NPJ Parkinson's Disease最新文献

Sensing-based deep brain stimulation should optimally consider both the motor and neuropsychiatric domain to maximize quality of life of Parkinson’s disease (PD) patients. Here we characterize the neurophysiological properties of the subthalamic nucleus (STN) in 69 PD patients using a newly established neurophysiological gradient metric and contextualize it with motor symptoms and apathy. We could evidence a STN power gradient that holds most of the spectral information between 5 and 30 Hz spanning along the dorsal-ventral axis. It shows elevated power in the sub-beta range (8-12 Hz) toward the ventral STN, and elevated dorsal beta power (16–24 Hz) indicative for the hemispheres contralateral to the more affected hemi-body side. The rigidity response to DBS was highest dorsally on the axis. Importantly, apathetic symptoms can be related to reduced ventral alpha power. In conclusion, the STN spectral gradient may inform about the motor and neuropsychiatric domain, supporting integrative closed-loop strategies.

Alpha-synuclein (αS) aggregation is a widely regarded hallmark of Parkinson’s disease (PD) and can be detected through synuclein amplification assays (SAA). This study investigated the association between cerebrospinal fluid (CSF) radiological measures in 41 PD patients (14 iPD, 14 GBA1-PD, 13 LRRK2-PD) and 14 age-and-sex-matched healthy controls. Quantitative measures including striatal binding ratios (SBR), whole-brain and deep gray matter volumes, neuromelanin-MRI (NM-MRI), functional connectivity (FC), and white matter (WM) diffusion-tensor imaging (DTI) were calculated. Nine LRRK2-PD patients were SAA-negative (PD-SAA−). PD-SAA+ patients showed lower whole-brain gray matter, putamenal, brainstem, and substantia nigra volumes, reduced FC in the left caudate, and lower fractional anisotropy in the left fronto-occipital fasciculus compared to PD-SAA−. Taken together, αS aggregation was observed in iPD, GBA1-PD, and 38% of LRRK2-PD patients, and this was associated with reduced regional brain volumes, altered caudal FC, and SBRs. These changes were less pronounced in PD-SAA−, possibly suggesting a milder neurodegenerative process.

The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating 17β−estradiol mediates this effect, we employ two mouse models aimed at depleting systemically circulating 17β-estradiol: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating 17β-estradiol in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of 17β-estradiol depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson’s disease.

The relationship between hearing loss (HL) and Parkinson’s disease (PD) remains unclear. Using individual-level and summary-level data from the UK Biobank and the largest genome-wide association studies, we examined this link through observational, Mendelian randomization and genetic pleiotropy analyses. Among 158,229 participants, PD risk rose with HL severity especially in elder and males, and hearing aids significantly reduced PD risk in males. Although our results did not support a causal association, genetic correlation analysis suggested a localized genetic overlap (17q21.31). We identified 1545 SNPs and 63 genes with pleiotropic effects on HL and PD, including 79 novel SNPs across 6 loci, with 3 showing strong co-localization. These loci were enriched in key tissues like brain, heart, liver and pancreas, linked to the dihydrolipoyl dehydrogenase complex pathway, and targeted by drugs such as Warfarin and Phenprocoumon. Overall, this study reveals the risk association, genetic basis, and pleiotropic loci connecting HL and PD.

We aimed to study the effect of Parkinson’s disease (PD) and motor-cognitive load on the interplay between activation level and spatial complexity. To that end, 68 PD patients and 30 controls underwent electroencephalography (EEG) recording while executing visual single- and dual- Go/No-go tasks. The EEG underwent source localization, followed by parcellation of the neural activity into 116 regions of interest. We observed alterations in activity within a distributed network of brain areas associated with attention and inhibition operations, including a circuit pathway connecting frontal and temporal/parietal regions and the limbic network. The alterations in activity were associated with task complexity (single- or dual- task) and group (PD or controls) and encompassed spatial, temporal and spectral dimensions. These results elucidate electrophysiological alterations in four core aspects of brain activity associated with motor-cognitive function in PD patients and hold potential implications for future studies involving adaptive electrical interventions.

