Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.

Providing genetic testing and genetic counseling for Parkinson's disease to the community.

PURPOSE: To evaluate the feasibility and impact of offering genetic testing and counseling to patients with Parkinson's disease (PD), with the potential to enroll in gene-targeted clinical trials and improve clinical care. METHODS: A multicenter, exploratory pilot study at 7 academic hospital sites in the United States tracked enrollment and randomized participants to receive results and genetic counseling at local sites or by genetic counselors, remotely. Follow-up surveys measured participant/provider satisfaction, knowledge, and psychological impact. RESULTS: From September 5, 2019 to January 4, 2021, 620 participants were enrolled and 387 completed outcome surveys. There were no significant differences in outcomes between local and remote sites, with both arms reporting high knowledge and satisfaction scores (>80%). Notably, 16% of those tested had reportable PD gene variants (pathogenic/likely pathogenic/risk allele). CONCLUSION: Local clinicians, as well as genetic counselors, with educational support as needed, can effectively return genetic results for PD as we observed favorable outcome measures in both groups. Increasing access to PD genetic testing and counseling is urgent; this can inform future efforts to integrate genetic testing and counseling into clinical care for all those with PD.

The Role of Genetic Testing for Parkinson's Disease.

PURPOSE OF REVIEW: To describe current practices and attitudes about genetic testing for Parkinson's disease (PD) among neurologists, highlight the changing scene of genetic testing for PD, and provide guidance on facilitating PD genetic testing in a clinical practice. RECENT FINDINGS: Since the 1990s, researchers have discovered several major gene variants contributing to PD etiology. A large body of literature now exists supporting the frequency of these variants in different populations and their effects on phenotype and clinical course. Recently, clinical trials have emerged with therapies targeting genetic forms of PD, specifically LRRK2 and GBA. Despite this growing knowledge, genetic testing for PD is not typically offered by neurologists including movement disorder specialists. Neurologists express concerns about the financial and practical issues of genetic testing as well as the potential impact on their patients. Researchers and specialists in the field are questioning this hesitation as clinical utility and consumer demand increase. Consideration of genetic testing for PD is shifting, as we enter a new era of precision medicine and gain clinical knowledge about PD. Barriers to testing, as perceived by clinicians, can be overcome with education, support, and involvement of multiple stakeholders with the goal of making PD genetic testing accessible to all patients.

Correction: Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.

PURPOSE: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD. METHODS: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD. RESULTS: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants. CONCLUSIONS: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.

Congenital extrahepatic portosystemic shunt with progressive myelopathy and encephalopathy.

Portosystemic encephalopathy commonly occurs in patients with portal hypertension caused by end-stage liver disease or portal vein thrombosis. Congenital extrahepatic portosystemic shunt (CEPS) is an underdiagnosed and treatable condition that can cause encephalopathy and various neuropsychiatric symptoms. We report an unusual case of type 2 CEPS in a 29-year-old woman who presented with progressive myelopathy and fluctuating encephalopathy on a background of congenital cardiac disease. Investigations showed hyperammonaemia, and despite no evidence of portal hypertension on ultrasound imaging, CT scan of abdomen showed a shunt between the mesenteric and left internal iliac veins. Patients with unexplained fluctuating or progressive neuropsychiatric symptoms should have their serum ammonia checked. A raised serum ammonia concentration without known portal hypertension should prompt further investigations for extrahepatic shunts.

Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features.

OBJECTIVE: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. METHODS: BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. RESULTS: CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid1-42 was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha-synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha-synuclein correlated with beta-amyloid1-42 , total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001). CONCLUSION: Lower CSF alpha-synuclein is associated with diagnosis and motor phenotype in moderate-advanced PD. Plasma and saliva alpha-synuclein neither correlate with CSF alpha-synuclein, nor distinguish PD from controls. CSF beta-amyloid1-42 remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.

