About

Andrew D. Siderowf, MD, is a Professor in Neurology at the University of Pennsylvania's Perelman School of Medicine. He is affiliated with the Department of Neurology and the Parkinson's Disease & Movement Disorders Center at Pennsylvania Hospital. Dr. Siderowf's educational background includes a B.A. in English from Yale University (1987), an M.D. from Duke University School of Medicine (1992), and an M.S.C.E. from the University of Pennsylvania (2003). His professional focus is on neurology, with particular expertise in Parkinson's disease and movement disorders. He has contributed to the field through research and publications related to Parkinson's disease, including clinical trials and studies on neuroprotective therapies and quality of life assessments for patients. Dr. Siderowf is actively involved in advancing understanding and treatment of movement disorders through his academic and clinical work.

Research topics

• Medicine
• Pathology
• Computer Science
• Psychology
• Surgery
• Psychiatry
• Oncology
• Nuclear medicine
• Neuroscience
• Bioinformatics
• Internal medicine
• Biology
• Family medicine

Selected publications

• Synuclein and dopamine transporter biomarkers among phenoconverters to parkinsonian disorders

  medRxiv · 2026-04-20

  article

  Abstract Background Phenoconversion to Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers—CSF α-synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging—offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. Methods We analyzed Parkinsońs Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimer’s disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with ≥1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS) staging was applied. Results Among 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2 + GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15/47 (31.9%) iRBDs and 7/38 (18.4%) hyposmics were already NSD-ISS stage ≥4 at time of phenoconversion. Conclusions Clinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.

  PublisherDOI

• PCR136 Improving the Conceptual Coverage of the 15-item Penn Parkinson’s Daily Activity Questionnaire (PDAQ-15) for Use in the Mild-to-Moderate Lewy Body Dementia Population

  Value in Health · 2025-12-01

  article
  PublisherDOI

• Iterative and data-driven development of a digital measure of motivation, impulsivity, and risk-taking (Preprint)

  2025-09-26

  preprintOpen access

  <sec> <title>BACKGROUND</title> Basal ganglia (BG) dysfunction is the hallmark of several neurological and neuropsychiatric disorders. BG dysfunction impairs cost-benefit decision-making, a brain computational process of trading off between reward and costs, and may underlie clinical observations of neuropsychiatric symptoms such as amotivation, impulsivity, and risk-taking. There is an unmet need for a remote digital monitoring tool for cost-benefit decision-making that can be administered repeatedly by a patient at home to provide a longitudinal proxy of basal ganglia functioning to inform clinical practice and drug development efforts. </sec> <sec> <title>OBJECTIVE</title> This report describes a data-driven and iterative prototyping effort of a smartphone-based, cost-benefit, decision-making test battery developed to measure basal ganglia functioning in three cost domains: effort, delay, and risk. Via an iterative process consisting of multiple rounds of data collection with online community-based samples, we aimed to establish feasibility, proof-of-concept, test-retest reliability over up to 4.5 months, and convergent validity with relevant clinical symptoms, namely apathy and impulsivity. </sec> <sec> <title>METHODS</title> We converted a lab-based, decision-making test battery to a URL-based test administered on private smartphones. An online pool of n = 879 volunteers aged 40-80 years participated. Using a data-driven approach, we iteratively (6 rounds) refined and shortened the test to a prototype with a target participant burden of less than 5 minutes while preserving its psychometric properties. Proof of concept, test-retest reliability (intraclass correlation coefficients (ICCs)), and convergent validity with the Starkstein Apathy Scale (SAS) and Barrat Impulsiveness Scale (BIS-11) were established for the final version. </sec> <sec> <title>RESULTS</title> Consistent monotonic effects of cost levels in all cost domains were observed, demonstrating proof of concept. Measures of motivation, impulsivity, and risk-taking showed good to excellent test-retest reliability (ICCs 0.69 – 0.97). Metrics of impulsivity showed convergent validity with its clinical anchor, BIS-11 (t = -2.83, p = 0.005)), and the metric of motivation showed convergent validity with SAS (t = -2.29, p = 0.022). </sec> <sec> <title>CONCLUSIONS</title> This accessible, short, scalable, and replicable digital smartphone-based decision-making test battery may represent an efficient and robust means to estimate cost-benefit decision-making associated with basal ganglia functioning and its changes over time. </sec> <sec> <title>CLINICALTRIAL</title> This is not a RCT </sec>

