antioxidant linked to slower Parkinson's in observational studies, found no slowing and more kidney stones.", "years": [ 2021, 2021 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "dead-end", "file": "66-sure-pd3-inosine-2021.md", "unverified": 2, "phase": 3, "n": 298 }, { "id": 207, "title": "Complex I loss in dopamine neurons", "oneline": "Mice whose dopamine neurons lacked a complex I part (Ndufs2) survived by switching to a Warburg-like metabolism but progressively lost their dopamine-making features, starting in the axons, and developed levodopa-responsive parkinsonism late.", "years": [ 2021, 2021 ], "kind": "model", "branch": [ "mitochondria" ], "outcome": "advanced", "file": "207-complex-i-loss-ndufs2-mice-2021.md", "unverified": 2 }, { "id": 219, "title": "Radotinib Phase 2 (France)", "oneline": "A 43-person French Phase 2 of the c-Abl blocker radotinib has finished dosing; registry completion is April 2027.", "years": [ 2021, 2027 ], "kind": "trial", "branch": [ "cell-survival" ], "outcome": "pending", "file": "219-radotinib-phase2-2021-2027.md", "unverified": 4, "expected": "2027-04", "phase": 2, "n": 43 }, { "id": 229, "title": "DNL151 (BIIB122) Phase 1 and 1b", "oneline": "In 184 healthy volunteers and 36 people with Parkinson's, a daily LRRK2 inhibitor was well tolerated for 28 days and cut LRRK2 markers in blood, spinal fluid and urine, setting up the LUMA trial and the LIGHTHOUSE Phase 3 (NCT05418673, terminated in 2023 by the sponsor with 7 enrolled).", "years": [ 2021, 2023 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "advanced", "file": "229-dnl151-biib122-phase1-1b-2021-2023.md", "unverified": 3, "phase": 1, "n": 220 }, { "id": 249, "title": "Diabetes and Parkinson's: Mendelian randomisation", "oneline": "A Mendelian randomisation study (using inherited gene variants as a natural experiment) found a small causal effect of type 2 diabetes on Parkinson's risk, an odds ratio of 1.08.", "years": [ 2021, 2021 ], "kind": "discovery", "branch": [ "metabolic-repurposing" ], "outcome": "advanced", "file": "249-type-2-diabetes-mendelian-randomisation-2021.md", "unverified": 1 }, { "id": 353, "title": "FOUNDIN-PD dopamine-neuron atlas", "oneline": "Bressan, Blauwendraat and colleagues grew dopamine neurons from stem cell lines of 95 PPMI participants and published layered gene-activity data, giving a public map to link Parkinson's risk variants to the genes they change.", "years": [ 2021, 2023 ], "kind": "infrastructure", "branch": [ "models", "genetics" ], "outcome": "advanced", "file": "353-foundin-pd-ipsc-dopamine-neuron-omics-2023.md", "unverified": 5 }, { "id": 29, "title": "Synuclein-lowering drugs (overview)", "oneline": "Three drugs that cut production of alpha-synuclein at its source are in early human trials, but none has reported whether it helps patients; each now has its own landmark.", "years": [ 2022, 2026 ], "kind": "trial", "branch": [ "synuclein-dosage" ], "outcome": "open", "file": "29-synuclein-lowering-drugs-2023-2026.md", "unverified": 3 }, { "id": 63, "title": "Prasinezumab: PASADENA and PADOVA", "oneline": "An antibody against clumped alpha-synuclein missed its main goal twice, narrowly the second time, but hints of slower motor decline put it into a 900-person Phase 3.", "years": [ 2022, 2026 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "63-prasinezumab-pasadena-padova-2022-2026.md", "unverified": 5, "phase": 2 }, { "id": 67, "title": "FAIRPARK-II: deferiprone", "oneline": "Removing iron from the substantia nigra with deferiprone worked on scans but made symptoms worse in newly diagnosed people, a reminder that hitting the target can backfire.", "years": [ 2022, 2022 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "dead-end", "file": "67-fairpark-ii-deferiprone-2022.md", "unverified": 1, "phase": 2, "n": 372 }, { "id": 98, "title": "Single-cell map of the Parkinson's midbrain", "oneline": "Reading the active genes of over 41,000 individual cell nuclei from Parkinson's midbrains found more activated, inflammatory microglia, fewer oligodendrocytes and a distinct dysfunctional dopamine-neuron state.", "years": [ 2022, 2022 ], "kind": "discovery", "branch": [ "inflammation" ], "outcome": "open", "file": "98-glial-activation-midbrain-single-cell-2022.md", "unverified": 2 }, { "id": 99, "title": "The most vulnerable dopamine neuron subtype", "oneline": "A single-nucleus atlas of human substantia nigra named ten dopamine-neuron types and found one, SOX6+ AGTR1+ in the ventral nigra, was most depleted in Parkinson's and most enriched for inherited risk genes.", "years": [ 2022, 2022 ], "kind": "discovery", "branch": [ "vulnerability" ], "outcome": "open", "file": "99-vulnerable-dopamine-neuron-subtype-2022.md", "unverified": 2 }, { "id": 106, "title": "Simvastatin (PD STAT)", "oneline": "A UK trial of 235 people found the statin simvastatin, tested because