進行性核上性麻痺

BACKGROUND: The relative value of nigrostriatal volumetry, quantitative T1 relaxation, and multicompartment diffusion MRI in neurodegenerative Parkinson syndromes is unclear. OBJECTIVES: To compare quantitative T1 relaxation and diffusion microstructure imaging-derived free fluid fraction (V-CSF) in the putamen and substantia nigra, together with putaminal volume, across Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls. METHODS: We retrospectively studied 178 participants, including 59 individuals with Parkinson's disease, 30 with MSA, 60 with PSP, and 29 healthy controls assessed between 2018 and 2023. Linear models adjusted for age and sex tested group differences and associations with Hoehn and Yahr stage. RESULTS: Putaminal volume and V-CSF differed across groups (both p < 0.001), whereas putaminal quantitative T1 did not (p = 0.10). Nigral V-CSF showed broader separation than nigral quantitative T1. In multiple system atrophy, lower putaminal quantitative T1 was associated with higher Hoehn and Yahr stage (p = 0.028). CONCLUSIONS: Diffusion-derived free fluid and volumetry captured neurodegeneration more consistently than quantitative T1.

Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.

We conducted a systematic review and meta-analysis of associations between apolipoprotein E (APOE) alleles and frontotemporal lobar degeneration (FTLD)-spectrum disorders. MEDLINE, Embase, CENTRAL, and Google Scholar were searched. APOE2 and APOE4 carrier status were compared between FTLD-spectrum disorders and healthy controls (HCs) or individuals with Alzheimer's disease (AD). Forty studies were included. APOE4 carriage was more frequent in frontotemporal dementia (FTD) compared with HC (OR = 1.72; 95% CI = 1.45-2.04) and less common than in AD (OR = 0.35; 95% CI = 0.29-0.42). In contrast, APOE2 carriage was less prevalent in FTD relative to HC (OR = 0.83; 95% CI = 0.70-0.98) but more frequent compared with AD (OR = 1.80; 95% CI = 1.29-2.52). APOE4 effects were most pronounced in behavioral variant FTD. In clinically confirmed progressive supranuclear palsy (PSP), APOE4 carriage was not associated with PSP. Analysis restricted to pathologically confirmed PSP cases, however, showed lower APOE4 carriage in PSP than in healthy controls (OR = 0.78, 95% CI = 0.65-0.94), although this association failed to reach the multiplicity-adjusted significance threshold. APOE2 carriage was not associated with PSP in either clinically established or pathologically confirmed samples. Evidence was insufficient to establish or exclude associations for other FTLD-spectrum disorders because of the limited available data. In conclusion, APOE alleles show distinct associations across the FTLD spectrum.

BACKGROUND: Distinguishing Parkinson's disease (PD) from progressive supranuclear palsy (PSP) remains challenging, particularly in early disease stages. Although axial motor impairment is typically more prominent in PSP and tremor in PD, the relative distribution of these motor domains has not been systematically quantified. OBJECTIVE: To evaluate whether the imbalance between axial and tremor-related motor features may aid in distinguishing PSP from PD. METHODS: We conducted a retrospective cross-sectional study including 533 patients with PD and 48 patients with PSP evaluated at a tertiary movement disorders center. Motor symptoms were assessed using the MDS-UPDRS part III in the OFF-medication state. Axial motor impairment was quantified using an axial core score, and tremor burden using rest tremor and total tremor scores. Derived ratios, particularly the axial/rest tremor ratio, were calculated. A PD cohort matched for age and disease duration was constructed, and receiver operating characteristic (ROC) analyses were performed. RESULTS: Across the overall, matched, and short-disease-duration cohorts, PSP patients showed consistently greater axial motor impairment and lower tremor burden than PD patients. In the matched cohort, the axial/rest tremor ratio showed the numerically highest AUC among the evaluated motor measures (AUC 0.909, 95% CI 0.869-0.944). A cut-off of ≥ 4.57 yielded 89.4% sensitivity and 79.0% specificity. Sensitivity analyses using alternative pseudocounts yielded similar AUCs, although the optimal numerical threshold varied. CONCLUSIONS: The axial/rest tremor ratio, derived from routine MDS-UPDRS part III examination, may serve as a simple and clinically accessible adjunctive marker for distinguishing PSP from PD.