Ryota Kobayashi

PURPOSE: Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer's disease (AD) brain tissue; however, their spatiotemporal dynamics in vivo remain poorly understood. This multicenter study aimed to investigate the progression of astrocyte reactivity across the AD continuum, including healthy controls (HC), mild cognitive impairment (MCI), and AD, using the novel monoamine oxidase B (MAO-B)-specific PET tracer [18F]SMBT-1, while exploring its association with cognitive performance and amyloid burden. METHODS: A total of 91 participants (35 HC, 44 MCI, 12 AD) underwent [18F]SMBT-1 PET, amyloid PET, T1-weighted MRI, and standardized neuropsychological assessments. Standardized uptake value ratios (SUVRs) were calculated based on [18F]SMBT-1 PET data using four reference regions for subgroup comparisons stratified by Aβ status. RESULTS: [18F]SMBT-1 uptake was significantly elevated in amyloid-positive MCI (MCI+) and AD groups compared with amyloid-negative HC (HC-) in the frontal, temporal, and posterior cingulate regions. Notably, astrogliosis patterns distinguished MCI subtypes: MCI+ individuals exhibited a widespread AD-like pattern, whereas the MCI- group showed a distinct profile. Furthermore, the uptake in symptomatic MCI+ individuals was significantly higher than that in asymptomatic HC+ individuals. Regional SMBT-1 uptake also strongly correlated with greater Aβ burden and worse cognitive scores. CONCLUSION: This study demonstrates that [18F]SMBT-1 is a promising tool for characterizing the spatial pattern and magnitude of reactive astrogliosis across the Aβ-defined AD continuum. Our findings further suggest that astrogliosis may represent an important mechanistic link between amyloid pathology and cognitive impairment, supporting its potential relevance in therapeutic development. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs031210602, registered Feb. 07, 2022. URL FOR THE TRIAL REGISTRY: https://jrct.mhlw.go.jp/en-latest-detail/jRCTs031210602 .

Few studies have longitudinally evaluated Hashimoto's encephalopathy with anti-NH2-terminal α-enolase (anti-NAE) antibodies using detailed imaging and neuropsychological assessments. We present the case of a man in his 50s who presented with acute hallucinations, catatonia, seizures, and cognitive decline. Initial MRI revealed diffuse white matter hyperintensities, and SPECT revealed widespread hypoperfusion. These symptoms improved with immunotherapy, but progressive frontal and temporal atrophy and residual hypoperfusion appeared over 33 months. His cognitive function improved, but he remained impaired, with persistent disinhibition and perseveration. This case suggests that Hashimoto's encephalopathy with anti-NAE antibodies can cause lasting structural and functional brain abnormalities and cognitive impairments, requiring long-term neuroimaging and neuropsychological follow-up.

Frontotemporal lobar degeneration (FTLD) encompasses frontotemporal dementia and related neurological disorders including motor neuron disease and movement disorders. During the 21th century, analyses of aggregative proteins suggested powerful hypotheses of gain-of-neurotoxicity or loss-of-function for aggregation-related proteins. However, recent translational researches in collaboration of basic studies and human pathology indicate that FTLD arises from more complex molecular mechanisms than dyshomeostasis of single molecules. Additionally, accumulation of clinicopathological evidences from various countries, genetic backgrounds or clinical specialties (e.g. neurology and psychiatry), suggests diverse phenotypes of FTLD, which are indicative of future paradigm-shift in the concept of FTLD. In this paper, we discuss FTLD pathomechanism on the basis of human pathology.