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Background The importance of rehabilitation therapy in Parkinson's disease is well recognized. However, the effects of an inpatient rehabilitation program for advanced Parkinson's disease have not been fully investigated. Aim To assess the effects of intensive inpatient rehabilitation. Methods We enrolled 31 patients (mean age 69.5 ± 9.4 years; mean disease duration 8.8 ± 6.4 years) with advanced Parkinson's disease, without severe cognitive impairment. The median Hoehn-Yahr stage was IV. Patients received 2 h of individualized rehabilitation for 6-7 days each week for 1 month. At hospital discharge, patients and caregivers were instructed to continue daily exercise. Results Motor and total scores of Functional Independence Measures significantly improved between admission and discharge in patients with stage III and IV disease, but not stage V. There was no significant effect of Hoehn-Yahr stage on improvements in Unified Parkinson's Disease Rating Scale scores, (total, part I, II or III), cognitive Functional Independence Measures or Berg Balance Scale. Conclusion Intensive inpatient rehabilitation was effective even in advanced Parkinson's disease. Intensive inpatient rehabilitation, together with home and day-care exercise, might counteract the progressive motor decline in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Translocated in liposarcoma/fused in sarcoma ( TLS/ FUS) is an RNA-binding protein that regulates the splicing pattern of mRNA transcripts and is known to cause a type of familial amyotrophic lateral sclerosis ( ALS). In the absence of TLS, Mammalian enabled (Mena), an actin-regulatory protein and a target of TLS, undergoes preferential alternative splicing. In the present study, we show that the ablation of TLS dysregulates the subcellular location and functions of Mena. When TLS knockout ( KO) mouse embryonic fibroblasts ( MEFs) were transfected with wild-type Mena, it no longer accumulated at focal adhesions and peripheral structures, whereas the localization of the alternatively spliced form was maintained. Additionally, the ability of Mena to suppress the motility of cells was lost in TLS KO MEFs. Moreover, Mena failed to promote neurite outgrowth in TLS KO primary neurons. Taken together, TLS is intimately involved in the local cytoskeletal dynamics surrounding Mena in both fibroblasts and neurons. The robust change in cytoskeletal dynamics, as indicated by the dysregulation of Mena in TLS KO cells, provides a new insight into the pathogenesis of certain types of ALS. [ABSTRACT FROM AUTHOR]

Aims Among the pathological findings in Alzheimer's disease ( AD), the temporal and spatial profiles of granulovacuolar degeneration ( GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles ( NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin-1, a marker of lipid rafts, accumulates in lysosomes of tangle-bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol-4,5-bisphosphate [ Ptd Ins(4,5) P2], in AD and other neurodegenerative disorders. Methods We compared Ptd Ins(4,5) P2 immunoreactivity in the hippocampus, entorhinal cortex and neocortex of five AD cases, 17 cases of other neurodegenerative disorders and four controls. In addition, we performed double staining using markers of GVD, NFTs and lipid rafts for further characterization. Results Immunohistochemical analysis revealed that Ptd Ins(4,5) P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for Ptd Ins(4,5) P2 was also evident in NFTs composed of hyperphosphorylated tau, Ptd Ins(4,5) P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, Ptd Ins(4,5) P2 colocalized with the lipid raft markers flotillin-1 and annexin 2, within GVD bodies and NFTs. Conclusions These results suggest that lipid raft components including Ptd Ins(4,5) P2 play a role in the formation of both GVD bodies and NFTs. [ABSTRACT FROM AUTHOR]

