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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Parkinson's disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [ 11 C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson's disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [ 11 C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [ 11 C](+)DTBZ to assess dopaminergic denervation and [ 11 C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [ 11 C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [ 11 C]PBB3 and [ 11 C]PBR28 binding in nigrostriatal regions. [ 11 C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [ 11 C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies., (© 2024. The Author(s).)

Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies., (© 2024. The Author(s).)

Background/objective: Multiple system atrophy (MSA) is a highly debilitating, rare neurodegenerative disorder with two clinical motor variants (parkinsonian or MSA-P and cerebellar or MSA-C). There is a wide span of motor and non-motor symptoms (NMS) that progress over time. We studied the cohort from the Catalan Multiple System Atrophy Registry (CMSAR) to determine which symptoms are most likely to progress throughout a 2-year follow-up., Methods: We analyzed baseline, 12-month, and 24-month follow-up evaluations from the 80 cases recruited by the CMSAR. Evaluations included the UMSARS assessment, cognitive and neuropsychiatric evaluations, and a non-motor scale (NMSS-PD). Statistical analysis was done using a Generalized Estimated Equations (GEE) model., Results: Both UMSARS I and II sub-scores significantly increased at 12- and 24-month follow-ups (p < 0.001), with a median total score increase of 11 and 12.5 points, respectively. Items on UMSARS I that significantly worsened were mostly motor affecting daily activities. NMS, including urinary and sexual dysfunction, as well as sleep difficulties showed a significant progression on the NMSS-PD; however, other NMS such as postural hypotension, gastrointestinal, and mood dysfunction, although prevalent, did not show a clear progression on clinical scales., Conclusion: Within 24 months and as early as 12 months, MSA cases may experience significant motor worsening, affecting basic daily activities. NMS are prevalent; however, not all clinical scales register a clear progression of symptoms, perhaps suggesting that they are not sensitive enough for non-motor evaluation.

Background and Objectives: MicroRNA (miRNA) changes are observed in PD but remain poorly explored in other α-synucleinopathies such as MSA., Methods: By genome-wide analysis we profiled microRNA expression in serum from 20 MSA cases compared to 40 controls. By qPCR we validated top differentially expressed microRNAs in another sample of 20 MSA and 20 controls. We also assessed the expression of MSA differentially expressed microRNAs in two consecutive sets of 19 and 18 PD patients., Results: In the discovery set we identified 25 differentially expressed microRNAs associated with MSA, which are related to prion disease, fatty acid metabolism, and Notch signaling. Among these, we selected nine differentially expressed microRNAs and by qPCR confirmed array findings in a second MSA sample. MicroRNA-7641 and microRNA-191 consistently differentiated between MSA and PD., Conclusions: Serum microRNA changes occur in MSA and may reflect disease-associated mechanisms. We identified two microRNAs which may differentiate MSA from PD. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C)., Objective: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes., Methods: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients., Results: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies., Conclusions: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results.

Introduction: The Child Behavior Checklist (CBCL/6-18) is the most commonly used parent-completed instrument that assesses child and adolescent psychopathology. It has been used in epidemiology and clinical studies. The last version contains DSM-oriented subscales., Objective: Investigate the psychometric properties of the CBCL/6-18 and develops a valid and reliable Mexican version., Method: Psychologists and child psychiatrists adapted the Spanish version of CBCL/6-18, and a back translation was done by a native English speaker. Discrepancies in the adaptation were solved by consensus. The checklist was applied to children in the community and to outpatients from a psychiatric children hospital. Reliability was evaluated by estimating internal consistency (Cronbach's alpha) on all scales: retest at one week was evaluated with intraclass correlation coefficients (ICC). A ROC curve was performed to estimate a cut-off which correctly identified children from the clinically referred patients and children recruited in the community (non-referred). Mean differences for the groups were calculated with the Student's t test., Results: The Mexican version of the CBCL/6-18 showed that the Cronbach's alpha coefficient was 0.90 for internalizing problems, 0.94 for externalizing problems and 0.97 for the total problem scale. The ICC was 0.97 for the total problem scale. Significant differences were found between the mean score in broad band, narrow and the new DSM/oriented scales., Conclusions: The Mexican version of CBCL/6-18 is a reliable and valid screening instrument for clinical and epidemiologic use.