  PublisherDOI

• Safety and Feasibility of Serial Lumbar Punctures: Long-term Results from the Parkinson’s Progression Markers Initiative

  medRxiv · 2025-05-06

  preprintOpen access

  Abstract Background and Objectives The collection of cerebrospinal fluid (CSF) serves an essential role in biomarker research. New Parkinson’s disease (PD) classifications include CSF α-synuclein status as a key biological anchor to enrich research trial design. Previous reports have established the safety of lumbar punctures (LPs) at baseline, but further investigation of longitudinal LP feasibility is needed. This study aimed to evaluate the safety and feasibility of serial CSF collection in participants enrolled in the Parkinson’s Progression Markers Initiative (PPMI). Methods PPMI participants were evaluated over a 13-year period. Descriptive statistics were calculated for all scheduled LPs occurring annually from baseline through year five and biennially thereafter. Adverse events were examined for all participants who attempted at least one LP. Compliance, defined as percentage of LPs with CSF collection, was assessed at baseline and for each longitudinal follow up visit. Logistic regression and generalized linear mixed effects models were used to calculate odds ratios and 95% confidence intervals for predictors of baseline and longitudinal LP success. Results 3479 participants enrolled in the PD (n=1412), prodromal (n=1768), and healthy control (n=299) cohorts were analyzed. 3360 participants attempted at least one LP of which 29.5% experienced an adverse event with 1.3% rated as severe. Compliance was 90% at baseline, 76.3% at year one, 67.8% at year three, 56.2% at year five, and 35.7% at year nine. From baseline to year five, percent change in compliance decreased by 39.4% in the PD cohort, 41.4% in the prodromal cohort, and 27.8% in the healthy control cohort. Predictive variables of baseline LP success included fewer years since diagnosis in the PD cohort (OR 0.82, 0.76-0.89), lower BMI in the prodromal cohort (OR 0.92, 0.89-0.94), and site location (U.S. vs. non-U.S.) for both PD (OR 1.5, 1.03-2.18) and healthy control (OR 3.6, 1.22-10.64) cohorts. Baseline LP success was the best predictor of longitudinal LP success (OR 7.82, 5.74-10.65). Discussion In this large study of longitudinal CSF collection, serial lumbar punctures were safe in PD research participants over a 13-year period. Although compliance was high over the first three years, further investigation is warranted to improve long term LP success.

  PublisherOA PDFDOI

• Pilot Study of [11C]HY-2-15: A Mixed Alpha-Synuclein and Tau PET Radiotracer

  Cells · 2025-07-26 · 2 citations

  articleOpen access

  A novel brain positron emission tomography (PET) radioligand, [11C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [3H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [11C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [11C]HY-2-15 in brain.

  PublisherDOI

• <scp>ENLITE PD:</scp> A Randomized Clinical Trial of Light Therapy for Impaired Sleep in Parkinson's Disease

  Movement Disorders · 2025-09-06 · 2 citations

  article

  BACKGROUND: Light therapy (LT) in Parkinson's disease improves sleep. Specific LT parameters require further study, including optimal frequency. OBJECTIVES: We aimed to determine if once- or twice-daily bright white light therapy (BWLT) improves sleep. Secondary aims compared once-weekly BWLT to twice-daily dim red light therapy (DRLT) as controls, estimated effects on fatigue, and adherence. METHODS: A 16-week, randomized, phase 2, sham-controlled, dose-selection trial to select the superior BWLT frequency based on change in Parkinson's Disease Sleep Scale-2 (PDSS-2), participant burden, and safety. Participants were randomized to 8 weeks of twice-daily BWLT, once-daily BWLT, once-weekly BWLT, or twice-daily DRLT. An improvement of ≥1.7 points in 8-week change of PDSS-2 by daily BWLT relative to either control warranted advancing to a phase 3 trial. RESULTS: A total of 150 participants were randomized (mean [SD], 67 [8.6] years; 57 [38%] female; PDSS-2 17.1 [6.7]). Mean 8-week change from baseline in PDSS-2 score improved (twice-daily BWLT -2.6 [95% CI: -4.4, -0.7]; once-daily BWLT -1.5 [-3.3, 0.3]; once-weekly BWLT -0.4 [-2.2, 1.4]; twice-daily DRLT -1.8 [-3.6, 0.1]) but did not meet criteria for advancing. Mean 8-week change from baseline in Parkinson's Disease Fatigue Scale (PFS-16) score improved (twice-daily BWLT -6.4 [-9.8, -3.0]; once-daily BWLT -2.2 [-5.5, 1.1]; once-weekly BWLT -0.5 [-3.9, 2.8]; and twice-daily DRLT -3.8 [-7.3, -0.4]). Mean adherence to LT was 63%-86%. CONCLUSIONS: ENLITE-PD did not meet the criteria for advancing daily LT to a phase 3 trial. LT was safe and well-tolerated with good adherence. Once-weekly BWLT was a non-inferior control compared with twice-daily DRLT. © 2025 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