Alpha-synuclein (αS) is one of the major constituents of Lewy bodies ( LBs). Several lines of evidence suggest that the autophagy-lysosome pathway ( ALP) is involved in the removal of αS. We have previously reported that granulovacuolar degeneration ( GVD) in neurons involved a subunit of the endosomal sorting complexes required for transport ( ESCRT). In this study, we examined the association between alpha-synucleinopathy and autophagy through immunohistochemical analysis of charged multivesicular body protein 2B ( CHMP2B), a component of the ESCRT-pathway. We examined the brainstems of 17 patients with Parkinson's disease ( PD), incidental Lewy body disease ( ILBD), multiple system atrophy ( MSA), and Alzheimer's disease ( AD) immunohistochemically using antibodies against phosphorylated αS (pαS), phosphorylated tau and CHMP2B. LBs and a proportion of glial cytoplasmic inclusions ( GCIs) were immunopositive for pαS and CHMP2B. Neurons containing CHMP2B-immunoreactive granules were detected in PD and ILBD, but not in MSA and AD brains. CHMP2B immunoreactivity was increased in the dorsal motor nucleus of the vagus nerve ( DMNX) in PD and ILBD brains, relative to that in MSA and AD. These findings indicate that the ESCRT-pathway is implicated in the formation of αS inclusions, especially in PD and ILBD. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Aim: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer-associated ischemic stroke. Methods: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into 'cancer-associated ischemic stroke,' the 'conventional ischemic stroke,' or 'other.' Results: A total of 15 patients (26%) were classified into the cancer-associated ischemic stroke in cancer patients. In univariate analysis of the cancer-associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d-dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d-dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer-associated ischemic stroke ( n = 111, χ2 = 67.21, P < 0.0001). Conclusion: In acute ischemic stroke, the cancer-associated ischemic stroke is associated with elevated d-dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). Geriatr Gerontol Int 2012; 12: 468-474. [ABSTRACT FROM AUTHOR]

Although intracellular stresses are believed to be involved in the process of neurodegeneration, it is not fully understood how one stress/stress response affects another. Herp is an endoplasmic reticulum (ER)-located membrane protein proposed to function in ER-associated degradation (ERAD). Herp is strongly induced by ER stress but rapidly degraded by proteasome. To elucidate the effect of Herp expression on proteolytic stress caused by impairment of the ubiquitin-proteasome system (UPS), we utilized 293T Herp knockdown (KD) cells and F9 Herp knockout cells. Knockdown of Herp gene unexpectedly facilitated the degradation of Parkinson’s disease-associated cytosolic proteins such as α-synuclein and its binding partner, synphilin-1, and improved cell viability during proteasomal inhibition. A similar tendency was observed in F9 Herp knockout cells transfected with synphilin-1. Herp temporarily bound to α-synuclein, synphilin-1 and the E3 ligase SIAH1a during proteolytic stress but not during ER stress. Furthermore, deletion of Herp enhanced the amount of ubiquitinated protein in the cytosol during proteasomal inhibition, although it did not affect the activity or expression of proteasome. These results suggest that ERAD molecule Herp may delay the degradation of cytosolic proteins at the ubiquitination step. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe a trigeminal neuropathy caused by the perineural spread of an amyloidoma. A 62-year-old woman had an amyloidoma of the Gasserian ganglion that was hypointense on T2-weighted images; the lesion was enhanced by gadolinium on thin-slice magnetic resonance imaging. There was no evidence of systemic amyloidosis or underlying inflammatory or neoplastic disorders. Her blink reflex and thin-slice magnetic resonance imaging demonstrated that the right trigeminal nerve was involved. A rare trigeminal neuropathy resulted from the perineural spread of a primary amyloidoma that was difficult to detect by conventional magnetic resonance imaging. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Exaggerated startle reflex is an abnormal phenomenon originating from the caudal brainstem in which unheralded sensory stimuli evoke massive, generalized motor responses. Some patients with exaggerated startle reflex are reported to fall during startle. We report a sporadic case of exaggerated startle reflex with unconscious drop attack elicited by unexpected auditory stimuli as late-onset involuntary movements. It is clinically important as one of the underlying diseases presenting unconscious drop attack, especially for older adults. [ABSTRACT FROM AUTHOR]

