The role of circulating branched-chain amino acids (BCAAs) in Parkinson’s disease (PD) remains unclear. We investigated the association between plasma BCAAs and incident PD and characterized their prediagnostic patterns and related biological signatures in 374,751 UK Biobank participants free of PD and other neurodegenerative diseases at baseline. Cox proportional hazards models were used to estimate associations of total BCAAs, leucine, isoleucine, and valine with incident PD. Restricted cubic splines assessed dose-response relationships, and LOESS smoothing modeled control-standardized pseudotemporal patterns of baseline BCAA levels according to time to PD diagnosis. Fully adjusted linear regression models evaluated associations of BCAAs with PD-related plasma protein biomarkers, PhenoAge acceleration, and diffusion MRI-derived white matter microstructure. Higher circulating levels of total BCAAs, leucine, and valine were associated with lower incident PD risk, with approximately linear inverse dose-response relationships. Baseline BCAA levels were lower among participants assessed at time points closer to subsequent PD diagnosis. Higher BCAA levels were also associated with lower PhenoAge acceleration, lower GFAP and NEFL levels, and more favorable white matter microstructural profiles. These findings suggest that altered BCAA metabolism may represent a prediagnostic metabolic feature of PD and support further investigation of its biological and translational relevance.
Dopamine (DA) cell replacement remains a promising therapeutic for Parkinson’s disease; however, mechanisms underlying graft-induced dyskinesias (GID) remain unclear/controversial. To understand potential genetic contributions, we have been investigating a single nucleotide polymorphism, rs6265, found in the brain-derived neurotrophic factor (BDNF) gene, which results in decreased BDNF release. Using a CRISPR knock-in rat model, we first reported that parkinsonian rs6265 rats engrafted with wild-type (WT) primary DA neurons uniquely developed GID compared to WT counterparts. Based on its importance for DA neuron maturation/function, we hypothesized that “replenishing” BDNF in rs6265-carriers would ameliorate GID. Unexpectedly, BDNF supplementation exacerbated GID, with evidence suggesting that a maintained immature DA/glutamate co-expression phenotype and/or excess DA release through a novel mechanism, vesicular synergy, contributes to GID expression. Our findings are supported by clinical data and reveal novel mechanisms related to an individual’s genetic profile that may be important to consider in ongoing cell transplantation clinical trials.
Posterior cortical impairments in visuospatial/perceptual function are common non-motor symptoms of the Lewy Body Dementias (LBD) and are relatively specific for LBDs compared to other dementias. Across populations, cognitive impairments correlate with the presence of α-synuclein (α-syn) pathology in limbic and neocortical brain regions. However, the specific role that α-syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing α-syn pathology in primary visual cortex (V1) in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this, we injected α-syn pre-formed fibrils (PFF) into V1, causing the formation of sparse Lewy-like pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified α-syn pathology using C05-05, a fluorescent ligand that binds aggregated α-syn. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4–5 months post-injection (MPI). Neurons with somatic Lewy-like inclusions showed reduced activity compared to neighboring neurons without inclusions. Conversely, neurons without somatic inclusions showed increased activity, positively correlated with the local burden of α-syn pathology. Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that α-syn pathology leads to reductions in neuronal activity in cells with somatic inclusions and reciprocal changes in local population activity but does not impair visuoperceptual function. Reflecting the early stages of neocortical α-syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and α-syn pathology across patients.
Peripheral inflammation and glymphatic system-related imaging abnormalities have been implicated in Parkinson’s disease (PD), but whether their associations with cognitive and motor manifestations differ by sex remains unclear. Using the Parkinson’s Progression Markers Initiative (PPMI) cohort, we analyzed 335 patients with PD cross-sectionally and 293 longitudinally over 5 years, and further evaluated the findings in an independent self-collected validation cohort of 159 patients with PD. Multivariable regression and linear mixed-effects models were performed, with sex-stratified and interaction analyses. In the PPMI cohort, cross-sectional analyses showed that ALPS was associated with the systemic immune-inflammation index, whereas a higher neutrophil-to-lymphocyte ratio was associated with lower delayed verbal memory performance. In females, ALPS was associated with multiple inflammatory markers, whereas in males ALPS was associated with motor severity; a significant FWF × sex interaction was observed for visuospatial performance. Longitudinally, lower baseline ALPS was associated with worse motor severity across follow-up, while baseline NLR, FWF, and ALPS were associated with domain-specific cognitive trajectories. Sex-stratified longitudinal analyses showed that NLR-related visuospatial decline was more evident in males, whereas FWF-related decline in processing speed was more evident in females. In the validation cohort, the overall associations of ALPS with UPDRS-III and of FWF with MoCA were reproduced, and broader inflammation-linked imaging and clinical associations were again observed in females. These findings support sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in PD, and highlight sex as an important modifier of biomarker-clinical relationships.
Cognitive impairment profoundly affects the quality of life in patients with Parkinson’s disease (PD), yet reliable early biomarkers remain lacking. This study enrolled 234 PD patients, who were stratified into cognitive impairment (PD-CI, n = 147) and normal cognition (PD-NC, n = 87) groups based on Montreal Cognitive Assessment scores. Brain MRI volumetric data were processed using FreeSurfer, and brain charts—applied to Parkinson’s disease for the first time—were computed to quantify deviation from normative brain aging trajectories. Compared with PD-NC patients, those with PD-CI exhibited significantly increased normalized choroid plexus volume (CPV/TIV), reduced brain chart scores, and lower serum albumin levels. After adjustment for age, sex, education, disease duration, UPDRS-III, and Hoehn-Yahr stage, the choroid plexus principal component remained the only imaging component independently associated with PD-CI (OR = 4.99, 95% CI 2.39–10.41, P < 0.001), whereas the brain regional volume component was independently protective. In internally validated models (repeated cross-validation with bootstrap optimism correction), adding the choroid plexus component improved discrimination of PD-CI (optimism-corrected AUC 0.845, 95% CI 0.829–0.916), whereas the normative brain-charts index provided no additional discriminative value. These findings identify choroid plexus enlargement as a promising imaging correlate and candidate predictor of cognitive impairment in PD; the association is consistent with, but does not by itself establish, a contribution of glymphatic dysfunction, and may inform future work on early detection and intervention.
