A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

Demographic Influences on the Relationship Between Fatigue and Quality of Life in Parkinson's Disease.

BACKGROUND: Fatigue has a major impact on health-related quality of life (HR-QOL) in Parkinson's disease (PD). OBJECTIVES: To determine whether demographic characteristics modify the relationship between fatigue and HR-QOL. METHODS: Patients with PD in the Fox Insight study completed the Parkinson Fatigue Scale (PFS-16) and Geriatric Depression Scale (GDS-15). Linear regression examined the relationship between the PFS-16 and Parkinson Disease Quality of Life, as modified by age, sex, and GDS-15. RESULTS: A total of 1029 participants (44% female, mean age 67.4 years, and mean disease duration 4.6 years) were included in this analysis. Multivariable regression modeling demonstrated a negative effect modification for age (ß = -0.07, P < 0.001) and a positive effect modification for the GDS-15 (ß = 0.057, P = 0.002), but not for sex (ß = -0.021, P = 0.231). CONCLUSION: The association between fatigue and worse HR-QOL is greater at younger ages and in individuals with more depressive symptoms. Targeted therapeutics for these individuals may provide the greatest impact on fatigue in PD.

Use of Figurative Language by People With Parkinson Disease to Describe "Off" Periods: Clear as Mud.

OBJECTIVE: "Off" periods are characterized by the reemergence of motor and nonmotor symptoms in individuals with Parkinson disease (PD) and often negatively affect daily functioning. Individuals' experiences are diverse and may be difficult to articulate; figurative language is often used by patients to describe such experiences. Our objective was to understand how individuals with PD use figurative language to explain off periods and how experts interpret such expressions. METHODS: Individuals with self-reported PD participating in the online Fox Insight study were invited to participate in a survey about off periods. Those endorsing off periods were asked to describe their experiences with open-ended free-text responses. Instances where any type of figurative language was used were identified and classified into themes. Three movement disorder neurologists reviewed each phrase and specified what symptoms they felt were likely represented. RESULTS: A total of 109 instances of figurative language phrases were identified across descriptions from 86 patients. Allusions to viscous materials (e.g., mud and cement) and effects of chemicals (e.g., drunkenness) were common (18.35% and 17.43% of phrases, respectively). Most phrases were interpreted by the neurologists as representing motor symptoms, but neurologists agreed on what specific symptom was being referred to for only 42 (38.5%) phrases. CONCLUSIONS: To describe off periods, individuals with PD use various forms of figurative language, but this language is not uniformly interpreted and understood by specialists. Given the subjective interpretation of figurative language, exploring what patients are trying to convey when they use such language is important and could improve patient-physician communication.

The Experience of OFF Periods in Parkinson's Disease: Descriptions, Triggers, and Alleviating Factors.

PURPOSE: Wearing off of Parkinson's disease medication is common, but triggers and coping strategies for this transient phenomenon are poorly understood. We aimed to assess the lived experience of OFF periods for people with Parkinson's disease. METHODS: Participants in the longitudinal Fox Insight study who endorsed OFF periods were invited to complete a survey consisting of both multiple-choice and free-text responses. Descriptive statistics were used to summarize multiple-choice responses, and free-text responses were classified into themes through iterative discussion by 3 movement disorders specialists. RESULTS: A total of 2110 participants (52.4% male) completed the survey. Tremor was the most common description of OFF periods (n=1038, 49.2%), followed by gait changes (n=535, 25.4%) and rigidity (n=430, 20.4%). Of 1498 specific triggers for OFF symptoms, the most common was stress (n=920, 61.4%), followed by anxiety/depression (n=476, 31.8%) and tiredness/fatigue (n=351, 23.4%). Common coping strategies (n=1416 responses) included exercise (n=678, 47.9%), taking a break (n=504, 35.6%), and meditation (n=276, 19.5%). CONCLUSIONS: Although OFF periods are common, the individual experiences of OFF vary. This knowledge could be used to develop new counseling strategies for OFF periods in people with Parkinson's disease.

Genetic Testing for Parkinson Disease: Are We Ready?

PURPOSE OF REVIEW: With the advent of precision medicine and demand for genomic testing information, we may question whether it is time to offer genetic testing to our patients with Parkinson disease (PD). This review updates the current genetic landscape of PD, describes what genetic testing may offer, provides strategies for evaluating whom to test, and provides resources for the busy clinician. RECENT FINDINGS: Patients with PD and their relatives, in various settings, have expressed an interest in learning their PD genetic status; however, physicians may be hesitant to widely offer testing due to the perceived low clinical utility of PD genetic test results. The rise of clinical trials available for patients with gene-specific PD and emerging information on genotype-phenotype correlations are starting to shift this discussion about testing. SUMMARY: By learning more about the various genetic testing options for PD and utility of results for patients and their care, clinicians may become more comfortable with widespread PD genetic testing in the research and clinical setting.

The experience of care partners of patients with Parkinson's disease psychosis.

BACKGROUND: Parkinson's disease psychosis (PDP) has a major impact on quality of life and care partner burden; however, little is known about the lived experiences of care partners in managing PDP. OBJECTIVE: To understand how care partners of individuals with PDP experience their role and articulate their needs related to psychosis. METHODS: This was a qualitative study of semi-structured telephone interviews. Recruitment was conducted online via the clinical study matching tool, Fox Trial Finder; study activities took place remotely via telephone interviews. Transcripts of the phone interviews were analyzed by grounded theory methods, and a codebook of key themes that emerged from the analysis was developed. RESULTS: Nine care partners (all female) were interviewed. Discussion topics in the codebook included (1) care partner burden and guilt; (2) communication with medical professionals; (3) coping strategies; (4) emotional reactions of the care partner to psychosis; (5) sources of knowledge about PD psychosis; (6) attitudes towards medications for PDP; (7) strategies to care for loved ones with psychosis; (8) psychosis triggers. CONCLUSIONS: This qualitative analysis uncovers important aspects of the care partner experience, including challenges in navigating the medical system and communicating with professionals. Providers treating patients with PDP should be aware of these constraints and provide added support for strained care partners.

Triggers and alleviating factors for fatigue in Parkinson's disease.

BACKGROUND: Fatigue is common in Parkinson's Disease, but few effective treatments are available for it. Exploring triggers and alleviating factors, including effects of exercise, could inform development of management strategies for Parkinson's Disease fatigue. OBJECTIVES: To examine triggers and alleviating factors for fatigue reported by individuals with Parkinson's Disease, including perceived effect of exercise. METHODS: A sample of individuals with self-reported Parkinson's Disease participating in the study Fox Insight were administered an online survey. The survey included the Parkinson's Fatigue Scale, the Physical Activity Scale for the Elderly, and multiple-choice questions about triggers and alleviating factors for fatigue. RESULTS: Among the sample of 1,029 individuals with Parkinson's disease, mean (standard deviation (SD)) age was 67.4 (9.3) years, 44.0% were female. Parkinson's Fatigue Scale score ranged from 16-80, mean (SD) 48.8 (16.2). Poor sleep (62.1%) and physical exertion (45.1%) were frequently reported triggers for fatigue. Coping strategies including sitting quietly (58.1%), laying down with or without napping, and exercise (20%). Physical Activity Scale for the Elderly scores were higher in those who reported that exercise alleviated their fatigue (49.7%) compared to those who reported it worsened their fatigue (18.9%) (mean (SD) score 158.5 (88.8) vs 119.8 (66.6) respectively; p<0.001). CONCLUSIONS: Several behavioral and environmental triggers and alleviating strategies for fatigue are reported by individuals with Parkinson's disease. Many feel that exercise alleviates fatigue, though the relationship between exercise and fatigue in Parkinson's Disease appears complex. This exploratory study may inform future development of treatments or coping strategies for Parkinson's disease fatigue.