Keywords: area postrema; imaging; intractable hiccup and nausea; MS and Related Diseases; neuromyelitis optica spectrum disorder EN area postrema imaging intractable hiccup and nausea MS and Related Diseases neuromyelitis optica spectrum disorder 218 219 2 07/03/20 20200701 NES 200701 INTRODUCTION A 76-year-old woman was admitted with intractable hiccup and nausea (IHN) lasting for 2 weeks. Area postrema, imaging, intractable hiccup and nausea, MS and Related Diseases, neuromyelitis optica spectrum disorder. [Extracted from the article]

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia and intermittent axial myoclonus. Various mutations have been found in the PRKCG gene encoding protein kinase C γ in SCA14 families. Most of those mutations have been found in exon 4 of the PRKCG gene. We performed polymerase chain reaction (PCR)-based screening to clarify the approximate morbidity rate of the disease in the Japanese SCA population. We screened exon 4 of the PRKCG gene in 882 SCA patients with undefined etiologies using denaturing high-performance liquid chromatography and subsequent direct sequencing. We found a novel C/T missense mutation with a Ser119-to-Phe substitution (S119F) in 2 patients and subsequently found that they belonged to the same family. This S119F mutation was not found in 259 control individuals. Further PCR-based analysis revealed an additional 5 members with the same mutation in this family. Cerebellar ataxia was manifested in 5 of those 7 members. The main symptom in 4 of the 5 affected members was pure cerebellar ataxia with late onset. They had no myoclonus, extrapyramidal signs, ophthalmoplegia, or intellectual disturbance, some of which were found in previously reported SCA families. One patient showed intractable epilepsy, severe walking disturbance, and trunk ataxia with early onset. The results of this study suggest that the frequency of SCA14 in the Japanese SCA population is very low. © 2006 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract: Synphilin-1 is an α-synuclein binding protein that is involved in the pathogenesis of Parkinson’s disease. The present study investigated the phospholipid-binding capacity of Synphilin-1. The C-terminus of Synphilin-1 was found to selectively bind to acidic phospholipids, including phosphatidic acid, phosphatidylserine, and phosphatidylglycerol, but not to naturally charged phospholipids. Synphilin-1 was targeted to cytoplasmic lipid droplets in mammalian cells. The amino acid sequence 610–640 was found to represent the primary determinant site for phospholipid binding. Moreover, the R621C mutation identified in Parkinson’s disease abolished Synphilin-1 association with lipid droplets. The lipophilicity of Synphilin-1 might prove relevant to its physiologic function. [Copyright &y& Elsevier]

Establishment of a Parkinson's disease (PD) neuron model was attempted with mouse embryonic stem (ES) cells. ES cell lines over-expressing mouse nuclear receptor-related 1 (Nurr1), together with human wild-type and alanine 30 → proline (A30P) and alanine 53 → threonine (A53T) mutant α-synuclein were established and subjected to differentiation into dopaminergic neurons. The ES cell-derived dopaminergic neurons expressing wild-type or mutant α-synuclein exhibited the fundamental characteristics consistent with dopaminergic neurons in the substantia nigra. The ES cell-derived PD model neurons exhibited increased susceptibility to oxidative stress, proteasome inhibition, and mitochondrial inhibition. Cell viability of PD model neurons and the control neurons was similar until 28 days after differentiation. Nonetheless, after that time, PD model neurons gradually began to undergo neuronal death over the course of 1 month, showing cytoplasmic aggregate formation and an increase of insoluble α-synuclein protein. Such delayed neuronal death was observed in a mutant α-synuclein protein level-dependent manner, which was slightly inhibited by a c- jun N-terminal kinase inhibitor and a caspase inhibitor. Such cell death was not observed when the same ES cell lines were differentiated into oligodendrocytes. The ES cell-derived PD model neurons are considered as prospective candidates for a new prototype modelling PD that would allow better investigation of the underlying neurodegenerative pathophysiology. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is a progressive degenerative disorder characterized by neuronal loss, gliosis and abnormal fibril formation of abnormally phosphorylated tau protein in neurons and glia cells, but the cause is not clear at present. For the purpose of clarifying the pathological significance of accumulation of tau protein in neurons and oligodendroglia in PSP, we morphologically classified neurofibrillary tangles (NFT) and coiled bodies (CB) in oligodendroglia in three PSP brains into four stages, using double staining for immunohistochemistry with AT8 antibody and modified Gallyas-Braak (GB) staining. AT8-positive neurons without abnormal fibril structure with GB staining were classified as stage I, AT8-positive neurons containing a few fibril structures with GB staining were classified stage II, AT8-positive neurons containing mature fibril structures were classified as stage III, and AT8 negative neurons containing abnormal fibril structures stained only with GB staining were classified as stage IV (ghost tangles). These stages were also assessed for CB. Then we counted the number of cells of each stage in various brain regions to investigate the relationship of NFT and CB with neuronal loss and gliosis. The results showed that there were very few stage IV NFT and CB, which reflect cell death, but that stage III NFT and CB were abundant. Moreover, CB were abundant in regions with severe neuronal loss. These results suggest that appearance of CB is closely associated with degenerative regions. [ABSTRACT FROM AUTHOR]

