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ObjectiveTo identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc).MethodsWe performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases.ResultsWe identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60–61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan.ConclusionsWe identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

Purpose Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is an indispensable method for investigating Parkinson’s disease (PD). However, it comprises several confounding factors for consideration in a multicentre study. We aimed to assess the impact of the harmonization of multisite data on the differentiation between patients with PD and healthy elderlies in this multicentre cohort study. Methods We acquired a specific binding ratio (SBR)s of DAT-SPECT in 72 healthy elderlies (HCs) and 81 patients with PD (PDs). We assessed the effects of the following correction method for SBR: age and sex correction, correction for scanner differences by phantom scanning (phantom correction), a standardized operation for SBR computation (operation standardization), and a data-driven statistical method. We investigated the changes in the SBR and area under the receiver operating characteristic curve (ROC-AUC) for PD diagnostic accuracy. Results Without correction, the SBR yielded fair discrimination of PDs and HCs (Hedge’s g = 2.82 and ROC-AUC = 0.926). Age-sex correction exerted a moderate effect (g = 2.76 and ROC-AUC = 0.936). Of the multisite harmonization methods, the combination of phantom and operation correction displayed the largest changes (g = 4.32, ROC-AUC = 0.992), followed by data-driven correction (g = 3.99, ROC-AUC = 0.987). Conclusions Our findings demonstrated the usefulness of the multisite harmonization of DAT-SPECT in a multicentre cohort. Prospective correction with phantom scanning and operation standardization was ideal for the robustness and interpretability of the corrected values. The data-driven correction was another powerful method; however, the corrected value requires cautious interpretation.