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Walking speed is primarily driven by the propulsion force generated during the late stance phase, but the translation of propulsion force to walking speed may differ across individuals. This study aimed to investigate inter-individual variability in the relationship between propulsion force and walking speed in patients with subacute stroke and identify the clinical characteristics associated with this variability. Twenty-five participants with subacute stroke performed walking trials at self-selected and highest possible speeds. We applied hierarchical linear modeling, which allows the estimation of both group-level effects and individual-level variations, to determine whether adding individual’s regression coefficients for propulsion forces improved the model fit. The association between an individual’s regression coefficient and their clinical characteristics was examined using Bayesian network analysis. The results showed meaningful inter-individual variability in the effect of the propulsion force on walking speed. A probabilistic association from the Trunk Impairment Scale to the regression coefficients of paretic propulsion force ( r  = − 0.42) and another from the regression coefficients of non-paretic propulsion force to paretic propulsion force ( r  = − 0.48) were observed. Individuals with reduced trunk function may tend to rely more on paretic propulsion to maintain walking speed. These patient-specific propulsion patterns may facilitate the development of effective rehabilitation strategies.

BackgroundThe 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).MethodsThis 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.ResultsIn 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.ConclusionsGrade 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.

We have previously reported that inositol hexakisphosphate kinase (InsP 6 K)2 mediates cell death. InsP 6 K2 is abundantly expressed in anterior horn cells of the mammalian spinal cord. We investigated the role of InsP 6 K2 in spinal cords of patients with amyotrophic lateral sclerosis (ALS). Autopsy specimens of lumbar spinal cords from ten patients with sporadic ALS and five non-neurological disease patients (NNDPs) were obtained. We performed quantitative real-time PCR, immunostaining, and western blotting for InsP 6 K1, InsP 6 K2, InsP 6 K3, protein kinase B (Akt), casein kinase 2 (CK2), and 90-kDa heat-shock protein (HSP90). In contrast to InsP 6 K1 and InsP 6 K3 mRNA expression, InsP 6 K2 levels in anterior horn cells of the spinal cord were significantly increased in ALS patients compared to NNDPs. In ALS patients, InsP 6 K2 translocated from the nucleus to the cytoplasm. However, we observed a decrease in HSP90, CK2, and Akt activity in ALS patients compared to NNDPs. A previous study reported that InsP 6 K2 activity is suppressed after binding to HSP90 and subsequent phosphorylation and degradation by CK2, thus decreasing InsP 6 K2 activity. However, InsP 7 , which is generated by InsP 6 K2, can compete with Akt for PH domain binding. Consequently, InsP 7 can inhibit Akt phosphorylation. Our results suggest that InsP 6 K2 is activated in the spinal cord of patients with ALS and may play an important role in ALS by inducing cell death mechanisms via Akt, CK2, and HSP90 pathways.

Keywords: Prion, Creutzfeldt-Jakob disease, Retina, Immunohistochemistry

Supercentenarians (aged 110 years old or more) are extremely rare in the world population (the number of living supercentenarians is estimated as 47 in the world), and details about their neuropathological information are limited. Based on previous studies, centenarians (aged 100–109 years old) exhibit several types of neuropathological changes, such as Alzheimer’s disease and Lewy body disease pathology, primary age-related tauopathy, TDP-43 pathology, and hippocampal sclerosis. In the present study, we provide results from neuropathological analyses of four supercentenarian autopsy cases using conventional and immunohistochemical analysis for neurodegenerative disorders. In particular, we focused on the pathology of Alzheimer’s disease and Lewy body disease, as well as the status of hippocampal sclerosis, TDP-43 pathology, aging-related tau astrogliopathy, and cerebrovascular diseases. Three cases were characterized as an “intermediate” level of Alzheimer’s disease changes (NIA-AA guideline) and one was characterized as primary age-related tauopathy. TDP-43 deposits were present in the hippocampus in two cases. Neither Lewy body pathology nor hippocampal sclerosis was observed. Aging-related tau astrogliopathy was consistently observed, particularly in the basal forebrain. Small vessel diseases were also present, but they were relatively mild for cerebral amyloid-beta angiopathy and arteriolosclerosis. Although our study involved a small number of cases, the results provide a better understanding about human longevity. Neuropathological alterations associated with aging were mild to moderate in the supercentenarian brain, suggesting that these individuals might have some neuroprotective factors against aging. Future prospective studies and extensive molecular analyses are needed to determine the mechanisms of human longevity.

