前頭側頭葉変性症

Frontotemporal dementia (FTD) and Lewy body dementia (LBD) are distinct neurodegenerative disorders that rarely co-occur. However, their overlapping features can obscure diagnosis and complicate management. We present the case of a 65-year-old man with a history of alcohol use disorder, diabetes, and blindness who developed acute behavioral changes, catatonia, and fluctuating mental status. He exhibited signs consistent with a behavioral variant FTD, including disinhibition, executive dysfunction, and hypersexuality, as well as features associated with LBD, including visual hallucinations, autonomic instability, and waxing-and-waning impairment in cognition. His hospital course was marked by episodic disorientation, variable language use, and persecutory delusions. Neuroimaging, cerebrospinal fluid analysis, and serial neuropsychological testing yielded mixed and inconclusive results, contributing to the diagnostic ambiguity. Treatment included lorazepam, which improved catatonic symptoms but was discontinued due to risk of delirium, and aripiprazole, which was tapered due to suspected neuroleptic sensitivity. The patient was ultimately discharged to memory care with a diagnosis of an unspecified dementia. This case underscores the challenges of diagnosing and managing patients with overlapping features of multiple neurodegenerative disorders. Recognizing points of overlap between syndromes like FTD and LBD is key to tailoring interventions and avoiding harm. Serial cognitive assessments, functional neuroimaging, and biomarker analysis may improve diagnostic accuracy, although these tools have limitations. A deeper understanding of the pathophysiology of overlapping dementia syndromes is crucial for improving diagnostic clarity and guiding treatment strategies.

BACKGROUND: Plasma phosphorylated tau (p-tau) biomarkers have improved the diagnosis of Alzheimer's disease (AD), but evidence in early-onset populations remains limited. We evaluated the diagnostic performance of plasma p-tau217 and p-tau181 levels in patients with early-onset AD (EOAD) and early-onset frontotemporal dementia (EOFTD). METHODS: We analyzed 185 patients (EOAD = 150, EOFTD = 35) aged ≤ 65 years from the LEAF study (2021-2023). Plasma p-tau217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) levels were measured by immunoassays. RESULTS: Both plasma p-tau217 (AUC = 0.831) and p-tau181 (AUC = 0.862) levels demonstrated high discriminative performance, with no significant difference between the two p-tau isoforms. P-tau levels were higher in patients with EOAD, whereas NfL levels were higher in EOFTD and were elevated in those with EOAD participants with severe hippocampal atrophy. Adding NfL, GFAP, and APOE ε4 status further improved the discriminative accuracy for differentiating EOAD from EOFTD. CONCLUSIONS: Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD. Incorporating NfL, GFAP, and APOE ε4 status further enhances diagnostic accuracy.

INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions. METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding. RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model. DISCUSSION: [18F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.

Neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial biological and clinical heterogeneity, complicating diagnosis, subtype characterization, and prediction of disease progression. We introduce PatientSpace, a multimodal graph-based latent representation framework designed to model neurodegenerative disease heterogeneity using T1-weighted MRI and FDG-PET. PatientSpace is built upon a structured variational autoencoder that integrates multimodal neuroimaging features while organizing patients within a latent space constrained by age, diagnosis, and a consistency regularization term encouraging similarity between neuroimaging phenotypes. This design enables the construction of an interpretable patient graph in which neighborhood relationships reflect biological similarity. Applied to cohorts of cognitively normal individuals, AD, and FTD patients, PatientSpace revealed multiple disease clusters associated with distinct neuroimaging patterns and clinical severity. Diagnostic classification achieved performance comparable to state-of-the-art deep learning models, while graph-based neighborhood inference enabled prediction of structural volumes, metabolic activity, and cognitive severity. Projection of mild cognitive impairment (MCI) subjects from an independent cohort further showed that cluster membership was associated with differential risks of dementia conversion and distinct longitudinal trajectories. Together, these results demonstrate that PatientSpace provides an interpretable framework linking multimodal neuroimaging representations to disease subtypes, patient-level characterization, and progression modeling in neurodegenerative disorders.

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.