  PublisherDOI

• α-Synuclein Seed Amplification Assay Amplification Parameters and the Risk of Progression in Prodromal Parkinson Disease

  Neurology · 2025-02-06 · 25 citations

  articleOpen access

  OBJECTIVES: Tools are needed to evaluate the risk of developing Parkinson disease (PD) in at-risk populations. In this study, we examine differences in alpha-synuclein seed amplification assay (αSyn-SAA) qualitative results and amplification parameters between nonmanifesting carriers (NMCs) of PD-related pathogenic variants, prodromal PD, and PD and the risk of developing a synucleinopathy in participants with prodromal PD. METHODS: Cross-sectional and longitudinal CSF αSyn-SAA results from participants in the Parkinson's Progression Markers Initiative were analyzed. αSyn-SAA positivity and amplification parameters (maximum fluorescence [Fmax], time-to-threshold [TTT], time-to-50% Fmax [T50], and area under the curve [AUC]) were compared between NMCs, participants with prodromal PD, and participants with PD, and their relationship with the likelihood of phenoconversion in participants with prodromal PD was investigated. RESULTS: < 0.0001). There were no changes in 48 participants with prodromal PD with longitudinal assays. DISCUSSION: αSyn-SAA positivity and faster seed amplification are associated with a greater risk of developing PD in at-risk individuals and may aid in predicting phenoconversion.

  PublisherDOI

• Safety and Feasibility of Serial Lumbar Punctures: Long-term Results from the Parkinson’s Progression Markers Initiative

  Clinical Parkinsonism & Related Disorders · 2025-01-01

  articleOpen access

  Background: Cerebrospinal fluid (CSF) serves an essential role in biomarker research. New Parkinson's disease (PD) classifications incorporate CSF α-synuclein status into trial design. This study evaluated the safety and feasibility of serial CSF collection in participants enrolled in the Parkinson's Progression Markers Initiative (PPMI). Methods: PPMI participants were evaluated over 13-years with lumbar punctures (LPs) occurring annually from baseline through year five and biennially thereafter. Adverse events and compliance, defined as percentage of LPs with CSF collection, were assessed at baseline and upon follow up. Logistic regression and generalized linear mixed effects models were used to calculate odds ratios and 95% confidence intervals for predictors of baseline and longitudinal LP success. Results: 3479 participants (PD: n = 1412, prodromal: n = 1768, healthy control: n = 299) were analyzed. 3360 attempted at least one LP with 29.5 % experiencing an adverse event (1.3 % severe). Baseline compliance was 90 %. From baseline to year five, percent change in compliance decreased by 39.4 % in the PD cohort, 41.4 % in the prodromal cohort, and 27.8 % in the healthy control cohort. Predictive variables of baseline LP success included fewer years since diagnosis (PD: OR 0.82, 0.76-0.89), lower BMI (prodromal: OR 0.92, 0.89-0.94), and site location U.S. vs. non-U.S. (PD: OR 1.5, 1.03-2.18, healthy control: OR 3.6, 1.22-10.64). Baseline LP success was the best predictor of longitudinal success (OR 7.82, 5.74-10.65). Conclusions: Lumbar punctures were safe in PD research participants over a 13-year period. Compliance was high over the first three years, but further investigation is warranted to improve long term success.

  PublisherDOI

• Wearable tracking of walking and non-walking as progression markers in early Parkinson’s disease