statin use had been linked to lower Parkinson's risk, did not slow progression and, on the main measure, trended slightly worse.", "years": [ 2022, 2022 ], "kind": "trial", "branch": [ "metabolic-repurposing", "inflammation" ], "outcome": "dead-end", "file": "106-simvastatin-pd-stat-2022.md", "unverified": 2, "n": 235 }, { "id": 180, "title": "Fosgonimeton (SHAPE)", "oneline": "An injected drug meant to boost a growth-factor pathway (HGF) was stopped at 28 of a planned 75 people with Parkinson's disease dementia or dementia with Lewy bodies, and missed its main target.", "years": [ 2022, 2023 ], "kind": "trial", "branch": [ "growth-factors" ], "outcome": "dead-end", "file": "180-fosgonimeton-shape-2022.md", "unverified": 5, "phase": 2, "n": 28 }, { "id": 183, "title": "UB-312 synuclein vaccine", "oneline": "Vaxxinity's UB-312 shot was safe in healthy volunteers and in 20 people with Parkinson's, but only 5 of 13 fully dosed patients had antibodies in spinal fluid, and no Phase 2 has been announced.", "years": [ 2022, 2025 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "183-ub-312-vaccine-2022-2025.md", "unverified": 2, "phase": 1, "n": 20 }, { "id": 200, "title": "DNL201 Phase 1/1b", "oneline": "A brain-penetrating LRRK2 inhibitor was safe at doses that hit its target in 122 healthy volunteers and 28 patients, and its lysosome marker moved, paving the way for BIIB122.", "years": [ 2022, 2022 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "superseded", "file": "200-dnl201-phase1-2022.md", "unverified": 2, "phase": 1, "n": 150 }, { "id": 209, "title": "NADPARK Phase 1", "oneline": "In 30 newly diagnosed, untreated people, a month of 1,000 mg daily nicotinamide riboside was safe and raised brain NAD, which led to the larger NOPARK trial, which failed.", "years": [ 2022, 2022 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "advanced", "file": "209-nadpark-phase1-2022.md", "unverified": 2, "phase": 1, "n": 30 }, { "id": 220, "title": "NOSE-PD: nasal insulin plus glutathione", "oneline": "A 56-person Phase 2 adds insulin to nasal glutathione, after the glutathione-only trial did no better than placebo.", "years": [ 2022, 2027 ], "kind": "trial", "branch": [ "oxidative-stress" ], "outcome": "pending", "file": "220-nose-pd-intranasal-insulin-glutathione-2022-2027.md", "unverified": 3, "expected": "2027-11", "phase": 2, "n": 56 }, { "id": 223, "title": "Blood seed amplification", "oneline": "Two groups detected misfolded synuclein \"seeds\" in blood, in serum and in nerve-cell-derived vesicles, which could replace a lumbar puncture, but neither test is validated for routine or trial use.", "years": [ 2022, 2023 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "223-blood-seed-amplification-2022-2023.md", "unverified": 4 }, { "id": 247, "title": "NR-SAFE: high-dose nicotinamide riboside", "oneline": "In 20 people with Parkinson's, 3,000 mg a day of nicotinamide riboside for four weeks caused no moderate or severe side effects, which cleared the way for dose-finding at that level.", "years": [ 2022, 2023 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "advanced", "file": "247-nr-safe-high-dose-nicotinamide-riboside-2022-2023.md", "unverified": 2, "phase": 1, "n": 20 }, { "id": 262, "title": "EFFACE-PD faecal transplant (Warsaw)", "oneline": "In a 59-person Polish placebo-controlled trial, one colonoscopic faecal transplant did not change the Parkinson's motor score over 12 months.", "years": [ 2022, 2026 ], "kind": "trial", "branch": [ "gut-brain" ], "outcome": "dead-end", "file": "262-effaced-pd-warsaw-fmt-2022-2026.md", "unverified": 4, "phase": 2, "n": 59 }, { "id": 289, "title": "ION464 / BIIB101 (synuclein antisense)", "oneline": "The first synuclein-lowering drug given to patients, an antisense injected into the spinal fluid, was safe in the first 22 people, but it is being tested in multiple system atrophy (MSA), not Parkinson's, and Biogen dropped it in 2025.", "years": [ 2022, 2027 ], "kind": "trial", "branch": [ "synuclein-dosage" ], "outcome": "dead-end", "file": "289-ion464-biib101-snca-antisense-2022-2027.md", "unverified": 3, "phase": 1, "n": 40 }, { "id": 320, "title": "AMBITIOUS: ambroxol in GBA carriers", "oneline": "The first placebo-controlled ambroxol trial in people with Parkinson's and a GBA1 mutation found no slowing of cognitive decline over 52 weeks, in a preprint that has not yet been peer reviewed.", "years": [ 2022, 2026 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "dead-end", "file": "320-ambitious-ambroxol-gba-pd-2022-2026.md", "unverified": 4, "phase": 2, "n": 65 }, { "id": 352, "title": "KOLF2.1J reference stem cell line", "oneline": "Pantazis and colleagues picked one well-behaved human stem cell line, KOLF2.1J, and shared it widely, so labs studying neurodegeneration can edit the same starting cells and compare results.", "years": [ 2022, 2022 ], "kind": "tool", "branch": [ "models" ], "outcome": "advanced", "file": "352-kolf2-1j-reference-ipsc-line-2022.md", "unverified": 4 }, { "id": 9, "title": "Seed amplification assay", "oneline": "A spinal-fluid test detects misfolded alpha-synuclein, so slowing-the-disease trials can finally confirm that participants have the target biology.", "years": [ 2023, 2023 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "09-seed-amplification-assay-2023.md", "unverified": 0 }, { "id": 69, "title": "Venglustat (MOVES-PD) in GBA1 carriers", "oneline": "Venglustat, a pill that blocks the enzyme making GCase's raw material, did not slow early Parkinson's in 221 people with a GBA1 variant; the score trended slightly worse than on placebo.", "years": [ 2023, 2023 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "dead-end", "file": "69-gba-drugs-venglustat-bia-2023-2026.md", "unverified": 2, "phase": 2, "n": 221 }, { "id": 74, "title": "STEM-PD trial", "oneline": "Eight patients in Sweden and the UK received embryonic-stem-cell-derived dopamine precursors at two doses; the 12-month safety results were clean for the cells, one patient died of a fungal infection on immunosuppression, and the 3-year efficacy data are due around late 2027.", "years": [ 2023, 2026 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "open", "file": "74-stem-pd-trial-2023-2026.md", "unverified": 3, "phase": 2, "n": 8 }, { "id": 116, "title": "Synuclein PET tracers", "oneline": "After a decade-long hunt, PET tracers showed alpha-synuclein clumps in living people with multiple system atrophy (2023) and, faintly, in Parkinson's (2024, 2026), but no tracer is yet validated for Parkinson's trials.", "years": [ 2023, 2026 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "116-synuclein-pet-tracers-2023-2025.md", "unverified": 3 }, { "id": 124, "title": "African and multi-ancestry GWAS", "oneline": "Two studies widened Parkinson's genetics beyond European ancestry, finding a new GBA1-region risk variant in African and admixed populations and 12 new risk loci across four ancestries.", "years": [ 2023, 2024 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "advanced", "file": "124-multi-ancestry-gwas-2023-2024.md", "unverified": 2 }, { "id": 143, "title": "NLY01 Phase 2", "oneline": "NLY01, a long-acting GLP-1-type drug designed to calm brain immune cells, did not beat placebo on its main measure in 255 people with early Parkinson's, according to the company's 2023 announcement.", "years": [ 2023, 2023 ], "kind": "trial", "branch": [ "metabolic-repurposing", "inflammation" ], "outcome": "dead-end", "file": "143-nly01-phase2-2023.md", "unverified": 5, "phase": 2, "n": 255 }, { "id": 150, "title": "UDCA (UP study)", "oneline": "In a 30-person, 48-week Phase 2, high-dose ursodeoxycholic acid (UDCA, an old liver drug) was safe and appeared to improve energy use in the midbrain on a scan, but the trial was too small to show it slows Parkinson's.", "years": [ 2023, 2023 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "150-udca-up-study-2023.md", "unverified": 4, "phase": 2, "n": 30 }, { "id": 156, "title": "First mitophagy drugs: MTX325, ABBV-1088", "oneline": "Two drugs built to restart the clearing of damaged mitochondria, a USP30 inhibitor and a PINK1 activator, have entered early human safety trials; no efficacy data exist.", "years": [ 2023, 2026 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "156-first-mitophagy-drugs-usp30-pink1-2023-2026.md", "unverified": 4 }, { "id": 174, "title": "Risvodetinib (c-Abl), Phase 2 \"201\"", "oneline": "A brain-penetrant c-Abl blocker was safe in 12 weeks of dosing but did not improve the top-ranked efficacy measure; the company's positive signals are secondary or exploratory.", "years": [ 2023, 2025 ], "kind": "trial", "branch": [ "cell-survival", "mitochondria" ], "outcome": "open", "file": "174-risvodetinib-c-abl-2025.md", "unverified": 5, "phase": 2, "n": 137 }, { "id": 210, "title": "N-DOSE nicotinamide riboside dose-finding", "oneline": "An 81-person dose-finding trial of up to 3,000 mg a day of nicotinamide riboside finished in April 2025, but no result has been located.", "years": [ 2023, 2025 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "pending", "file": "210-n-dose-nicotinamide-riboside-2025.md", "unverified": 2, "expected": "2026-12", "phase": 2, "n": 81 }, { "id": 218, "title": "MOST-ABLE: oral semaglutide (Osaka)", "oneline": "A 99-person Japanese Phase 2 tests whether a daily semaglutide tablet slows motor decline; no results yet.", "years": [ 2023, 2027 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "pending", "file": "218-most-able-oral-semaglutide-2023-2027.md", "unverified": 4, "expected": "2027-03", "phase": 2, "n": 99 }, { "id": 235, "title": "BIA 28-6156 (ACTIVATE) in GBA1 carriers", "oneline": "An oral pill that raises activity of the recycling enzyme GCase, tested for 18 