A critical obstacle to developing effective medications to prevent and/or treat alcohol use disorders is the lack of specific knowledge regarding the plethora of molecular targets and mechanisms underlying alcohol (ethanol) action in the brain. To identify the role of individual receptor subunits in ethanol-induced behaviors, we developed a novel class of ultra-sensitive ethanol receptors (USERs) that allow activation of a single receptor subunit population sensitized to extremely low ethanol concentrations. USERs were created by mutating as few as four residues in the extracellular loop 2 region of glycine receptors (GlyRs) or γ-aminobutyric acid type A receptors (GABA(A)Rs), which are implicated in causing many behavioral effects linked to ethanol abuse. USERs, expressed in Xenopus oocytes and tested using two-electrode voltage clamp, demonstrated an increase in ethanol sensitivity of 100-fold over wild-type receptors by significantly decreasing the threshold and increasing the magnitude of ethanol response, without altering general receptor properties including sensitivity to the neurosteroid, allopregnanolone. These profound changes in ethanol sensitivity were observed across multiple subunits of GlyRs and GABA(A)Rs. Collectively, our studies set the stage for using USER technology in genetically engineered animals as a unique tool to increase understanding of the neurobiological basis of the behavioral effects of ethanol.

Participant-reported personal utility of genetic testing for Parkinson's disease and interest in clinical trial participation.

Genetic testing for Parkinson's disease (PD) is infrequently performed due to perceptions of low utility. We investigated the personal utility in PD GENEration and how results lead to enrollment in additional research studies. Participants (n = 972) underwent genetic testing, results disclosure, genetic counseling, and completed a survey examining the perceived personal utility of their results and interest in participating in additional studies. Most participants found their genetic test results useful, including satisfying curiosity (81%), feeling good about helping the medical community (80%), and having information to share with family (77%). There were no significant differences in responses based on result type. Forty-five percent of participants expressed interest in participating in research studies; whereas 16% of participants confirmed enrollment. Our results suggest that participants find personal utility in genetic testing regardless of results. Although participants may be interested in enrolling in additional research, they may need support and resources.

Improving Parkinson's Disease Care through Systematic Screening for Depression.

BACKGROUND: Depression is common in Parkinson's disease (PD) but is underrecognized clinically. Although systematic screening is a recommended strategy to improve depression recognition in primary care practice, it has not been widely used in PD care. METHODS: The 15-item Geriatric Depression Scale (GDS-15) was implemented at 5 movement disorders clinics to screen PD patients. Sites developed processes suited to their clinical workflow. Qualitative interviews with clinicians and patients provided information on feasibility, acceptability, and perceived utility. RESULTS: Prior to implementation, depression screening was recorded in 12% using a formal instrument; 64% were screened informally by clinical interview, and no screening was recorded in 24%. Of 1406 patients seen for follow-up care during the implementation period, 88% were screened, 59% using the GDS-15 (self-administered in 51% and interviewer administered in 8%), a nearly 5-fold increase in formal screening. Lack of clinician or staff time and inability to provide the GDS-15 to the patient ahead of the visit were the most commonly cited reasons for lack of screening using the GDS-15; 378 (45%) patients completing the GDS-15 screened positive for depression, and 137 were enrolled for a 12-month prospective follow-up. Mean GDS-15 scores improved from 8.8 to 7.0 (P < 0.0001) and the 39-item Parkinson's Disease Questionnaire emotional subscore from 42.2 to 36.7 (P = 0.0007). CONCLUSIONS: Depression screening in PD using a formal instrument can be achieved at much higher levels than is currently practiced, but there are barriers to implementing this in clinical practice. An individual site-specific process is necessary to optimize screening rates.

Racial and Ethnic Differences in Health-Related Quality of Life for Individuals With Parkinson Disease Across Centers of Excellence.

BACKGROUND AND OBJECTIVES: Racial and ethnic minorities have been underrepresented in Parkinson disease (PD) research, limiting our understanding of treatments and outcomes across all non-White groups. The goal of this research is to investigate variability in health-related quality of life (HRQoL) and other outcomes in patients with PD across different races and ethnicities. METHODS: This was a retrospective, cross-sectional and longitudinal, cohort study of individuals evaluated at PD Centers of Excellence. A multivariable regression analysis adjusted for sex, age, disease duration, Hoehn and Yahr (H&Y) stage, comorbidities, and cognitive score was used to investigate differences between racial and ethnic groups. A multivariable regression with skewed-t errors was performed to assess the individual contribution of each variable to the association of 39-item PD Questionnaire (PDQ-39) with race and ethnicity. RESULTS: A total of 8,514 participants had at least 1 recorded visit. Most of them (90.2%) self-identified as White (n = 7,687), followed by 5.81% Hispanic (n = 495), 2% Asians (n = 170), and 1.9% African American (n = 162). After adjustment, total PDQ-39 scores were significantly higher (worse) in African Americans (28.56), Hispanics (26.62), and Asians (25.43) when compared with those in White patients (22.73, p < 0.001). This difference was also significant in most PDQ-39 subscales. In the longitudinal analysis, the inclusion of cognitive scores significantly decreased the strength of association of the PDQ-39 and race/ethnicity for minority groups. A mediation analysis demonstrated that cognition partially mediated the association between race/ethnicity and PDQ-39 scores (proportion mediated 0.251, p < 0.001). DISCUSSION: There were differences in PD outcomes across racial and ethnic groups, even after adjustment for sex, disease duration, HY stage, age, and some comorbid conditions. Most notably, there was worse HRQoL among non-White patients when compared with White patients, which was partially explained by cognitive scores. The underlying reason for these differences needs to be a focus of future research.