  medRxiv · 2025-08-21

  preprintOpen access

  Abstract IMPORTANCE Wearable-based measures of walking (as proxy for physical activity) may quantify disease progression and modification thereof in early-stage Parkinson’s disease (PD). OBJECTIVES Establishing the validity of digital measures of walking and non-walking in PD. DESIGN Retrospective longitudinal analyses of data from cohorts within 3 larger studies, consisting of wearable sensor, demographic, and clinical data collected during 2017-2023, with 1-2 year follow up. SETTING Three independent multicenter cohort studies. PARTICIPANTS People with PD, and age/sex matched non-PD cohort. EXPOSURES None. MAIN OUTCOMES AND MEASURES Digital measures’ test-retest reliability, analyzed using intraclass correlation coefficients across consecutive monthly-aggregated data. Digital measures’ sensitivity: ability to detect within-participant changes, analyzed over 24 months using linear mixed-effect models, and analyzed as effect-size changes-from-baseline comparing 1- and 2-year longitudinal Cohen’s-d (mean and 95% CIs) vs conventional clinical endpoints. Analyses replicated in two independent PD cohorts (internal validation and external evaluation). Compared within-participant changes between PD and non-PD cohorts using linear mixed-effect model slopes. RESULTS We analyzed 57 digital measures (51 individual, 6 composite) in a development cohort (N=171), selecting 32 (26 individual, 6 composite) for further study based on their sensitivity and test-retest reliability. During internal validation (N=101), 20 measures could detect statistically significant within-participant changes and 7 showed larger 2-year effect-size changes than conventional clinical measures; non-walking bout (NWB) duration (12.4% yearly change; 2-year Cohen’s-d 0.623 [95% CI: 0.461,0.811]) and 95th percentile of NWB duration (17.1% yearly change; 2-year Cohen’s-d, 0.623 [95% CI: 0.461,0.811]) performed best. Measures could detect significant and persisting changes from baseline at 10 months. During external evaluation (N=67), 15 measures could detect statistically significant within-participant changes and 12 showed larger 1-year effect-size changes than conventional clinical measures; 12 measures showed significantly greater change in people with PD than in matched non-PD individuals (N=171). CONCLUSION AND RELEVANCE Internal validation and external evaluation of 32 digital measures that quantified walking and non-walking behaviors in patients with early-stage PD showed that they could have greater sensitivity to detect longitudinal changes than conventional measures, and that these changes were disease-specific (e.g., separate from aging), making them candidates for disease-specific progression markers. Key Points Question Can wearable sensor-based digital measures of physical activity and mobility serve as markers of disease progression in early-stage Parkinson’s disease (PD)? Findings In two independent longitudinal cohorts of people with PD, digital measures detected statistically-significant changes in walking and non-walking behaviors after 1 and 2 years of follow-up; additionally, a comparison between people with and without PD (from a third cohort) showed that these changes were disease-specific. Compared with MDS-UPDRS-based conventional metrics, measures of non-walking behavior showed greater effect size (such as mean non-walking bout duration, with an annual increase of 12.4% and a 2-year Cohen’s-d of 0.623). Meaning Wearable sensor-based digital measures can detect and quantify disease-specific changes in walking and non-walking behaviors over time in people with early-stage PD.

  PublisherOA PDFDOI

• Evidence for alpha-synuclein aggregation in older individuals with hyposmia: a cross-sectional study

  EBioMedicine · 2025-02-01 · 16 citations

  articleOpen accessSenior author

  BACKGROUND: Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (α-syn SAA) may detect aggregated synuclein before symptoms occur. METHODS: Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. α-syn aggregates in CSF were measured in 100 PARS participants using α-syn SAA. FINDINGS: CSF α-syn SAA was positive in 48% (34/71) of hyposmic compared to 4% (1/25) of normosmic PARS participants (relative risk, 11.97; 95% CI, 1.73-82.95). Among α-syn SAA positive hyposmics 65% remained without a DAT deficit for up to four years follow-up. α-syn SAA positive hyposmics were at higher risk of having DAT deficit (12 of 34) compared to α-syn SAA negative hyposmics (4 of 37; relative risk, 3.26; 95% CI, 1.16-9.16), and 7 of 12 α-syn SAA positive hyposmics with DAT deficit developed symptoms consistent with synucleinopathy. INTERPRETATION: Approximately fifty percent of PARS participants with hyposmia, easily detected using simple, widely available tests, have synuclein pathology detected by α-syn SAA. Approximately, one third (12 of 34) α-syn SAA positive hyposmic individuals also demonstrate DAT deficit. This study suggests a framework to investigate screening paradigms for synuclein pathology that could lead to design of therapeutic prevention studies in individuals without symptoms. FUNDING: The study was funded by the U.S. Department of Defense, the Helen Graham Foundation and the Michael J. Fox Foundation for Parkinson's Research.

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Recent grants

• NIH Grant P50NS053488

  NIH · $33.7M · 2018

• NIH Grant U10NS044451

  NIH · $932k · 2015

• NIH Grant K08HS000004

  NIH · $635k · 2006

Frequent coauthors

• Daniel Weintraub

  Veterans Health Administration

  247 shared

• John Q. Trojanowski

  University of Pennsylvania

  173 shared

• Kenneth Marek

  Institute for Neurodegenerative Disorders

  170 shared

• Howard I. Hurtig

  University of Pennsylvania

  166 shared

• Leslie M. Shaw

  University of Pennsylvania

  161 shared

• Brit Mollenhauer

  University of Göttingen

  133 shared

• Alice Chen‐Plotkin

  University of Pennsylvania

  133 shared

• Tanya Simuni

  104 shared

Labs

• Siderowf LabPI