Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications

Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.130696

Long-term dementia prevalence in Parkinson Disease: Glass half-full?

Introduction: Dementia occurs in up to 80% of Parkinson’s disease (PD) patients long-term, but studies reporting such high rates were published years ago and had relatively small sample sizes and other limitations. Objective: To determine long-term, cumulative dementia prevalence rates in PD using data from two large, ongoing, prospective observational studies. Design: Analyses of data from the Parkinson’s Progression Markers Initiative (PPMI) and a longstanding PD research clinical core at the University of Pennsylvania (Penn). Setting: PPMI is a multi-site international study, and Penn is a single site study at a tertiary movement disorders center. Participants: PPMI enrolls de novo, untreated PD participants at baseline, and Penn enrolls a convenience cohort from a large clinical center. Methods: For PPMI a cognitive battery and MDS-UPDRS Part I are administered annually, and the site investigator assigns a cognitive diagnosis annually. At Penn a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Main Outcomes: Kaplan-Meier (KM) survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using assigned cognitive diagnosis of dementia as the primary endpoint (for both PPMI and Penn), and MoCA score <21 and MDS-UPDRS Part I cognition score ≥3 as secondary endpoints (for PPMI). In addition, cumulative dementia prevalence by PD disease duration was tabulated for each study and endpoint. Results: For the PPMI cohort, 417 PD participants were seen at baseline; estimated cumulative probability of dementia at year 10 disease duration were: 7% (site investigator diagnosis), 9% (MoCA) or 7.4% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 PD participants were followed over time, with 184 participants (47% of cohort) eventually diagnosed with dementia. The KM curve for the Penn cohort had median time to dementia diagnosis =15 years (95% CI: 13-15) disease duration; the estimated cumulative probability of dementia was 27% at year 10, 50% at year 15, and 74% at year 20. Conclusions and Relevance: Results from two large, prospective studies suggest that dementia in Parkinson disease occurs less frequently, or later in the disease course, than often-cited previous research studies have reported

Lewy Body Dementia Association\u27s Research Centers of Excellence Program: Inaugural Meeting Proceedings

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator\u27s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson\u27s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression

Background: The objective of this study was to assess neurofilament light chain as a Parkinson’s disease biomarker. Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson’s disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson’s disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results: In the Parkinson’s Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson’s disease patients (13 � 7.2 pg/mL) than in controls (12 � 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson’s disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions: Neurofilament light chain in serum samples is increased in Parkinson’s disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson’s disease severity. Although the specificity of neurofilament light chain for Parkinson’s disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson’s disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed

Motor function in Parkinson's disease and supranuclear palsy: simultaneous factor analysis of a clinical scale in several populations

BACKGROUND: In order to better understand the similarities and differences in the motor behaviour of different groups of patients, their scores on the Motor Examination section of the Unified Parkinson's Disease Rating Scale (UPDRS) were analysed simultaneously. The three groups consisted, respectively, of patients with Parkinson's disease (PD) on medication, patients with Parkinson's disease withdrawn from anti-parkinsonian medication for at least 12 hours, and patients diagnosed with a specific Parkinsonism syndrome: Progressive Supranuclear Palsy (PSP). METHODS: A total of 669 consecutively sampled patients from three separate hospital-based clinics participated (294 PD on medication; 200 PD off medication: 175 PSP). The Motor Examination section of the UPDRS was administered by neurologists at the three participating clinics. The patient scores on each item were recorded. To assess similarities and differences among the components of the UPDRS in these samples, we performed simultaneous or multigroup factor analysis on the covariance matrices of the three groups. In addition, it was investigated whether a single model for the Motor Examination section of the UPDRS could be developed which would be valid for all three groups at the same time. RESULTS: A single six-dimensional factor solution was found that fitted all groups, although this was not straightforward due to differences between the tremor-at-rest variables. The factors were identified as Tremor-at-rest, Postural Tremor, Axial Dysfunctioning, Rigidity, Left Bradykinesia and Right Bradykinesia. The analysis also pointed to a somewhat lower lateralization in bradykinesia for PSP patients. The groups differed in intensity of motor impairment, especially with respect to Tremor-at-Rest, but the overall relationships between the variables were shared by the three groups. In addition, apart from the common factor structure evidence of differences in body part-specific and motor-specific variances was found. CONCLUSION: From a clinical point of view, the analyses showed that using the Motor Examination section of the UPDRS is also appropriate for patients with PSP, because the correlational structure of the items is directly comparable to that of Parkinson's patients. Methodologically, the analysis of all groups together showed that it is possible to evaluate similarities and differences between factor structures in great detail

Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study

BACKGROUND: The pathological hallmarks of multiple system atrophy and Parkinson's disease are, respectively, misfolded-α-synuclein-laden glial cytoplasmic inclusions and Lewy bodies. CSF-soluble misfolded α-synuclein aggregates (seeds) are readily detected in people with Parkinson's disease by α-synuclein seed amplification assay (synSAA), but identification of seeds associated with multiple system atrophy for diagnostic purposes has proven elusive. We aimed to assess whether a novel synSAA could reliably distinguish seeds from Lewy bodies and glial cytoplasmic inclusions. METHODS: In this multicentre cohort study, a novel synSAA that multiplies and detects seeds by fluorescence was used to analyse masked CSF and brain samples from participants with either clinically diagnosed or pathology-confirmed multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, isolated rapid eye movement sleep behaviour disorder (IRBD), disorders that were not synucleinopathies, or healthy controls. Participants were from eight available cohorts from seven medical centres in four countries: New York Brain Bank, New York, USA (NYBB); University of Pennsylvania, Philadelphia, PA, USA (UPENN); Paracelsus-Elena-Klinik, Kassel, Germany (DeNoPa and KAMSA); Hospital Clinic Barcelona, Spain (BARMSA); Universität Tübingen, Tübingen, Germany (EKUT); Göteborgs Universitet, Göteborgs, Sweden (UGOT); and Karolinska Institutet, Stockholm, Sweden (KIMSA). Clinical cohorts were classified for expected diagnostic accuracy as either research (longitudinal follow-up visits) or real-life (single visit). Sensitivity and specificity were estimated according to pathological (gold standard) and clinical (reference standard) diagnoses. FINDINGS: In 23 brain samples (from the NYBB cohort), those containing Lewy bodies were synSAA-positive and produced high fluorescence amplification patterns (defined as type 1); those containing glial cytoplasmic inclusions were synSAA-positive and produced intermediate fluorescence (defined as type 2); and those without α-synuclein pathology produced below-threshold fluorescence and were synSAA-negative. In 21 pathology-confirmed CSF samples (from the UPENN cohort), those with Lewy bodies were synSAA-positive type 1; those with glial cytoplasmic inclusions were synSAA-positive type 2; and those with four-repeat tauopathy were synSAA-negative. In the DeNoPa research cohort (which had no samples from people with multiple system atrophy), the novel synSAA had sensitivities of 95% (95% CI 88–99) for 80 participants with Parkinson's disease and 95% (76–100) for 21 participants with IRBD, and a specificity of 95% (86–99) for 60 healthy controls. Overall (combining BARMSA, EKUT, KAMSA, UGOT, and KIMSA cohorts that were enriched for cases of multiple system atrophy), the novel synSAA had 87% sensitivity for multiple system atrophy (95% CI 80–93) and specificity for type 2 seeds was 77% (67–85). For participants with multiple system atrophy just in research cohorts (BARMSA and EKUT), the novel synSAA had a sensitivity of 84% (95% CI 71–92) and a specificity for type 2 seeds of 87% (74–95), whereas cases from real-life cohorts (KAMSA, KIMSA, and UGOT) had a sensitivity of 91% (95% CI 80–97) but a decreased specificity for type 2 seeds of 68% (53–81). INTERPRETATION: The novel synSAA produced amplification patterns that enabled the identification of underlying α-synuclein pathology, showing two levels of fluorescence that corresponded with different pathological hallmarks of synucleinopathy. The synSAA might be useful for early diagnosis of synucleinopathies in clinical trials, and potentially for clinical use, but additional formal validation work is needed. FUNDING: Michael J Fox Foundation for Parkinson's Research, Amprion

Assessment of heterogeneity amongaAssessment of Heterogeneity Among Participants in the Parkinson’s Progression Markers Initiative Cohort Using α-Synuclein Seed Amplification: A Cross-Sectional Study participants in the Parkinson\u27s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson\u27s disease from healthy controls. We used the well characterised, multicentre Parkinson\u27s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson\u27s disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson\u27s disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson\u27s disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson\u27s disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson\u27s disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson\u27s disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson\u27s disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson\u27s disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson\u27s disease. Our results show that the assay classifies people with Parkinson\u27s disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson\u27s disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinson\u27s Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson\u27s, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity

Accelerating Parkinson’s Disease drug development with federated learning approaches

\ua9 The Author(s) 2024.Parkinson’s Disease is a progressive neurodegenerative disorder afflicting almost 12 million people. Increased understanding of its complex and heterogenous disease pathology, etiology and symptom manifestations has resulted in the need to design, capture and interrogate substantial clinical datasets. Herein we advocate how advances in the deployment of artificial intelligence models for Federated Data Analysis and Federated Learning can help spearhead coordinated and sustainable approaches to address this grand challenge

Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease

Objective: To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design: Cross-sectional observational study. Setting: Thirteen movement disorders centers. Participants: Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures: LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results: Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). Conclusion: Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course