Knowledge, Responsibilities, and Peer Advice From Care Partners of Patients With Parkinson Disease Psychosis.

Introduction: Care partners (CPs) of individuals with Parkinson disease psychosis (PDP) experience increased strain and rely on informal support networks. The objective of this study was to characterize CP responsibilities, sources of support, and peer advice. Methods: This was a mixed-methods cross-sectional study. The sample was recruited from the online Fox Insight study cohort. CPs who indicated their care recipient suffered hallucinations and/or delusions were administered a questionnaire regarding their caregiving experience to person with PDP. A free-text question asked CPs to give advice to a hypothetical peer CP. Responses to multiple-choice questions were tabulated; responses to the free-text question were grouped into advice categories. Results: 145 CP of individuals with PDP were included in this analysis, mean age (standard deviation, SD) 66.4 (9.4) years; 110 (75.9%) were women. Most (115, 79.3%) provided caregiving on a daily basis, with a range of responsibilities. Only 16 (11%) learned about PDP from a physician; communication challenges included perceived embarrassment or having to prioritize other issues in a limited appointment time. The most common peer advice was to alert the care recipient's neurologist (n = 38, 30.4%); only 8 (6.4%) suggested medication changes. Conclusion: CPs face challenges with clinician communication and learn about psychosis from a variety of informal sources. Few CPs advocate for medications to control PDP, instead preferring non-pharmacological management strategies. Peer advice favored alerting the care recipient's physician, suggesting that CPs do desire more information from the medical team.

Design of a virtual longitudinal observational study in Parkinson's disease (AT-HOME PD).

OBJECTIVE: The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site-centric therapeutic trials in Parkinson's disease and generate novel insights. The value of this approach has never been more evident than during the current COVID-19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow-up of clinical trial participants, (2) compare changes in smartphone-based assessments, online patient-reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson's disease disability and progression. METHODS: Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele-Health Outcomes in Multiyear Extensions of Parkinson's Disease trials (AT-HOME PD), a two-year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone-based assessments of motor function and socialization, and patient-reported outcomes online. RESULTS: From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study's smartphone application and 161 (71%) have completed patient-reported outcomes on the online platform. INTERPRETATION: It is feasible to conduct a large-scale, international virtual observational study following the completion of participation in brick-and-mortar clinical trials in Parkinson's disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow-up of clinical trial participants and design of future clinical trials.

In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.

OBJECTIVE: The Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs). METHODS: S4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA. RESULTS: The final cohort included 59 patients with PD and 21 HCs. CSF α-synuclein was lower in patients with PD vs HCs; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2%, respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100%, respectively. There were no significant relationships between different measures of α-synuclein within participants. CONCLUSIONS: S4 confirms lower total α-synuclein levels in CSF in patients with PD compared to HCs, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within participants across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that total CSF α-synuclein does not accurately distinguish patients with PD from HCs, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.

Current and projected future economic burden of Parkinson's disease in the U.S.

Parkinson's disease (PD) is one of the world's fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey (n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson's disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.

Understanding the Lexicon of Fatigue in Parkinson's Disease.

BACKGROUND: Fatigue in Parkinson's disease (PD) is multifaceted and associated with reduced quality of life. In turn, the language used by people with PD to describe fatigue is variable and poorly understood. We sought to elucidate the lexicon of fatigue using a qualitative grounded theory approach. OBJECTIVE: The objective of this study was to understand how patients with PD describe fatigue. METHODS: A pre-study phase of online journaling (Phase 1) provided information regarding topics of importance to patients. Following this, two independent samples of fatigued subjects were studied. Individuals with PD participated in a telephone interview (Phase 2); interview transcripts were analyzed to develop a detailed codebook. To ensure trustworthiness of the findings, an online survey (Phase 3) was administered to individuals with self-reported PD participating in the online study Fox Insight. The survey included the following question: "How do you define fatigue? Please provide your definition in the space below." The codebook developed from Phase 2 was applied to the Phase 3 responses. RESULTS: Fifteen individuals participated in Phase 2 and 413 individuals completed Phase 3. Fatigue was subdivided into three domains: cognitive, emotional, and physical. Nearly all individuals experienced more than one domain of fatigue. The most common themes included tiredness, lack of energy, and negative motivation. CONCLUSION: Fatigue in PD is multidimensional. Questionnaires that only assess the physical impact of fatigue may not be adequate to capture the broad range of experiences of fatigue among people with PD.