months in 273 people with GBA1-linked Parkinson's, left progression no different from placebo, and Bial stopped the drug for this use.", "years": [ 2023, 2026 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "dead-end", "file": "235-bia-28-6156-activate-gba-carriers-2023-2026.md", "unverified": 4, "phase": 2, "n": 273 }, { "id": 313, "title": "Fasudil (ROCK-PD)", "oneline": "An 81-person German Phase 2a of fasudil, a ROCK-enzyme blocker approved in Japan since 1995, finished in August 2026; the main measure is safety, so it cannot show slowing, and no result is posted.", "years": [ 2023, 2026 ], "kind": "trial", "branch": [ "cell-survival" ], "outcome": "open", "file": "313-fasudil-rock-pd-2023-2026.md", "unverified": 4, "phase": 2, "n": 81 }, { "id": 325, "title": "ACI-7104 VacSYn Phase 2", "oneline": "An improved version of the PD01A vaccine produced antibodies in every one of 25 treated people and entered spinal fluid, but the first part was designed to test safety, so whether it slows Parkinson's is unknown.", "years": [ 2023, 2028 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "pending", "file": "325-aci-7104-vacsyn-phase2-2023-2028.md", "unverified": 5, "expected": "2028-06", "phase": 2, "n": 150 }, { "id": 338, "title": "Camp Lejeune solvent-water cohort", "oneline": "A cohort of US Marines and Navy personnel exposed to trichloroethylene (TCE, a degreasing solvent) in base drinking water showed 1.70 times the odds of Parkinson's decades later, a large test of the TCE idea in people exposed through a documented water supply.", "years": [ 2023, 2023 ], "kind": "discovery", "branch": [ "environment" ], "outcome": "open", "file": "338-camp-lejeune-tce-cohort-2023.md", "unverified": 1 }, { "id": 28, "title": "NSD-ISS and SynNeurGe definitions", "oneline": "Two competing proposals redefine Parkinson's by biology (alpha-synuclein, dopamine-system damage, genes) rather than symptoms, so trials can enrol people before symptoms; the proposals are debated.", "years": [ 2024, 2024 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "28-biological-definitions-2024.md", "unverified": 3 }, { "id": 65, "title": "ORCHESTRA: minzasolmin", "oneline": "The first pill designed to stop alpha-synuclein misfolding inside cells, minzasolmin (UCB0599), showed no clinical benefit in a Phase 2 trial of about 500 people.", "years": [ 2024, 2024 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "dead-end", "file": "65-orchestra-minzasolmin-2024.md", "unverified": 5, "phase": 2, "n": 496 }, { "id": 76, "title": "Aspen ASPIRO: patient-own-cell neurons", "oneline": "An uncontrolled Phase 1/2a trial of neurons grown from each patient's own cells reported safe grafts and large motor gains in eight people at 12 months, but nothing yet separates the cells from placebo effect.", "years": [ 2024, 2026 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "76-aspen-autologous-aspiro-2024-2026.md", "unverified": 5, "expected": "2027-03", "phase": 2, "n": 15 }, { "id": 88, "title": "RAB32 Ser71Arg", "oneline": "A single-letter change in RAB32, a protein that LRRK2 works with, segregates with dominantly inherited Parkinson's and makes LRRK2 about twice as active in cells, strengthening the LRRK2 pathway as a cause and drug target.", "years": [ 2024, 2024 ], "kind": "discovery", "branch": [ "lrrk2", "genetics" ], "outcome": "advanced", "file": "88-rab32-ser71arg-2024.md", "unverified": 2 }, { "id": 108, "title": "Buntanetap Phase 3", "oneline": "Annovis Bio's oral drug buntanetap, said to lower several toxic proteins including alpha-synuclein, was tested in 523 people for six months; the registry results show no overall change on the primary measure, and the company's reported benefit is in subgroups.", "years": [ 2024, 2024 ], "kind": "trial", "branch": [ "synuclein-dosage" ], "outcome": "dead-end", "file": "108-buntanetap-phase3-2024.md", "unverified": 4, "phase": 3, "n": 523 }, { "id": 134, "title": "Skin-biopsy synuclein (Syn-One)", "oneline": "A skin punch biopsy found abnormal, phosphorylated synuclein in 92.7% of people with Parkinson's and 3.3% of controls, a less invasive route than spinal fluid, but with caveats.", "years": [ 2024, 2024 ], "kind": "tool", "branch": [ "biomarkers" ], "outcome": "open", "file": "134-skin-biopsy-synuclein-2024.md", "unverified": 3 }, { "id": 138, "title": "ML-designed synuclein aggregation inhibitors", "oneline": "An iterative machine-learning pipeline found small molecules that block the surface where synuclein clumps multiply, far more potent in a test tube than the oral drug anle-138b, but with no animal or human data yet.", "years": [ 2024, 2024 ], "kind": "preclinical", "branch": [ "synuclein-spread" ], "outcome": "open", "file": "138-ml-synuclein-aggregation-inhibitors-2024.md", "unverified": 3 }, { "id": 139, "title": "GUT-PARFECT faecal transplant", "oneline": "A 46-person Belgian trial of