Kuwabara, Satoshi

Background The purpose of this study was to clarify the usefulness of the ‘hot cross bun’ sign (HCBS) as a diagnostic imaging marker in a large cohort of patients with multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Methods This multicentre study included 97 patients with neuropathologically confirmed MSA, and 105 patients with genetically confirmed SCA. Neuroimaging features, including HCBS and middle cerebellar peduncle (MCP) hyperintensities, were assessed. HCBS was graded from 0 to 2: 0, none; 1, only a vertical hyperintense line; and 2, a cruciform hyperintense line. The neuropathological correlates of HCBS were evaluated in 15 patients with MSA with ≤3 months between MRI and autopsy. Results In patients with a disease duration <3 years, grade 1 or 2 HCBS was detected in 100% patients with MSA with predominant cerebellar ataxia (MSA-C) and 39.0% with SCA; whereas grade 2 HCBS was observed in 50% with MSA-C and 2.4% with SCA. Moreover, the coexistence of grade 2 HCBS and MCP hyperintensities exhibited a specificity of 100%. A neuropathological assessment revealed myelin loss, alpha-synuclein aggregates and astrocytic reaction in the MCP, transverse fibres, central zone between longitudinal fasciculi and raphe nucleus, with relative preservation in the longitudinal fasciculi and medial lemniscus in patients with MSA and grade 2 HCBS. Conclusions Grade 1 or 2 HCBS is a highly sensitive finding in patients with MSA-C, and the observation of grade 2 HCBS within 3 years of motor symptom onset has excellent specificity for discriminating MSA-C from SCA, especially when accompanied by MCP hyperintensities.

Abstract To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European, and North American samples. In the GWAS stage, rs2303744 on chromosome 19 showed a suggestive association (P = 6.5 × 10− 7) that was replicated in additional Japanese samples (P = 2.9 × 10− 6, odds ratio (OR) = 1.58; 95% confidence interval (CI), 1.30–1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P = 5.0 × 10− 15, OR = 1.49; 95% CI 1.35–1.65). The association of rs2303744 with MSA remained significant in combined European/North American samples (P = 0.017, OR = 1.12; 95% CI 1.02–1.23) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform, and may perturb membrane phospholipids and promote oligodendroglial pathology.

AbstractBackground[11C]pyridinyl‐butadienyl‐benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP.ObjectivesTo explore the usefulness of [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients.MethodsWe assessed 13 PSP patients and 13 age‐matched healthy control subjects. Individuals negative for amyloid β PET with [11C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET.ResultsThere were significant differences in binding potential for [11C]pyridinyl‐butadienyl‐benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11C]pyridinyl‐butadienyl‐benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11C]pyridinyl‐butadienyl‐benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl‐butadienyl‐benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues.ConclusionsOur findings support the in vivo detectability of tau fibrils characteristic of PSP by [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET potentially provides a neuroimaging‐based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.