Structural underpinnings and long-term effects of resilience in Parkinson's disease.

Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.

Educational level and its association with dopamine transporter loss in patients with Parkinson's disease.

BACKGROUND: According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD). METHODS: Dopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade). RESULTS: Only PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort. CONCLUSION: Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.

Gray Matter Volume Loss in Proposed Brain-First and Body-First Parkinson's Disease Subtypes.

BACKGROUND: α-Synuclein pathology is associated with neuronal degeneration in Parkinson's disease (PD) and considered to sequentially spread across the brain (Braak stages). According to a new hypothesis of distinct α-synuclein spreading directions based on the initial site of pathology, the "brain-first" spreading subtype would be associated with a more asymmetric cerebral and nigrostriatal pathology than the "body-first" subtype. OBJECTIVE: Here, we tested if proposed markers of brain-first PD (ie, higher dopamine transporter [DaT] asymmetry; absence of rapid eye movement sleep behavior disorder [RBD]) are associated with a greater or more asymmetric reduction in gray matter volume (GMV) in comparison to body-first PD. METHODS: Data of 255 de novo PD patients and 110 healthy controls (HCs) were retrieved from the Parkinson's Progression Markers Initiative. Structural magnetic resonance images were preprocessed, and GMVs and their hemispherical asymmetry were obtained for each of the neuropathologically defined Braak stages. Group and correlation comparisons were performed to assess differences in GMV and GMV asymmetry between PD subtypes. RESULTS: PD patients demonstrated significantly smaller bilateral GMVs compared to HCs, in a pattern denoting stage-dependent disease-related brain atrophy. However, the degree of putaminal DaT asymmetry was not associated with reduced GMV or higher GMV asymmetry. Furthermore, RBD-negative and RBD-positive patients did not demonstrate a significant difference in GMV or GMV asymmetry. CONCLUSIONS: Our findings suggest that putative brain-first and body-first patients do not present diverging brain atrophy patterns. Although certainly not disproving the brain-first/body-first spreading hypothesis, this study fails to provide evidence in support of it. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High-throughput proteomics fiber typing (ProFiT) for comprehensive characterization of single skeletal muscle fibers.

BACKGROUND: Skeletal muscles are composed of a heterogeneous collection of fiber types with different physiological adaption in response to a stimulus and disease-related conditions. Each fiber has a specific molecular expression of myosin heavy chain molecules (MyHC). So far, MyHCs are currently the best marker proteins for characterization of individual fiber types, and several proteome profiling studies have helped to dissect the molecular signature of whole muscles and individual fibers. METHODS: Herein, we describe a mass spectrometric workflow to measure skeletal muscle fiber type-specific proteomes. To bypass the limited quantities of protein in single fibers, we developed a Proteomics high-throughput fiber typing (ProFiT) approach enabling profiling of MyHC in single fibers. Aliquots of protein extracts from separated muscle fibers were subjected to capillary LC-MS gradients to profile MyHC isoforms in a 96-well format. Muscle fibers with the same MyHC protein expression were pooled and subjected to proteomic, pulsed-SILAC, and phosphoproteomic analysis. RESULTS: Our fiber type-specific quantitative proteome analysis confirmed the distribution of fiber types in the soleus muscle, substantiates metabolic adaptions in oxidative and glycolytic fibers, and highlighted significant differences between the proteomes of type IIb fibers from different muscle groups, including a differential expression of desmin and actinin-3. A detailed map of the Lys-6 incorporation rates in muscle fibers showed an increased turnover of slow fibers compared to fast fibers. In addition, labeling of mitochondrial respiratory chain complexes revealed a broad range of Lys-6 incorporation rates, depending on the localization of the subunits within distinct complexes. CONCLUSION: Overall, the ProFiT approach provides a versatile tool to rapidly characterize muscle fibers and obtain fiber-specific proteomes for different muscle groups.