大脳皮質基底核変性症

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.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primary tauopathies that are neuropathologically characterized by deposits of 4-repeat tau proteins. Both diseases lead to a progressive impairment of motor skills, balance, speech, cognition, and everyday functioning. While PSP is often associated with axially emphasized symptoms and characteristic midbrain atrophy, CBD usually presents with asymmetric frontoparietal atrophy with cortical and subcortical deficits. Due to overlapping clinical phenotypes, it is often difficult to distinguish the two diseases from other neurodegenerative diseases in everyday clinical practice. A distinction must be made between neuropathologically defined CBD and the clinical phenotype of corticobasal syndrome (CBS), which can also be caused by other pathologies, such as Alzheimer's disease. The diagnosis of PSP or CBD is made according to current clinical criteria, based on the evaluation of multiple functional domains and the severity of presenting symptoms. Disease-modifying therapies are not yet available. Treatment currently follows symptom-oriented approaches with the aim of maintaining the quality of life and independence of patients for as long as possible. This article provides an up-to-date overview of the diagnosis, clinical presentation, management strategies, and treatment options for individuals affected by PSP and CBD.

Neurodegenerative disorders are increasing in prevalence, yet disease-modifying therapies remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates tau and regulates inflammatory signaling, making it a potential therapeutic target for neurodegenerative diseases. To investigate the relevance of DYRK1A to primary tauopathies, we first evaluated DYRK1A protein levels in the superior frontal gyrus of individuals with Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. DYRK1A protein expression was significantly elevated in individuals with primary tauopathies compared with healthy controls and positively correlated with Braak stage. Conversely, DYRK1A levels inversely correlated with last Mini-Mental State Examination (MMSE) scores and brain weight, linking elevated DYRK1A expression to disease severity. We next developed DYR533, a selective, orally bioavailable, brain-penetrant small-molecule DYRK1A inhibitor with an S(35) score of 1.4 nM based on a 403-target KINOMEscan assay. Mechanistically, DYR533 prevented the autophosphorylation of newly translated DYRK1A, rendering the kinase inactive and thereby inhibiting phosphorylation of downstream substrates. We next evaluated the therapeutic efficacy of DYR533 in the PS19 mouse model of primary tauopathy, assessing tau hyperphosphorylation, neuroinflammation, motor function, and spatial cognition. DYR533 reduced tau hyperphosphorylation at threonine 217, threonine 181, and serine 396, and attenuated the expression of neuroinflammatory cytokines and chemokines implicated in disease progression. In PS19 mice, DYR533 treatment produced modest improvements on behavior. Together, these findings establish an association between elevated DYRK1A and disease severity in human primary tauopathies and demonstrate that pharmacological inhibition of DYRK1A with DYR533 reduces pathological tau phosphorylation and neuroinflammatory signaling in vivo.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative syndrome that often results from a 4-repeat tauopathy. Abnormalities on tau PET, structural MRI, and diffusion MRI (dMRI) have been observed in CBS, although no prior work has systematically compared the relative sensitivity of these modalities. In addition, the relationships between tau uptake, volume loss, and white matter degeneration remain incompletely understood. OBJECTIVE: To compare the sensitivity of tau PET, structural volume, and dMRI metrics to differentiate CBS from controls, and to characterize relationships between regional tau uptake, volume loss, and white matter tract abnormalities. METHODS: Thirty-two participants meeting criteria for possible or probable CBS and 35 healthy controls underwent standardized 3T dMRI, 18 F-flortaucipir tau PET, and detailed neurologic assessment. Diffusion data were processed using complementary diffusion tensor, free-water, and Neurite Orientation Dispersion and Density Imaging (NODDI) pipelines, with tract-level metrics extracted using the Johns Hopkins University-Eve (JHU EVE) White Matter atlas. Regional gray matter volumes and flortaucipir standardized uptake value ratios (SUVRs) were calculated. Global tau PET uptake, represented by the first principal component (PC1), was removed in a secondary tau analysis. Modality-level discrimination was assessed using area under the curve (AUC) analyses. Cross-modality relationships were evaluated using regional correlations and covariate-adjusted models comparing volume- and tau-related predictors of white matter abnormalities. RESULTS: Relative to controls, CBS showed widespread higher mean diffusivity (MD) and lower intracellular volume fraction (ICVF), especially in sensorimotor and projection white matter pathways. Structural volume reductions were most prominent in precentral cortex and subcortical regions including putamen, thalamus, and pallidum, whereas tau PET abnormalities were weaker and less spatially extensive. MD showed the strongest overall discrimination between CBS and controls, followed by ICVF, structural volume, PC1-removed tau PET, and original tau PET. In targeted sensorimotor analyses, higher DTI-MD was most strongly associated with lower gray matter volume. PC1-removed sensorimotor tau uptake was also associated with higher sensorimotor DTI-MD, whereas original tau uptake and broader cortical or subcortical tau measures were not significant predictors. CONCLUSIONS: White matter microstructural disruption is a dominant imaging signature of CBS and is more closely linked to gray matter volume loss than to measurable uptake on tau PET. dMRI, particularly MD and ICVF, may provide greatest sensitivity for detecting disease-related changes in CBS.