Innovative Recruitment Strategies to Increase Diversity of Participation in Parkinson's Disease Research: The Fox Insight Cohort Experience.

BACKGROUND: Clinical research in Parkinson's disease (PD) faces practical and ethical challenges due to two interrelated problems: participant under-recruitment and lack of diversity. Fox Insight (FI) is a web-based longitudinal study collecting patient-reported outcomes and genetic data worldwide to inform therapeutic studies. FI's online platform provides an opportunity to evaluate online strategies for recruiting large, diverse research cohorts. OBJECTIVE: This project aimed to determine 1) whether FI's digital marketing was associated with increased enrollment overall and from under-represented patient groups, compared to traditional recruitment methods; 2) the clinical and demographic characteristics of samples recruited online, and 3) the cost of this online recruitment. METHOD: FI recruitment during a 6-week baseline period without digital promotion was compared to recruitment during several periods of digital outreach. Separate online recruiting intervals included general online study promotion and unique Facebook and Google ad campaigns targeting under-represented subgroups: early PD, late/advanced PD, and residents of underrepresented/rural geographic areas. RESULTS: Early PD, late PD, and geotargeting campaigns enrolled more individuals in their respective cohorts compared to baseline. All online campaigns also yielded greater total FI enrollment, attracting more participants who were non-White, Hispanic, older, female, and had lower educational attainment and income, and more medical comorbidities. Cost per new participant ranged from $21 (Facebook) to $108 (Google). CONCLUSION: Digital marketing may allow researchers to increase, accelerate, and diversify recruitment for PD clinical studies, by tailoring digital ads to target PD cohort characteristics.

The Most Bothersome Aspects of Off Periods Reported by Individuals with Parkinson's Disease.

INTRODUCTION: The off periods in Parkinson's disease have a significantly negative impact on quality of life. What the most bothersome aspects of off periods are from the patient's perspective are not well studied, nor is the degree to which screening tools for wearing off such as the Wearing Off Questionnaires (WOQs) capture what bothers patients most. METHODS: A questionnaire was deployed to eligible participants of Fox Insight, an online study of individuals with self-reported Parkinson's disease. Inclusion criteria were the use of ≥1 dopaminergic medications and an affirmative response to a question on experiencing off periods. Participants provided free-text responses regarding the top 3 most bothersome symptoms they experience when off. A determination was made regarding whether each response would have been captured by the 32-item, 19-item, and 9-item WOQs. RESULTS: The final sample had 2106 participants, a mean age of 66.6 years, 52.3% were men, and had a disease duration of 4.9 years. The WOQ-32 items covered all of the most bothersome symptoms for 53.2% of respondents. Among bothersome aspects of off not captured by the WOQs, 597 (66.2%) were specific symptoms, with freezing of gait, apathy, and memory problems being the most common. The functional consequences of off periods were most bothersome to 232 (25.7%), with walking problems being the most common. The emotional response to off periods was the most bothersome aspect to 169 respondents (18.7%). DISCUSSION: This study emphasizes the value of narrative data in understanding patient experiences, and what bothers patients most about off periods. The WOQs, although of established utility in the screening for wearing off, may not capture those symptoms most bothersome to patients.

Video research visits for atypical parkinsonian syndromes among Fox Trial Finder participants.

