Disease‐Duration–Specific Percentiles for Prospective Subtyping of Parkinson's Disease: A PPMI‐Based Study

Evaluating the Relationship Between Early Non‐Motor Symptoms and Late Diagnosis of Parkinson's Disease Based on the PPMI Database From 2012 to 2018: A Retrospective Cross‐Sectional Study

Socio‐demographic variables, rather than individual non‐motor symptoms, demonstrate the strongest independent associations with diagnostic timing in this cohort, highlighting the need for socio‐demographically tailored screening strategies in the prodromal phase of PD.

Dystonia in Parkinson's disease: Clinical characteristics and predictors of treatment response.

BACKGROUND Dystonia causes pain and disability in Parkinson's disease (PD) but remains inadequately characterized. OBJECTIVE To characterize temporal features, somatotopic distribution, clinical correlates, and treatment response of dystonia in PD. METHODS We performed a retrospective, observational case-control study with longitudinal treatment-response assessment of patients seen between 2014 and 2025 at University of Cincinnati. Data from medical charts of individuals with PD and dystonia were compared to those without dystonia from the same source population. Clinical variables included age at PD onset, disease duration, dystonia phenotype and timing, levodopa equivalent daily dose (LEDD), Hoehn and Yahr (H&Y) stage, and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) scores. Multivariable logistic regression analyses were performed to summarize adjusted associations. RESULTS Data on 246 PD patients (164 with and 82 without dystonia) were analyzed. Focal dystonia was the predominant phenotype (75.0%), most commonly involving lower limbs, followed by cervical dystonia. Age (odds ratio [OR], 0.93; P < 0.001), disease duration (OR, 0.90; P = 0.002), and MDS-UPDRS III scores (OR, 0.96; P = 0.002) were inversely associated with dystonia, whereas advanced H&Y stage ≥3 (OR, 3.61; P = 0.002) was directly associated with it. Levodopa dose increases improved dystonia in 51.6% of patients, and botulinum neurotoxin (BoNT) improved dystonia (OR, 3.01; P = 0.05). CONCLUSION PD-associated dystonia most commonly affects lower limbs and is associated with younger age at PD onset, shorter disease duration, and milder overall motor severity of PD.

Data-Driven Biological Subtypes of Parkinson ' s Disease

The Vall d’Hebron Initiative for Parkinson (VHIP) cohort: a prospective, longitudinal, and observational study enrolling de novo Parkinson’s disease patients for biomarker identification and validation

Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing a variety of motor and non-motor symptoms. To date, no disease modifying treatment exists, and diagnosis is based on the manifestation of the clinical motor symptoms, which occurs when the neurodegenerative process is already advanced. Studies designed to find diagnostic/prognostic biomarkers and pathophysiological pathways involved in disease onset/progression are needed. Objective To describe the study protocol of the Vall d’Hebron Initiative for Parkinson (VHIP) Cohort, a prospective and longitudinal observational cohort study aimed at deeply phenotyping de novo PD patients, including carriers of PD-linked mutations. We anticipate this initiative will contribute to identifying biomarkers for PD risk, diagnosis, and prognosis, as well as to stratify disease subtypes and increase our understanding of pathophysiology at early disease stages. Methods/Design Subjects are prospectively recruited by movement disorder specialists at the Vall d’Hebron University Hospital (VHUH). To date, the study cohort includes 174 subjects—consisting of 117 patients with de novo Parkinson’s disease, 17 individuals with REM sleep behavior disorder (RBD), and 33 healthy controls—and recruitment is still ongoing. After informed consent, subjects are evaluated in detail to primarily assess objectives within four major domains of PD: motor, cognitive-affective, autonomic function, and vision. This includes first an extensive clinical evaluation (i) recording demographic, personal history, lifestyle, and dietary habits and (ii) performing clinical scales covering motor and non-motor symptoms. Second, data from autonomic function and visual function tests, together with neuroimaging data, are acquired. And finally, a wide range of biospecimens are collected for biochemical and molecular assessments including the genotyping of all participants. Participants receive follow-up assessments at 2.5 and 5-year intervals. Results/Discussion VHIP is the first study to establish a Spanish cohort combining clinical, imaging, biochemical and molecular data over time in de novo patients, including PD-linked mutation carriers. VHIP provides a unique opportunity to link pre-diagnosis disturbances to PD development, as well as to identify risk, diagnosis, and prognosis biomarkers. Clinical trial registration https://vhir.vallhebron.com/es/investigacion/proyecto-vall-dhebron-iniciativa-para-el-parkinson-vhip.

Modern Directions in Early Biomarker Diagnostics of Parkinson's Disease

Background: Parkinson’s disease (PD) is the fastest-growing neurological disorder globally. Traditional diagnosis, which relies on motor symptoms, is associated with a 15–24% error rate and occurs after significant loss of dopaminergic neurons. Early biomarker identification is essential for biological redefinition of PD and timely intervention.Objective: To synthesize evidence from the past five years on minimally invasive biomarkers and assess whether multimodal panels offer greater diagnostic precision than single tests.Methods: A systematic review of PubMed and Scopus (January 2021–January 2026) was conducted per PRISMA guidelines, including meta-analyses and original studies on α-synuclein seed amplification assays (SAA), neuronally derived extracellular vesicles (LIEVs), neurofilament light chain (NfL), and advanced imaging (OCT-A, MRI).Results: SAA exhibited 96% sensitivity in GBA1 mutation carriers and 98.6% in hyposmic individuals with dopaminergic deficits, but only 67.5% in LRRK2 carriers. Serum LIEV-associated α-synuclein distinguished prodromal cases with high precision (AUC=0.91). NfL predicted functional decline (OR=2.54) up to five years before diagnosis. Advanced neuroimaging and skin RT-QuIC tests showed diagnostic accuracies from 82% to 100%.Conclusion: PD diagnosis is shifting from clinical observation to biological profiling. Multimodal biomarker panels integrating molecular, microvascular, and imaging data provide the most precise risk stratification, enabling timely, targeted neuroprotective interventions by rehabilitation specialists.

Prospective Validation of the Movement Disorder Society Prodromal Multiple System Atrophy Criteria in Pure Autonomic Failure

Background: The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. Objective: To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods: Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson’s disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results: Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions: The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials.