Savica, Rodolfo

Background Parkinson's disease (PD) typically presents after age 60; however, approximately 10% of individuals experience early-onset PD (EOPD), with symptoms beginning between ages 21 and 50. Beyond motor and non-motor symptoms, PD can impact personal relationships through stigma, social isolation, and emotional burden. This study aims to examine the influence of PD on relationship outcomes such as divorce or separation. Methods This exploratory study analyzed data from the Fox Insight cohort, an online longitudinal research initiative supported by The Michael J. Fox Foundation. We included 470 individuals with self-reported PD who had complete data on marital status (“married” or “divorced”) and age at PD onset. Participants were categorized as having EOPD (<50 years) or late-onset PD (≥50 years). Chi-square tests assessed the association between PD onset group and marital status. A binary logistic regression model further evaluated gender and onset age as predictors of marital status in a subset of 330 participants. Results A significant association was found between PD onset group and marital status, with a higher divorce rate among the EOPD group (17.5%; 7/40) compared to late-onset PD (6.1%; 26/430) (p = 0.017). Logistic regression revealed no statistically significant predictors, though trends suggested lower odds of divorce in men and those with late-onset PD. Conclusion This exploratory analysis identified a potential association between early PD onset and higher divorce rates; however, with only 7 events in 40 EOPD participants, this finding is inherently unstable and should be regarded as hypothesis-generating only. Confirmation in larger, longitudinal cohorts is required before any conclusions can be drawn.

Abstract Cognitive impairment is among the most common non-motor symptoms in parkinsonism and Parkinson’s disease, ranging from subjective complaints to dementia. Although several predictive factors have been described, their prognostic relevance remains uncertain. This study aims to examine the predictive association between clinical features and the risk of dementia and determine the incidence of dementia in a population-based cohort of incident parkinsonism cases. Patients with parkinsonism onset between 1991 and 2020 were identified using the Rochester Epidemiology Project records-linkage system. Subjects with cognitive impairment preceding motor symptoms onset or concomitant Alzheimer’s disease were excluded. Diagnoses of dementia and mild cognitive impairment were established using neuropsychological testing or brief cognitive screening. Development of dementia was assessed using a Cox proportional hazards regression model. Associations between dementia and each risk factor were individually estimated in adjusted Cox models. All risk factors were also included in a least absolute shrinkage and selection operator (LASSO) penalized multivariable Cox model. A total of 1,104 patients were included: 153 (13.9%) developed mild cognitive impairment and 543 (49.2%) developed dementia during follow-up. The cumulative incidence of dementia was 30.3% at 5 years, 48.6% at 10 years, 61.4% at 15 years, and 69.3% at 20 years, indicating that a considerable portion of patients remained free of dementia after a prolonged follow-up. The majority of patients with dementia were males (61.5%), and older age at disease onset was associated with risk of dementia (hazard ratio [HR] = 1.32, P &lt; 0.001 per 5-year increment). In the penalized model, dementia risk was significantly higher among individuals presenting with impaired postural reflexes (HR = 1.26, P = 0.014), consistent with a poorer prognosis in akinetic-rigid-predominant parkinsonism. Eye movement abnormalities including reduced ocular range of motion (HR = 1.86, P &lt; 0.001), and smooth pursuit alterations (HR = 1.34, P = 0.024) were also associated with dementia. Non-motor symptoms, including REM sleep behavior disorder (HR = 1.51, P &lt; 0.001), orthostatic hypotension (HR = 1.30, P = 0.009), and constipation (HR = 1.24, P = 0.022), were linked to dementia risk, supporting a potential involvement of non-dopaminergic and central autonomic pathways in cognitive decline. These findings were largely confirmed in the Parkinson’s disease/Parkinson’s disease with dementia group, in which 77 (13.5%) developed mild cognitive impairment and 249 (43.5%) developed dementia. Among these patients, smooth pursuit alterations, reduced ocular range of motion, orthostatic hypotension, and constipation were associated with dementia.

Juvenile Parkinson's disease (JPD) is a rare condition characterized by the onset of parkinsonian motor symptoms before the age of 21. Sixteen patients with JPD who presented to the Mayo Clinic between 1990-2020 were included. The median age of symptoms onset was 18.5 years, and six cases had pathogenic PRKN mutations. Resting tremor was the most frequent initial symptom (81.3%), and non-motor symptoms were notably common, including mild cognitive impairment (56.3%), anxiety (62.5%), and depression (56.3%). Levodopa responsiveness was suboptimal in 9 patients and 14 exhibited motor fluctuations. JPD demonstrates distinct clinical characteristics compared with early-onset and late-onset PD.

Background Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut–brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Methods Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Results Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. Discussion These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P &amp;lt; .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.