BACKGROUND: Use of video research visits in neurologic conditions is rising, but their utility has not been assessed in atypical parkinsonian syndromes. We sought to evaluate the diagnostic concordance between video-based vs self-reported diagnoses of multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and corticobasal syndrome. We also assessed patient satisfaction with video-based visits. METHODS: We conducted a study of video-based research visits in individuals with an atypical parkinsonian syndrome enrolled in The Michael J. Fox Foundation's Fox Trial Finder. Participants completed a recorded real-time video visit with a remote evaluator who was blinded to the participant's self-reported diagnosis. The investigator conducted a structured interview and performed standard assessments of motor function. Following the visit, the investigator selected the most likely diagnosis. The recorded visit was reviewed by a second blinded investigator who also selected the most likely diagnosis. We evaluated diagnostic concordance between the 2 independent investigators and assessed concordance between investigator consensus diagnosis and self-reported diagnosis using Cohen's kappa. We assessed participant satisfaction with a survey. RESULTS: We enrolled 45 individuals with atypical parkinsonian syndromes, and 44 completed the investigator-performed video assessment. We demonstrated excellent concordance in diagnosis between the investigators (κ = 0.83) and good reliability of self-reported diagnosis (κ = 0.73). More than 90% of participants were satisfied or very satisfied with the convenience, comfort, and overall visit. CONCLUSIONS: Video research visits are feasible and reliable in those with an atypical parkinsonian syndrome. These visits represent a promising option for reducing burden and extending the reach of clinical research to individuals with these rare and disabling conditions.

Fox Insight collects online, longitudinal patient-reported outcomes and genetic data on Parkinson's disease.

Fox Insight is an online, longitudinal health study of people with and without Parkinson's disease with targeted enrollment set to at least 125,000 individuals. Fox Insight data is a rich data set facilitating discovery, validation, and reproducibility in Parkinson's disease research. The dataset is generated through routine longitudinal assessments (health and medical questionnaires evaluated at regular cycles), one-time questionnaires about environmental exposure and healthcare preferences, and genetic data collection. Qualified Researchers can explore, analyze, and download patient-reported outcomes (PROs) data and Parkinson's disease- related genetic variants at https://foxden.michaeljfox.org. The full Fox Insight genetic data set, including approximately 600,000 single nucleotide polymorphisms (SNPs), can be requested separately with institutional review and are described outside of this data descriptor.

Comparison of an Online-Only Parkinson's Disease Research Cohort to Cohorts Assessed In Person.

BACKGROUND: Online tools for data collection could be of value in patient-oriented research. The Fox Insight (FI) study collects data online from individuals with self-reported Parkinson's disease (PD). Comparing the FI cohort to other cohorts assessed through more traditional (in-person) observational research studies would inform the representativeness and utility of FI data. OBJECTIVE: To compare self-reported demographic characteristics, symptoms, medical history, and PD medication use of the FI PD cohort to other recent observational research study cohorts assessed with in-person visits. METHODS: The FI PD cohort (n = 12,654) was compared to 3 other cohorts, selected based on data accessibility and breadth of assessments: Parkinson's Progression Markers Initiative (PPMI; PD n = 422), Parkinson's Disease Biomarker Program (PDBP; n = 700), and PD participants in the LRRK2 consortium without LRRK2 mutations (n = 508). Demographics, motor and non-motor assessments, and medications were compared across cohorts. Where available, identical items on surveys and assessments were compared; otherwise, expert opinion was used to determine comparable definitions for a given variable. RESULTS: The proportion of females was significantly higher in FI (45.56%) compared to PPMI (34.36%) and PDBP (35.71%). The FI cohort had greater educational attainment as compared to all other cohorts. Overall, prevalence of difficulties with motor experiences of daily living and non-motor symptoms in the FI cohort was similar to other cohorts, with only a few significant differences that were generally small in magnitude. Missing data were rare for the FI cohort, except on a few variables. DISCUSSION: Patterns of responses to patient-reported assessments obtained online on the PD cohort of the FI study were similar to PD cohorts assessed in-person.

Motor phenotype classification in moderate to advanced PD in BioFIND study.

BACKGROUND: Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established. METHODS: To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study. RESULTS: PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement. CONCLUSIONS: Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.