Michael J. Fox Foundation

For 25 years, The Michael J. Fox Foundation has made it our mission to harness the Parkinson's community's grit and generosity and turn it into tangible progress toward better treatments and cures. People and families living with Parkinson's, academic and industry researchers, treating physicians and allied health professionals, and regulators all have jumped in feet-first to get this job done. I am endlessly grateful for the vast wisdom and energy they have poured into our shared cause. This combined strength is nowhere more evident than in the Parkinson's Progression Markers Initiative (PPMI). Fifteen years in, two sets of experts — those who choose to be part of taking down Parkinson's and those who, like me, are here involuntarily — have formed a powerful partnership that is steadily dismantling the secrets of this complex disease. Quite frankly, there's nothing more rock-and-roll than PPMI: out of the gates a pioneering, bold, and astronomically expensive undertaking. “While there is no guarantee that validated biomarkers will result from PPMI,” we wrote in the 2010 press release announcing the study's launch, “their importance to therapeutic progress requires that we accept this risk.” Plenty of voices told us it would never work. Others underestimated the degree of difficulty, like the science reporter who patiently listened to us describing PPMI's ambitious goals, then wrapped up the conversation with a breezy “Call me when you find the biomarker!” That call didn't happen the next day, year, or decade. There were gaps — human-sized gaps — in our understanding of Parkinson's. But while we couldn't be certain when or even if the science would pan out, we were pretty sure we could motivate people with Parkinson's, those at risk, and control volunteers to join our study and be part of the solution they seek. Sure enough, the earliest participants to enroll in PPMI — those first 400 de novo patients and 200 age- and gender-matched controls — would eagerly blaze a path for tens of thousands to come. Scientists now had real-time access to deep, rich, and highly standardized clinical data and precious biosamples from a cohort that would come to span the entire continuum of Parkinson's risk, onset, and progression. Liberated from the challenge of assembling and funding small, ad hoc cohorts, they could turn their full attention to answering longstanding questions about the insidious biology of the human disease. Visit by visit, test by test, study participants helped us build an incredible data set. Researchers avidly leveraged it, with millions of data downloads powering thousands of individual studies worldwide. In addition, in 2023, the Foundation's CEO and co-founder Debi Brooks and founding Board member Nelle Fortenberry came to my home for an urgent meeting. Todd Sherer, chief mission officer, joined us remotely. Together, they shared the news that PPMI had done what it set out to do: validated a test to objectively and accurately detect Parkinson's biology in living people, even years before they had experienced a single symptom of the disease. Outside of milestone life events like my wedding or the births of my children, I'm not sure I have ever been so moved. I remember leaning forward to kiss Todd's forehead on my laptop screen. This was a game-changing moment for the field, not least for patients (myself included) who have had the singularly devastating experience of receiving a bolt-from-the-blue diagnosis and learning that by that point, more than half the dopamine cells in our brains have already been laid waste. The biomarker kicked down the door to a totally different way forward. From detecting Parkinson's before symptoms develop, to testing next-generation drugs against a wide range of biological targets, to the dream of precision medicine and even disease prevention, we are on the threshold of big things. Fueling PPMI on its path are the efforts of our nonprofit and philanthropic partners, scores of biotech and pharmaceutical companies, and hundreds of thousands of individual donors. For 15 years, alongside study volunteers and leadership, this incredible crew has built toward a cure that is now tantalizingly within reach. Their dedication runs deep — just like my gratitude for them. PPMI was once a bold risk. It's now widely recognized as the premier study in Parkinson's, a transformative resource that researchers can leverage to accelerate measurable scientific progress. But the contributions of strength and courage that got us here are impossible to measure. Thanks to the phenomenal Parkinson's community, PPMI is truly the study that is changing everything — and creating unprecedented opportunity for more breakthroughs. So, let's keep rocking and rolling until Parkinson's is only a memory. Michael J. Fox: Writing – original draft; writing – review and editing.

