暂无摘要。

OBJECTIVE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD.
METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication \'off\' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence.
RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage.
CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.

Recent studies in Parkinson\'s disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson\'s Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson\'s Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine\'s role in brain network dynamics in two Parkinson\'s disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson\'s Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

暂无摘要。

The genetic architecture of Parkinson\'s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson\'s disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson\'s (STAB1, KCNA10), Alzheimer\'s (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson\'s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Pathogenic mechanisms implicated in the development of Parkinson disease (PD) are multifaceted and include alpha synuclein aggregation, oxidative stress due to generation of reactive oxygen species (ROS), mitochondrial dysfunction, apoptosis, imbalance of trace elements as well as endoplasmic reticulum stress, and inflammation. Alteration in the homeostasis of bivalent cations, such as iron, magnesium and calcium, has been implicated in the pathogenesis of PD. Low levels of magnesium have been associated with accelerated dopaminergic cell loss in animal PD models, and magnesium has been shown to have a neuroprotective effect in PD models. Evidence of a low magnesium level in the brain of PD individuals, with a low magnesium level in the diet, increasing the risk of PD, further strengthens the role of magnesium deficiency in the pathogenesis of PD. The presence of low-level magnesium in brain tissue and high level in CSF and serum support the possibility of dysfunctional magnesium transporters in PD. Indeed, variants in magnesium transport channels, such as TRPM7 and SLC41A1, have been recently detected in PD individuals. Magnesium, being an NMDA antagonist, could also have a therapeutic role in levodopa-induced dyskinesia. There are no clinical studies indicating a neuroprotective role of magnesium in PD, however, the Mediterranean diet and variants of the diet have been associated with a lower risk of PD, which may be due to the magnesium-rich constituents of the diet. Further clinical trials encompassing therapeutic models to optimize channel function, coupled with a high magnesium diet, may pave the way for promising neuroprotective intervention for PD.

Deep brain stimulation (DBS) has emerged as an important therapeutic option for several movement disorders; however, the management of acute complications, such as acute subdural hematoma (ASDH), remains challenging. This is the case of a 71-year-old woman with Parkinson\'s disease who developed ASDH 12 years after bilateral DBS placement. On admission with altered consciousness, imaging revealed significant displacement of the DBS electrodes because of the hematoma. Emergent craniotomy with endoscopic evacuation was performed with preservation of the DBS system. Postoperatively, complete evacuation of the hematoma was confirmed, and the patient experienced significant clinical improvement. ASDH causes significant electrode displacement in patients undergoing DBS. After hematoma evacuation, the electrodes were observed to return to their proper position, and the patient exhibited a favorable clinical response to stimulation. To preserve the DBS electrodes, endoscopic hematoma evacuation via a small craniotomy may be useful.

UNASSIGNED: Frozen shoulder may be an early preclinical symptom of Parkinson\'s disease (PD).
UNASSIGNED: To examine PD risk after frozen shoulder diagnosis and to evaluate this disorder as a possible manifestation of parkinsonism preceding the clinical recognition of PD and possible target for screening.
UNASSIGNED: Danish population-based medical registries were used to identify patients aged ≥40 years with a first-time frozen shoulder diagnosis (1995-2016). A comparison cohort was randomly selected from the general population matched on age and sex. To address detection bias and the specificity of frozen shoulder diagnosis, we performed a sensitivity analysis, using similar matching criteria to select a cohort of patients with back pain diagnosis. The outcome was incident PD. Cumulative incidences and adjusted hazard ratios (HRs) were estimated with 95% confidence intervals (CIs).
UNASSIGNED: We identified 37,041 individuals with frozen shoulder, 370,410 general population comparators, and 111,101 back pain comparators. The cumulative incidence of PD at 0-22 years follow-up was 1.51% in the frozen shoulder cohort, 1.03% in the general population cohort, and 1.32% in the back pain cohort. For frozen shoulder versus general population, adjusted HRs were 1.94 (CI: 1.20-3.13) at 0-1 years and 1.45 (CI: 1.24-1.70) at 0-22 years follow-up. For frozen shoulder versus back pain, adjusted HRs were 0.89 (CI: 0.54-1.46) and 1.01 (CI: 0.84-1.21), respectively.
UNASSIGNED: Patients with frozen shoulder had an increased PD risk compared with the general population, although the absolute risks were low. Frozen shoulder might sometimes represent early manifestations of PD. Detection bias probably cannot account for the increased PD risk during the long-term follow-up.