donor gut bacteria showed a motor gain at 12 months in 2024, the only faecal transplant trial in this record with a positive primary result, though a Finnish trial of the same year ([landmark 349](349-finnish-fmt-trial-scheperjans-2020-2024.md)) did not confirm it.", "years": [ 2024, 2024 ], "kind": "trial", "branch": [ "gut-brain" ], "outcome": "open", "file": "139-fmt-trials-2024.md", "unverified": 2, "phase": 2, "n": 46 }, { "id": 141, "title": "Lixisenatide Phase 2 (LixiPark)", "oneline": "In 156 people with early Parkinson's, the diabetes drug lixisenatide left motor scores flat over 12 months while placebo scores worsened by 3 points, but the gap was small and side effects may have unblinded the trial.", "years": [ 2024, 2024 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "open", "file": "141-lixisenatide-lixipark-2024.md", "unverified": 4, "phase": 2, "n": 156 }, { "id": 159, "title": "BEACON BIIB122 in LRRK2 carriers", "oneline": "After the LRRK2 inhibitor failed in broad early Parkinson's, Denali is testing it in people who carry a LRRK2 mutation; data expected first half of 2027.", "years": [ 2024, 2027 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "pending", "file": "159-beacon-biib122-lrrk2-carriers-2024-2027.md", "unverified": 3, "expected": "2027-03", "phase": 2, "n": 50 }, { "id": 160, "title": "REGENERATE-PD AB-1005", "oneline": "A sham-surgery-controlled Phase 2 of a one-time GDNF gene therapy in moderate Parkinson's; primary completion estimated August 2028.", "years": [ 2024, 2028 ], "kind": "trial", "branch": [ "growth-factors", "gene-delivery" ], "outcome": "pending", "file": "160-regenerate-pd-ab1005-gdnf-gene-therapy-2024-2028.md", "unverified": 3, "expected": "2028-08", "phase": 2, "n": 127 }, { "id": 182, "title": "Exidavnemab (EXIST)", "oneline": "BioArctic's antibody that targets clumped (aggregated) alpha-synuclein finished a 38-person Phase 2a safety study in Parkinson's and multiple system atrophy in August 2026; BioArctic says safety looks good and full results are due in the second half of 2026, and Phase 2b studies are planned for 2027 in other diseases.", "years": [ 2024, 2026 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "pending", "file": "182-exidavnemab-exist-2024-2026.md", "unverified": 5, "expected": "2026-12", "phase": 2, "n": 38 }, { "id": 185, "title": "VTX3232 (NLRP3 inhibitor)", "oneline": "A 28-day, open-label study of an oral NLRP3 inhibitor in about 10 people with early Parkinson's lowered inflammation markers in blood and spinal fluid with no drug-related adverse events; it is not evidence of benefit, and a controlled trial is only planned.", "years": [ 2024, 2025 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "open", "file": "185-vtx3232-nlrp3-2024-2025.md", "unverified": 6, "phase": 2, "n": 11 }, { "id": 232, "title": "LRP10 and alpha-synuclein secretion", "oneline": "Cell experiments from Rotterdam suggest the LRP10 protein controls how much alpha-synuclein cells secrete, and that a patient variant disrupts this, but the work does not prove LRP10 causes Parkinson's.", "years": [ 2024, 2024 ], "kind": "discovery", "branch": [ "genetics" ], "outcome": "open", "file": "232-lrp10-regulates-synuclein-secretion-2024.md", "unverified": 3 }, { "id": 255, "title": "Capsids that grip human TfR1", "oneline": "Broad Institute researchers designed an AAV capsid (BI-hTFR1) that binds human transferrin receptor 1 and gave 40–50 times the brain expression of AAV9 in mice carrying the human receptor; no primate data was found.", "years": [ 2024, 2024 ], "kind": "tool", "branch": [ "gene-delivery" ], "outcome": "open", "file": "255-human-tfr1-aav-capsids-2024.md", "unverified": 5 }, { "id": 273, "title": "iSCORE-PD cell collection", "oneline": "A public collection of 65 genome-edited human stem cell lines carrying variants in 11 Parkinson's genes, all from one embryonic stem cell line, was released as a preprint in 2024 and published in *Nature Communications* in 2026.", "years": [ 2024, 2026 ], "kind": "infrastructure", "branch": [ "models", "infrastructure" ], "outcome": "advanced", "file": "273-iscore-pd-isogenic-collection-2024-2026.md", "unverified": 2 }, { "id": 288, "title": "LY3962681 (Lilly siRNA)", "oneline": "An siRNA injected into the spinal fluid is being tested for safety and for lowering spinal-fluid alpha-synuclein in up to 124 people, with Parkinson's patients required to have a positive seed-amplification test.", "years": [ 2024, 2030 ], "kind": "trial", "branch": [ "synuclein-dosage" ], "outcome": "pending", "file": "288-ly3962681-sirna-2024-2030.md", "unverified": 2, "expected": "2030-07", "phase": 1, "n": 124 }, { "id": 292, "title": "TJ0113 (mitophagy inducer)", "oneline": "A Chinese oral drug said to speed the clearing of damaged mitochondria cut off-medication motor scores by about 6 points more than placebo over 12 weeks in 149 