BackgroundFalls and cognitive impairment are major sources of disability in Parkinson disease (PD). The ability to accurately identify individuals with PD at high risk for falls and cognitive impairment would provide an opportunity for intervention and potentially improve long-term outcomes. In a previous study, Assessing Telehealth Outcomes in Multiyear Extensions of Parkinson Disease Trials (AT-HOME PD), we remotely characterized participants with early PD who had participated in 1 of 2 PD clinical trials over 2 years of follow-up. These participants with advancing disease provide a unique opportunity to examine whether the capture of objective in-home measures via digital tools and bothersome symptoms via direct participant report improves the prediction of disease milestones.ObjectiveAssessing Telehealth Outcomes in Multiyear Extensions of Parkinson Disease Trials–2 (AT-HOME PD2) aims to examine whether digital tools and remote participant reporting can improve the prediction of falls and cognitive impairment, quantify changes in physical activity over time, and explore the relationship between physical activity and clinical progression over time.MethodsThis is a decentralized observational study of up to 200 individuals with PD, with clinical and digital phenotyping for up to 3 years of follow-up. Participants are those who took part in the STEADY-PD III (NCT02168842), Study of Urate Elevation in Parkinson’s Disease, Phase 3 (SURE-PD3; NCT02642393), AT-HOME PD (NCT03538262), or PD GENEration (NCT04057794) studies. All participants complete 2 video visits per year, wear 2 wrist-worn sensors (Fitbit Charge 5 and ActiGraph CentrePoint Insight Watch) for 1 week each month, complete smartphone-based motor tasks (using the mPower 2.0 app) for 10 days each quarter, and complete online surveys (within the companion Fox Insight study) each quarter. Falls are assessed via a weekly automated telephone call. A cognitive diagnosis is determined by a consensus committee that considers scores on a global cognitive measure, detailed neuropsychological tests, a cognitive-related disability measure, and clinical information. Prediction models will be constructed, and prediction accuracy will be compared across the models.ResultsRecruitment for the study was initiated in September 2023. Enrollment is ongoing, with 142 participants enrolled as of January 2025. Within the cohort, the average age is 69.2 (SD 8.7) years; 85 (59.9%) participants are male, 137 (96.5%) are White, and 2 (1.4%) are Hispanic or Latino; and the average disease duration is 8.9 (SD 1.3) years.ConclusionsAT-HOME PD2 is remotely clinically and digitally phenotyping participants with midstage PD to predict falls and cognitive impairment and to provide insights into long-term progression.International Registered Report Identifier (IRRID)DERR1-10.2196/71955

Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson’s disease (PD). Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1, can contribute to atypical or familial forms of PD, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing on 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, alongside 1,429 additional controls from the NIH CARD initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic FGF14 GAA repeat expansions in five individuals with PD and one control. All five individuals fit the clinical criteria of PD and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to PD. To our knowledge, this is the first report implicating FGF14 in PD and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.

Alpha-synuclein (aSyn) is linked to Parkinson's disease (PD) through SNCA genetic mutations, phosphorylated aSyn in Lewy bodies and Lewy neurites, and most recently through evidence of aSyn aggregation in patient spinal fluid using the aSyn seed amplification assay. Therefore, understanding the biology of this protein and developing therapeutic interventions targeting pathological processing of aSyn are a key area of focus for novel treatments to slow or stop PD. Reliable preclinical models are imperative for these efforts. To this end, we developed a novel model using CRISPR/Cas9 to humanize the regions surrounding the naturally occurring threonine 53 amino acid in the Sprague Dawley rat to generate a humanized A53T aSyn rat model (aSyn A53T KI). We also generated an Snca knockout (aSyn KO) line to pair with the humanized A53T aSyn rat line to confirm that phenotypes were not due to loss of endogenous rat aSyn protein. A systematic phenotyping study was performed on these lines, assessing PD-related pathology and phenotypes at multiple timepoints. The aSyn KO rat line was profiled at 6 and 12 months of age, revealing successful aSyn protein knockout. The aSyn A53T KI model was profiled at 4, 8, 12, and 18 months of age for motor and non-motor phenotypes, nigrostriatal degeneration, and brain pathology. We confirmed the aSyn A53T KI rat expresses human aSyn while lacking endogenous rat aSyn. Motor function and non-motor function remain largely unaffected in this model, and no overt nigrostriatal degeneration or brain pathology are observed up to 18 months of age. Although the aSyn A53T KI rat lacks the ability to model PD pathology and phenotypes at baseline, it is an ideal model for investigating the impact of exogenous synuclein aggregates or environmental triggers on human aSyn in an in vivo model system.

A comprehensive, patient-centered conceptual model of early Parkinson’s is lacking and is greatly needed. A systematic review and meta-synthesis of qualitative and quantitative research was conducted by a multi-stakeholder taskforce using JBI Mixed Methods Review criteria and GRADE-CERQual standards for assessment of evidence. Over 340 symptoms and impacts were identified across ten symptom domains (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) and two impact domains (Physical and Psychosocial functioning). A wide range of motor and non-motor symptoms were present in early disease, with strongest support for tremor, dexterity, gait, stiffness, slow movements, cognitive, mood, and sleep alterations, urinary dysfunction, constipation, pain, and fatigue. These affected mobility, self-concept, coping, effort of living, interactions and important activities, with evidence of many understudied concepts. This model offers the most comprehensive catalogue of symptoms and impacts in Parkinson’s to date and will support clinical practice and endpoint selection for therapeutic trials.