The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrPSc. Real-time quaking-induced conversion can amplify very small amounts of PrPSc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affected human brains. End-point assay using serially diluted brain homogenates of sporadic Creutzfeldt-Jakob disease patients demonstrated that 50% seeding dose (SD50) is reached approximately 10(10)/g brain (values varies 10(8.79-10.63)/g). A genetic case (GSS-P102L) yielded a similar level of seeding activity in an autopsy brain sample. The range of PrPSc concentrations in the samples, determined by dot-blot assay, was 0.6-5.4 μg/g brain; therefore, we estimated that 1 SD50 unit was equivalent to 0.06-0.27 fg of PrPSc. The SD50 values of the affected brains dropped more than three orders of magnitude after autoclaving at 121°C. This new method for quantitation of human prion activity provides a new way to reduce the risk of iatrogenic prion transmission.

Transferrin, an iron-binding protein, plays an important role in the transport and delivery of circulating ferric iron to the tissues. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of Bunina bodies, skein-like inclusions, Lewy body-like inclusions/round inclusions, and basophilic inclusions in the remaining anterior horn cells in the spinal cord. We examined transverse paraffin sections of lumbar spinal cords from 12 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibodies to human transferrin. The results demonstrated that transferrin localized in Bunina bodies and some of the basophilic inclusions. In contrast, skein-like inclusions and Lewy body-like inclusions or round inclusions did not show obviously detectable transferrin immunoreactivities. Our findings suggest that although the mechanisms underlying transferrin accumulation in Bunina bodies and basophilic inclusions are unknown, transferrin could be involved in forming these inclusions. Furthermore, following cystatin C, transferrin is the second protein that localizes in the Bunina bodies.

We report a case of acute myelitis associated with hepatitis C virus (HCV) infection. A Japanese woman developed left calf pain and weakness, but this quickly generalised to paraplegia. We diagnosed acute myelitis based on the results of clinical manifestations, an MRI examination and a cerebrospinal fluid (CSF) examination. The clinical condition and spinal cord lesions improved following intravenous administration of methylprednisolone. The patient had been diagnosed with HCV infection 11 years before the onset. We detected HCV RNA in the CSF, supporting the strong association of our patient's myelitis. However, it is difficult to conclude whether the neurological condition was caused directly by the viral load or indirectly by the immune response. We suggest that testing for HCV infection is important in patients with myelitis. In particular, anti-HCV antibody and HCV RNA should be measured in the patients’ serum as well as CSF.

A Japanese male developed deafness, pyramidal signs and ataxia at age 50. A cerebrospinal fluid examination showed elevated levels of iron, transferrin and ferritin. Brain MRI showed atrophy of the cerebellum and pons as well as potential iron deposits on the surface of the brain. At autopsy, the brain weighed 1090 g and showed severe atrophy and necrosis of the cerebellum. No vascular malformation was observed. Extensive deposits of hemosiderin that were well stained with Berlin blue and ferritin immunohistochemistry were present at the surface and in the superficial layers of the cerebrum, brainstem, cerebellum and spinal cord. In these regions, numerous AT8 (p-τ)-immunopositive deposits were present in neurons and glia. In addition, phosphorylated α-synuclein-immunopositive Lewy bodies and neurites were observed in the brainstem nuclei. In the present report, the authors derive the novel insight that superficial siderosis is a distinctive entity associated with tauopathy and synucleinopathy.

Human prion diseases are neurodegenerative disorders caused by prion protein. Although infectivity was historically detected only in the central nervous system and lymphoreticular tissues of patients with sporadic Creutzfeldt-Jakob disease, recent reports suggest that the seeding activity of Creutzfeldt-Jakob disease prions accumulates in various non-neuronal organs including the liver, kidney, and skin. Therefore, we reanalyzed autopsy samples collected from patients with sporadic and genetic human prion diseases and found that seeding activity exists in almost all digestive organs. Unexpectedly, activity in the esophagus reached a level of prion seeding activity close to that in the central nervous system in some CJD patients, indicating that the safety of endoscopic examinations should be reconsidered.