people; a 300-person Phase 3 is registered, but the result is short-term and not peer-reviewed.", "years": [ 2024, 2028 ], "kind": "trial", "branch": [ "mitochondria" ], "outcome": "open", "file": "292-tj0113-mitophagy-2024-2028.md", "unverified": 4, "phase": 3, "n": 300 }, { "id": 297, "title": "NouvNeu001 (iRegene)", "oneline": "iRegene's donor-made (allogeneic) dopamine progenitor cells, grown from induced stem cells with a chemical recipe, have been put into patients' brains in China since January 2024 and in the US since January 2026; the efficacy claims come from company releases only.", "years": [ 2024, 2026 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "open", "file": "297-nouvneu001-ipsc-dopamine-cells-2024-2026.md", "unverified": 4, "phase": 2, "n": 30 }, { "id": 346, "title": "FDA letter of support for the seed assay", "oneline": "On 19 August 2024 the FDA told the Critical Path for Parkinson's consortium it supports using the spinal-fluid alpha-synuclein seed amplification assay (SAA) to select participants for trials, the second such letter in Parkinson's (the first, in March 2015, was for DaTscan).", "years": [ 2024, 2024 ], "kind": "infrastructure", "branch": [ "biomarkers" ], "outcome": "advanced", "file": "346-fda-letter-of-support-synuclein-saa-2024.md", "unverified": 2 }, { "id": 347, "title": "Brigham and Women's autologous iPSC dopamine cells", "oneline": "A Mass General Brigham team is grafting dopamine neurons made from each patient's own blood cells into the brain in a 12-person Phase 1 trial; the first patient was treated in September 2024 and primary completion is estimated for December 2028.", "years": [ 2024, 2028 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "347-mclean-brigham-autologous-ipsc-dopamine-phase-1-2024-2028.md", "unverified": 4, "expected": "2028-12", "phase": 1, "n": 12 }, { "id": 348, "title": "UC San Diego CT1-DAP001 donor iPSC cells", "oneline": "UC San Diego is running the first US test of the donor iPSC dopamine progenitors that Kyoto tested in Japan, in a seven-person open-label trial; primary completion is estimated for December 2027.", "years": [ 2024, 2028 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "348-ucsd-ct1-dap001-ipsc-dopamine-phase-1-2-2024-2028.md", "unverified": 3, "expected": "2027-12", "phase": 1, "n": 7 }, { "id": 10, "title": "Bemdaneprocel embryonic stem-cell dopamine neurons", "oneline": "Dopamine neurons grown from embryonic stem cells and transplanted into 12 patients were safe and made dopamine in a first-in-human trial; the product, bemdaneprocel, is now in Phase 3. The parallel Kyoto trial of iPSC-derived cells is [landmark 300](300-kyoto-ipsc-dopamine-cells-phase-1-2-2018-2025.md).", "years": [ 2025, 2025 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "advanced", "file": "10-stem-cell-dopamine-neurons-2025.md", "unverified": 4 }, { "id": 80, "title": "EJS ACT-PD platform trial", "oneline": "A £26 million UK platform trial opened in October 2025 to test several repurposed drugs against one shared placebo group, dropping failures early and adding new drugs over time.", "years": [ 2025, 2025 ], "kind": "infrastructure", "branch": [ "trial-methods" ], "outcome": "open", "file": "80-ejs-act-pd-platform-trial-2025.md", "unverified": 4 }, { "id": 142, "title": "Exenatide Phase 3 (Exenatide-PD3)", "oneline": "The first Phase 3 of a GLP-1 drug in Parkinson's, 194 people for two years, found no benefit from weekly exenatide, and in June 2026 the journal added an expression of concern about one trial site.", "years": [ 2025, 2025 ], "kind": "trial", "branch": [ "metabolic-repurposing" ], "outcome": "dead-end", "file": "142-exenatide-phase3-pd3-2025.md", "unverified": 5, "phase": 3, "n": 194 }, { "id": 157, "title": "PARAISO prasinezumab Phase 3", "oneline": "The first Phase 3 of an anti-synuclein antibody; about 900 people, primary completion estimated June 2029.", "years": [ 2025, 2029 ], "kind": "trial", "branch": [ "synuclein-spread" ], "outcome": "pending", "file": "157-paraiso-prasinezumab-phase3-2025-2029.md", "unverified": 1, "expected": "2029-06", "phase": 3, "n": 900 }, { "id": 158, "title": "exPDite-2 bemdaneprocel Phase 3", "oneline": "A sham-surgery-controlled Phase 3 of lab-grown dopamine neurons in about 102 people; primary completion estimated March 2027.", "years": [ 2025, 2027 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "158-expdite-2-bemdaneprocel-phase3-2025-2027.md", "unverified": 2, "expected": "2027-03", "phase": 3, "n": 102 }, { "id": 188, "title": "NEU-411 (NEULARK)", "oneline": "After BIIB122 failed in unselected early Parkinson's, Neuron23's 150-person Phase 2 gives a second LRRK2 inhibitor only to people whose disease a companion test flags as LRRK2-driven; the main phase is due to finish around December 2027.", "years": [ 2025, 2027 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "pending", "file": "188-neu-411-neulark-2025-2027.md", "unverified": 3, "expected": "2027-12", "phase": 2, "n": 150 }, { "id": 234, "title": "GT-02287 Phase 1b (GCase modulator)", "oneline": "A pill meant to refold and restore the enzyme GCase was given to about 20 people with Parkinson's for 3 to 12 months; the company reports safety and a spinal-fluid marker fall, and a Phase 2 is being set up, but nothing is peer-reviewed.", "years": [ 2025, 2026 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "open", "file": "234-gt-02287-gcase-phase1b-2025-2026.md", "unverified": 7, "phase": 1, "n": 20 }, { "id": 287, "title": "ALN-SNCA (Regeneron siRNA)", "oneline": "A first-in-human study of ALN-SNCA, a drug that switches off the SNCA gene's messages, is testing safety and spinal-fluid synuclein in 46 people with early Parkinson's; it ends in mid-2029.", "years": [ 2025, 2029 ], "kind": "trial", "branch": [ "synuclein-dosage" ], "outcome": "pending", "file": "287-aln-snca-sirna-2025-2029.md", "unverified": 4, "expected": "2029-06", "phase": 1, "n": 46 }, { "id": 291, "title": "VENT-02 (NLRP3)", "oneline": "Ventus ended a 28-day placebo-controlled study of its brain-penetrant NLRP3 inhibitor in Parkinson's after 29 people, giving \"sponsor decision\" as the only reason, and has not published results.", "years": [ 2025, 2025 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "open", "file": "291-vent-02-nlrp3-phase-1b-2025.md", "unverified": 3, "phase": 1, "n": 29 }, { "id": 293, "title": "BHV-8000 (TYK2/JAK1 inhibitor)", "oneline": "Biohaven is testing an oral drug that blocks two immune-signalling enzymes (TYK2 and JAK1) in 550 people with early Parkinson's, with time to everyday-function worsening as the main measure.", "years": [ 2025, 2027 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "pending", "file": "293-bhv-8000-tyk2-jak1-2025-2027.md", "unverified": 3, "expected": "2027-08", "phase": 3, "n": 550 }, { "id": 294, "title": "TB006 (galectin-3 antibody)", "oneline": "TrueBinding is testing a monthly infusion of an antibody against galectin-3, a sugar-binding protein that drives microglial inflammation, in 62 people with early Parkinson's; enrolment is closed and the primary data are due about November 2026.", "years": [ 2025, 2026 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "pending", "file": "294-tb006-galectin-3-antibody-2025-2026.md", "unverified": 3, "expected": "2026-11", "phase": 2, "n": 62 }, { "id": 296, "title": "Hydroxychloroquine (HCQ-PD)", "oneline": "A 40-person, open-label, 48-week Canadian study will give the old arthritis and malaria drug hydroxychloroquine to people with early Parkinson's, after a Finnish health-record study linked it to lower Parkinson's risk in people with rheumatoid arthritis and a Taiwanese study found the opposite in Sjögren's syndrome.", "years": [ 2025, 2027 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "open", "file": "296-hydroxychloroquine-hcq-pd-ottawa-2025-2027.md", "unverified": 3, "phase": 2, "n": 40 }, { "id": 298, "title": "Wave of Chinese iPSC dopamine-cell trials", "oneline": "Five Chinese companies, besides iRegene, registered eight Phase 1 or Phase 1/2 trials of iPSC-derived dopamine cells in 2025–26, all small and open-label, and only company press releases report early results.", "years": [ 2025, 2026 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "open", "file": "298-china-ipsc-dopamine-cell-trial-wave-2025-2026.md", "unverified": 5, "phase": 2 }, { "id": 299, "title": "RNDP-001 (Kenai) REPLACE", "oneline": "Kenai Therapeutics is testing frozen, donor-made dopamine progenitor cells in up to 12 people in the US (REPLACE trial); the first patient was dosed in December 2025, enrolment was announced complete in July 2026, and no results exist yet.", "years": [ 2025, 2027 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "299-rndp-001-kenai-replace-2025-2027.md", "unverified": 6, "expected": "2027-09", "phase": 2, "n": 12 }, { "id": 301, "title": "Mass General autologous iPSC implant", "oneline": "Jeffrey Schweitzer's team at Massachusetts General Hospital is repeating the 2020 one-patient graft of a person's own reprogrammed skin cells in a Phase 1 trial of up to eight people; primary completion is estimated for December 2027.", "years": [ 2025, 2028 ], "kind": "trial", "branch": [ "cell-replacement" ], "outcome": "pending", "file": "301-mgh-autologous-ipsc-dopamine-phase-1-2025-2028.md", "unverified": 5, "expected": "2027-12", "phase": 1, "n": 8 }, { "id": 303, "title": "CAP-003 intravenous GBA1 gene therapy (Capsida)", "oneline": "Capsida's planned 31-person trial of an intravenous gene therapy for GBA1-linked Parkinson's was withdrawn with no patients dosed, after a child died in the company's trial of a drug using the same engineered virus shell.", "years": [ 2025, 2026 ], "kind": "trial", "branch": [ "gene-delivery", "lysosome-gba" ], "outcome": "dead-end", "file": "303-cap-003-capsida-iv-gba1-gene-therapy-2025-2026.md", "unverified": 3, "phase": 2, "n": 0 }, { "id": 306, "title": "VCAP-102 capsid crosses primate blood-brain barrier", "oneline": "Voyager Therapeutics evolved an AAV9 variant that carries genes from a vein into the brains of mice and three primate species at 20 to 400 times AAV9's rate (the paper's headline range), and found it uses a conserved receptor, ALPL.", "years": [ 2025, 2025 ], "kind": "tool", "branch": [ "gene-delivery" ], "outcome": "open", "file": "306-voyager-vcap-102-alpl-capsid-2025.md", "unverified": 2 }, { "id": 321, "title": "ASPro-PD: ambroxol Phase 3", "oneline": "The only Phase 3 test of whether a GCase-boosting drug slows Parkinson's: 330 people on ambroxol or placebo for two years, with a main readout expected around 2029.", "years": [ 2025, 2029 ], "kind": "trial", "branch": [ "lysosome-gba" ], "outcome": "pending", "file": "321-aspro-pd-ambroxol-phase3-2025-2029.md", "unverified": 3, "expected": "2029-02", "phase": 3, "n": 330 }, { "id": 326, "title": "PreCoDe: prasinezumab in GBA carriers", "oneline": "A planned Tübingen Phase 2 gives the anti-synuclein antibody prasinezumab to people with Parkinson's and a severe GBA mutation to see whether it slows loss of thinking skills; registry shows it not yet recruiting.", "years": [ 2025, 2030 ], "kind": "trial", "branch": [ "synuclein-spread", "lysosome-gba" ], "outcome": "pending", "file": "326-prasinezumab-gba-precode-2025-2030.md", "unverified": 5, "expected": "2030-12", "phase": 2, "n": 120 }, { "id": 110, "title": "LRRK2 antisense BIIB094", "oneline": "A spinal-fluid antisense drug cut LRRK2 protein by up to 59% in an 82-person safety trial, but Biogen halted its development in early 2025 and it was never tested for benefit.", "years": [ 2026, 2026 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "dead-end", "file": "110-biib094-lrrk2-antisense-2026.md", "unverified": 2, "phase": 1, "n": 82 }, { "id": 145, "title": "BIIB122 / DNL151 (LUMA)", "oneline": "An oral LRRK2 inhibitor cut its blood target by over 90% in 648 people with early Parkinson's yet did not slow progression, so Biogen and Denali dropped it in general Parkinson's and kept only a mutation-carrier study.", "years": [ 2026, 2026 ], "kind": "trial", "branch": [ "lrrk2" ], "outcome": "dead-end", "file": "145-biib122-luma-2026.md", "unverified": 7, "phase": 2, "n": 648 }, { "id": 186, "title": "DAPA-PD (dapansutrile)", "oneline": "A 36-person placebo-controlled Phase 2 at Cambridge is testing whether an oral NLRP3 inhibitor is safe and reduces inflammation in early Parkinson's; it began in February 2026 and is due to finish its main phase around May 2027.", "years": [ 2026, 2027 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "pending", "file": "186-dapa-pd-dapansutrile-2026-2027.md", "unverified": 3, "expected": "2027-05", "phase": 2, "n": 36 }, { "id": 225, "title": "PRISMS: adalimumab in RBD", "oneline": "The first registered placebo-controlled drug trial I could find that aims to stop people with REM sleep behaviour disorder from developing Parkinson's or Lewy body dementia; the Path to Prevention platform trial is being set up alongside.", "years": [ 2026, 2029 ], "kind": "trial", "branch": [ "trial-methods", "inflammation" ], "outcome": "pending", "file": "225-prevention-trials-prodromal-rbd-2026.md", "unverified": 3, "expected": "2029-08", "phase": 2, "n": 108 }, { "id": 290, "title": "RO7568282 (TARBELA-PD, NLRP3)", "oneline": "Roche plans the largest placebo-controlled test yet of an NLRP3 inflammation blocker in Parkinson's: 474 people with early disease, with time to motor worsening as the main measure.", "years": [ 2026, 2028 ], "kind": "trial", "branch": [ "inflammation" ], "outcome": "pending", "file": "290-ro7568282-nlrp3-tarbela-pd-2026-2028.md", "unverified": 4, "expected": "2028-12", "phase": 2, "n": 474 }, { "id": 302, "title": "VGN-R08b GBA1 gene therapy (Vitalgen)", "oneline": "A Chinese Phase 1/2 trial plans to give a one-time AAV9 gene therapy carrying a working GBA1 gene by injection into the brain's ventricles in 17 people with Parkinson's caused by GBA1 mutations; the registry lists it as not yet recruiting.", "years": [ 2026, 2027 ], "kind": "trial", "branch": [ "gene-delivery", "lysosome-gba" ], "outcome": "open", "file": "302-vgn-r08b-gba1-gene-therapy-2026-2027.md", "unverified": 5, "phase": 2, "n": 17 }, { "id": 356, "title": "Japan conditionally approves Amchepry (iPS-cell dopamine precursors)", "oneline": "On 6 March 2026 Japan approved Amchepry (raguneprocel), lab-grown dopamine-neuron precursors made from donor iPS cells, for Parkinson's with a time limit and a duty to prove benefit afterwards; it reported as the world's first conditional approval of an iPS-cell therapy (Michael J. 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