ObjectiveRemote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha‐synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single‐photon emission computed tomography imaging (DAT‐SPECT) and alpha‐synuclein aggregation.MethodsThe Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60‐years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT‐SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha‐synuclein seed amplification assay (aSynSAA).ResultsAs of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT‐SPECT, 1,060 (69%) had DAT‐SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT‐SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85–4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT‐SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile).InterpretationRemote screening for hyposmia and reduced DAT‐SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials. ANN NEUROL 2025;97:730–740

Objectives:To determine the impact of dopamine deficiency and isolated REM sleep behavior disorder (iRBD) on cognitive performance in early neuronal alpha-synuclein disease (NSD) with hyposmia.Methods:Using Parkinson’s Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) developed by applying regression-based internal norms derived from a robust healthy control (HC) group. Performance was examined for participants with hyposmia classified as NSD-Integrated Staging System (NSD-ISS) Stage 2, either Stage 2A (CSF alpha-synuclein seed amplification assay [SAA]+, SPECT dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).Results:Participants were Stage 2A (N=101), Stage 2B (N=227) and HCs (N=158). Although Stage 2 overall had intact Montreal Cognitive Assessment scores (mean (SD) =27.0 (2.3)), Stage 2A had a numerically worse CSS (z-score mean difference =0.05, p-value NS; effect size=0.09) and Stage 2B had a statistically worse CSS (z-score mean difference =0.23, p-value <0.05; effect size=0.40) compared with HCs. In Stage 2A participants with hyposmia alone had normal cognition, but presence of comorbid iRBD was associated with significantly worse cognition (z-score mean difference =0.33, p-value <0.05, effect size =0.50). In Stage 2B participants with hyposmia had abnormal cognition (z-score mean difference =0.18, p-value =.0078, effect size =0.29), and superimposed iRBD had a non-statistically significant additive effect.Interpretation:Using a CSS, early NSD with hyposmia is associated with measurable cognitive deficits compared with robust HCs, particularly in presence of dopamine system impairment or comorbid iRBD, highlighting the importance of focusing on cognition in early-stage synuclein disease.

Abstract ImportanceThe lack of information on progression, phenoconversion, and risk of dementia in a large genotyped sample impedes reliable enrichment for early interventional trials in Parkinson’s disease (PD).ObjectiveTo investigate PD penetrance, risk, motor/non-motor phenotypes, andAPOEallele effects inLRRK2G2019S andGBAN370S carriers.DesignObservational longitudinal case-control self-report survey study.SettingA US population-based study cohort enrolled in the 23andMe, Inc. and Fox Insight Genetic Substudy (FIGS) databases.ParticipantsThe total cohort included 7,586,842 participants (n=35,163 PD; 27% of PD cases from FIGS); 8,791LRRK2G2019S carriers (565 with PD), 37,427GBAN370S carriers (524 with PD), 244 dual carriers (37 with PD), and 7.5 million non-carriers (34,037 with PD).Exposure(s)LRRK2G2019S,GBAN370S,APOEE2/E3/E4 alleles and PD polygenic risk scores (PRS).Main Outcome(s) and Measure(s)Cumulative incidence of PD was estimated using Kaplan-Meier and accelerated failure time models. Relative odds of developing motor and non-motor symptoms were calculated using logistic regression models according to genetic exposure. Impact of theAPOEalleles was estimated in a dose-dependent analysis.ResultsBy the age of 80 years, the cumulative incidence of PD was 43% for dual carriers, 32% forLRRK2G2019S carriers, 6% forGBAN370S carriers, and 3% for non-carriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. Motor symptoms were similar inLRRK2G2019S,GBAN370S, and non-carriers with PD.GBAN370S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, andLRRK2G2019S the lowest.APOEE4 dosage was associated with greater odds of developing hallucinations and cognitive decline in addition to carrier status.Conclusions and RelevanceOur findings support the use of genetic screening—includingLRRK2G2019S,GBAN370S,APOEE4, and PRS—to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetic risk factors.

Fox Insight is an online, longitudinal study of over 54,000 people with and without Parkinson’s disease, facilitating discovery, validation, and reproducibility in Parkinson’s disease research. The study administers routine longitudinal assessments, one-time questionnaires on an array of topics such as environmental exposure or COVID-19, plus genetic and microbiome data collection. Researchers can explore and download patient-reported outcomes data and Parkinson’s disease related genetic variants upon completing a Data Use Agreement. The full genetic data set, including approximately 650,000 single nucleotide polymorphisms for over 10,000 participants, and the microbiome data set for over 650 participants, can be requested with a heightened level of access. Since the first Fox Insight data descriptor was published in 2020, the data captured has been extended significantly, so this paper supersedes the previous one. Since then, the number of participants has increased by more than 20,000; an additional 1,747,729 surveys were completed; 130 gigabytes of genetic data were released; responses from 16 new one-time surveys were collected; and, data from one additional sub-study was made available.