大脳皮質基底核変性症

Background/Objectives: The use of quantitative neuroimaging to establish objective biomarkers in neurodegenerative diseases (NDD) has attracted increasing interest over the last decade. Advanced magnetic resonance imaging (MRI) such as arterial spin labeling (ASL) and diffusion tensor imaging (DTI), as well as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET), could provide clinically meaningful biomarkers and may support differential diagnosis. The aim of this investigator-initiated, single-center, retrospective comparative study was to implement a framework for multimodal neuroimaging to evaluate cases with rare NDD, using a methodological approach that integrates metabolic, perfusion, and microstructural parameters from simultaneous FDG-PET/MRI, and to investigate its potential to facilitate diagnosis. Methods: Three patients with pathological motor signs (1f/2m; 63, 73, and 52 years) and 19 control subjects with subjective cognitive deficits (SCDs) underwent combined FDG-PET/MRI with pseudo-continuous ASL and DTI. Standardized uptake values (SUVs), relative cerebral blood flow (rCBF), and fractional anisotropy (FA) were calculated to identify pattern alterations in individual patients based on parameterization mapping. The final diagnosis was corticobasal degeneration (CBD, n = 1) or primary lateral sclerosis (PLS, n = 2). Results: At the individual patient level, disease-specific changes in defined brain regions could be demonstrated and quantified compared to control subjects. All three patients showed significantly decreased FA, primarily along parts of the course of the corticospinal tract (CST). In the patient with CBD, asymmetric SUVR and rCBF decreases were observed, mostly overlapping with motor regions. In the two patients with PLS, SUVR revealed mostly unspecific findings (hypothetically due to a slow progression rate or due to potentially early disease stages), while ASL indicated decreased rCBF primarily overlapping within the motor cortex. Changes at the gray matter level were primarily located adjacent to changes in white matter, as indicated by the multimodal analysis approach using simultaneously acquired FDG-PET/MRI data. Conclusions: According to this proof-of-concept study, multimodal neuroimaging by the combination of quantitative MRI and FDG-PET has the potential to guide differential diagnosis in rare NDDs, especially if clinical diagnosis is not straightforward to achieve. Since particularly early diagnosis remains essential for patient counseling, effective treatment, and clinical management, the present framework appears helpful to be developed further until it aligns and integrates with clinical routine.

BACKGROUND: Blood-based biomarkers are increasingly recognized as promising tools for the diagnosis and monitoring of neurodegenerative diseases, offering a minimally invasive alternative to cerebrospinal fluid (CSF) testing. We evaluated the analytical performance and clinical utility of the Olink Target 48 Neurodegeneration panel, a novel multiplex proteomic platform based on the proximity extension assay (PEA) technology, in a large, clinically diverse dementia cohort. METHODS: We retrospectively analyzed plasma samples from 238 patients with Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, along with 65 healthy controls, quantifying 41 proteins in each sample. We assessed analytical performance using intra- and inter-assay coefficients of variation, evaluated diagnostic accuracy through receiver operating characteristic curve analysis, and investigated associations between biomarker levels, clinical severity measures, and pathology-specific CSF biomarkers for AD and Lewy body pathology (LBP) using general linear models. RESULTS: The platform quantified 32 proteins with variable analytical performance; nine were excluded due to poor detectability. Strong correlations were observed between PEA-based measurements and established immunoassays for plasma pTau217, NEFL, and GFAP (all p < 0.001). Plasma pTau217 demonstrated superior diagnostic accuracy for AD, achieving an area under the curve (AUC) exceeding 0.91 against all comparison groups. Novel ratios combining NEFL with markers of immune function or synaptic integrity (NEFL/ITGB2, NEFL/ITGAM, NEFL/SCG2) achieved AUCs exceeding 0.93 for discriminating patients from controls, significantly outperforming NEFL alone (all p < 0.001). Thirteen proteins, spanning markers of neuroaxonal damage, myelin-associated processes, and immune function (i.e., Abeta40, Abeta42, BMP7, CLSTN3, ENO2, KLK8, MMP10, NEFL, NPTXR, OMG, RTN4R, SCG2, SDC4, all p < 0.01) showed significant independent associations with disease stage as measured by the Clinical Dementia Rating scale. Four proteins (i.e., pTau217, GFAP, SYT1, and SDC4) were significantly associated with AD pathology, while three (ENO2, ITGAM, and ITGB2) showed significant associations with LBP (all p < 0.05). CONCLUSIONS: This multiplex platform provides multiplex biomarker measurements with potential utility for AD diagnosis and disease staging across neurodegenerative disorders. These findings support further validation studies for its implementation in clinical and research settings.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease diagnosed according to its histopathologic pattern of tau proteinopathy ("tauopathy"). It is increasingly appreciated that PSP is heterogeneous in both clinical and pathological presentations. However, the prevalence of PSP subtypes, in comparison to other tauopathies, remain incompletely characterized. Here we analyzed NACC Neuropathology Data Set data aggregated from 37 U.S. Alzheimer's Disease Research Centers (ADRCs). Clinical and gold-standard neuropathologic features of autopsied participants were compared, stratifying on cognitive status at recruitment into the study. The final sample comprised 6994 individuals who were followed approximately annually for 4.0 years on average before autopsy. Among those with dementia at recruitment (n=4309), 2.9% had autopsy-confirmed corticobasal degeneration (CBD), 2.6% Pick's disease, and 4.6% PSP. By contrast, among those recruited while cognitively normal (n=1452), 0.7% had CBD, 0.1% Pick's disease, and, remarkably, 3.3% were diagnosed with PSP pathology. The relatively high frequency of PSP pathology detected among individuals recruited while cognitively normal suggests there is a subtype of PSP that is unexpectedly common in the broader population. In comparing between incident (recruited normal) and prevalent (recruited with dementia) autopsy-confirmed PSP, those with incident PSP died older (89.6 years versus 76.2 years on average). Furthermore, incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features, but more likely to have parkinsonism, compared to prevalent PSP pathology cases. In a convenience sample of autopsy-confirmed PSP from the University of Kentucky ADRC (n=23), digital pathology analyses using HALO software and AI-based analytic modules revealed that PSP tau pathology was more severe in prevalent PSP, but in the putamen, incident cases had a higher proportion of tufted astrocytes and lower proportion of NFTs. In summary, incident PSP pathology is a relatively common tauopathy in older ADRC participants, often differing clinically and pathologically from prevalent PSP.

We report an autopsy case of frontotemporal lobar degeneration (FTLD)-TDP type C with severe striatal involvement and annexin A11- and phosphorylated TDP-43-positive glial cytoplasmic inclusions. The patient developed progressive asymmetric rigidity accompanied by marked striatal atrophy and showed both upper and lower motor neuron involvement. These findings expand the clinicopathological spectrum of FTLD-TDP type C and may support the concept of an annexin A11-associated pathogenic continuum linking FTLD and amyotrophic lateral sclerosis.