The switch from oxidative phosphorylation to glycolysis is crucial for microglial activation. Recent studies highlight that histone lactylation promotes macrophage homeostatic gene expression via transcriptional regulation, but its role in microglia activation in Parkinson’s disease (PD) remains unclear. Here, we demonstrated that inhibiting glycolysis with 2-deoxy-d-glucose alleviates microgliosis, neuroinflammation and dopaminergic neurons damage by reducing lactate accumulation in PD mice. Notably, we observed a marked increase in histone lactylation, particularly H3K9 lactylation, in microglia in the substantia nigra of PD mice. Mechanistically, CUT&Tag and Chip-qPCR analyses revealed that H3K9 lactylation enriched at the SLC7A11promoter and activated its expression. Importantly, inhibiting SLC7A11 by sulfasalazine mitigated microglia-mediated neuroinflammation and improved motor function in PD mice. Moreover, we found that lactate-induce histone lactylation is dependent on P300/CBP. Collectively, our findings demonstrate that glycolysis-derived lactate promotes microglial activation via histone lactylation and provide a potential therapeutic strategy for PD.

In a prospective longitudinal study with 218 Parkinson’s disease (PD) patients in the discovery cohort and 84 in the validation cohort, we aimed to identify novel blood biomarkers predicting disability milestones in PD. Through Least Absolute Shrinkage and Selection Operator-Cox (Lasso-Cox) regression, developed nomogram predictive model and Linear mixed-effects models, we identified low level of plasma fibronectin (pFN) as one of the best-performing risk markers in predicting disability milestones. A low level of pFN was associated with a short milestone-free survival period in PD. Longitudinal analysis showed an annual decline in the rate of pFN was significantly associated with the annual elevation rate in the Hoehn-Yahr stage. Moreover, pFN level was negatively correlated with phosphorylated α-synuclein, and a low level of pFN was associated with BBB disruption in the striatum on neuroimaging, providing evidence for pFN’s role in PD progression. We finally identified pFN as a novel blood biomarker that predicted first-milestone disability in PD.

α-synucleinopathies progression involves the spread of α-synuclein aggregates through the extracellular space (ECS). Single-particle tracking studies showed that α-synuclein-induced neurodegeneration increases ECS molecular diffusivity. To disentangle the consequences of neuronal loss versus α-synuclein-positive intracellular assemblies formation, we performed near-infrared single-particle tracking to characterise ECS rheology in the striatum of mouse models of α-synucleinopathies. We showed that intracellular α-synuclein assemblies, without neurodegeneration, suffice to alter nanoscale diffusion in the striatal ECS.

Oculomotor behaviour changes in patients with Parkinson’s disease (PD) are a promising source of prodromal disease markers. Capitalizing on this phenomenon to facilitate early diagnosis requires oculomotor assessment in prodromal cohorts. We examined oculomotor behaviour in non-manifesting LRRK2 G2019S mutation carriers (LRRK2-NM), who have heightened PD risk.

Seventeen LRRK2-NM participants, 47 patients with idiopathic PD, and 63 healthy age-matched control participants completed an interleaved pro- and antisaccade task while undergoing video-based eye-tracking. We analyzed between-group differences in saccade, pupil, blink, and fixation acquisition behaviour. Patients with PD showed previously demonstrated abnormalities (saccade hypometria, antisaccade errors). Relative to controls, LRRK2-NM participants and patients with PD both displayed increased short-latency prosaccades and reduced pupil velocity, plus altered fixation acquisition—less preemptive returning of gaze to the future fixation point location. Interestingly, the effect on blink probability was opposite—higher than controls in LRRK2-NM participants but lower in patients with PD. Future longitudinal studies must confirm the viability of these features as prodromal PD markers.