Association of women-specific health factors in the severity of Parkinson's disease.

Parkinson's disease (PD) is an age-related neurological disorder known for the observational differences in its risk, progression, and severity between men and women. While estrogen has been considered to be a protective factor in the development of PD, there is little known about the role that fluctuations in hormones and immune responses from sex-specific health experiences have in the disease's development and severity. We sought to identify women-specific health experiences associated with PD severity, after adjusting for known PD factors, by developing and distributing a women-specific questionnaire across the United States and creating multivariable models for PD severity. We created a questionnaire that addresses women's specific experiences and their PD clinical history and deployed it through The Parkinson's Foundation: PD Generation. To determine the association between women-specific health factors and PD severity, we constructed multivariable logistic regression models based on the MDS-UPDRS scale and the participants' questionnaire responses, genetics, and clinical data. For our initial launch in November 2021, we had 304 complete responses from PD GENEration. Univariate and multivariate logistic modeling found significant associations between major depressive disorder, perinatal depression, natural childbirth, LRRK2 genotype, B12 deficiency, total hysterectomy, and increased PD severity. This study is a nationally available questionnaire for women's health and PD. It shifts the paradigm in understanding PD etiology and acknowledging how sex-specific experiences may contribute to PD severity. In addition, the work in this study sets the foundation for future research to investigate the factors behind sex differences in PD.

Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson's disease.

The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson's disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.

Study in Parkinson's disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial.

BACKGROUND: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS: This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION: SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

The commercial genetic testing landscape for Parkinson's disease.

INTRODUCTION: There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation. METHODS: The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally. RESULTS: We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial. CONCLUSION: There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.

Personality traits of alexithymia and perfectionism in impaired awareness of hypoglycemia in adults with type 1 diabetes - An exploratory study.

OBJECTIVE: Severe hypoglycemia complicates insulin therapy for type 1 diabetes, with impaired awareness of hypoglycemia (IAH) being a major risk factor. We explored associations between the personality traits, alexithymia and perfectionism, and cognitive barriers to hypoglycemia avoidance described in IAH, and evaluated their prevalence in people with and without IAH. METHODS: Cross-sectional exploratory study. Ninety adults with type 1 diabetes, 54 hypoglycemia aware and 36 with IAH, completed validated questionnaires exploring alexithymia (Total Alexithymia Scale [TAS-20]) and perfectionism (Frost Multidimensional Perfectionism Scale [FMPS]); and cognitive barriers related to hypoglycemia avoidance (Attitudes to Awareness Questionnaire [A2A]. RESULTS: Alexithymia and perfectionism scores correlated positively with cognitive barriers associated with IAH. Specifically, alexthymia scores correlated with the 'Hyperglycaemia Avoidance Prioritised' factor (r = 0.265; p = .02, n = 77) and the 'Asymptomatic Hypoglycemia Normalised' factor (r = 0.252-0.255; p = .03, n = 77). Perfectionism scores correlated with the 'Hyperglycaemia Avoidance Prioritised' factor (r = 0.525; p < .001, n = 66). Overall, IAH participants were significantly more likely to score at the high end for alexithymia (17.6% vs. 1.9%, p = .008, n = 87) and at the extreme ends (high and low) for perfectionism (69.0% vs. 40.0%, χ2 (1) = 6.24, p = .01, n = 77). CONCLUSION: These novel data showing associations between alexithymia and perfectionism scores and maladaptive health beliefs in IAH suggest the intriguing possibility that personality traits may contribute to the risk of IAH, perhaps through their influence on incentives to avoid hypoglycemia. If confirmed, measuring such traits may help tailor early adjunctive psychological intervention to reduce hypoglycemia burden for people with IAH.

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.

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.