We recently recorded somatosensory evoked fields (SEFs) elicited by compressing the glabrous skin of the finger and decompressing it by using a photosensor trigger. In that study, the equivalent current dipoles (ECDs) for these evoked fields appeared to be physiologically similar to the ECDs of P30m in median nerve stimulation. We sought to determine the relations of evoked fields elicited by mechanically stimulating the glabrous skin of the great toe and those of electrically produced P40m. We studied SEFs elicited by mechanical and electrical stimulations from the median and tibial nerves. The orientations of dipoles from the mechanical stimulations were from anterior-to-posterior, similar to the orientations of dipoles for P30m. The direction of the dipole around the peak of N20m from median nerve electrical stimulation was opposite to these directions. The orientations of dipoles around the peak of P40m by tibial nerve stimulation were transverse, whereas those by the compression and decompression stimulation of the toe were directed from anterior-to-posterior. The concordance of the orientations in ECDs for evoked fields elicited by mechanical and electrical stimulations suggests that the ECDs of P40m are physiologically similar to those of P30m but not to those of N20m. The discrepancy in orientations in ECDs for evoked field elicited by these stimulations in the lower extremity suggests that electrical and compression stimulations elicit evoked fields responding to fast surface rubbing stimuli and/or stimuli to the muscle and joint. Hum. Brain Mapping 24:274-283, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

α-Synuclein (αS) is a neuronal protein that has been implicated in the pathogenesis of Parkinson’s disease. The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of αS. Hyperosmotic stress induced tyrosine phosphorylation of αS via Pyk2/RAFTK at tyrosine residue 125. Pyk2/RAFTK-mediated phosphorylation of αS was primarily achieved with Src-family kinases. In addition, osmotic stress-induced phosphorylation of αS was dependent on Pyk2/RAFTK activation. Accordingly, such results indicate that Pyk2/RAFTK lies upstream of Src-family kinases in the signaling cascade by which osmotic stress induces tyrosine phosphorylation of αS. [Copyright &y& Elsevier]

Abstract: To identify genes induced by transient forebrain ischemia, we used the mRNA differential display technique in the four-vessel occlusion model in rats. Some genes were identified as candidates that encode ischemia-responsive protein, and one of them was cloned as ischemia-responsive protein 94 kDa (irp94) from the rat hippocampal cDNA library. Sequence analysis suggested that rat irp94 was a transcriptional variant or a homologue of mouse apg-2 and human heat shock protein (hsp) 70RY and a member of the HSP110 family, because IRP94 was >90% identical to APG-2 and HSP70RY and ∼60% identical to the other members of the HSP110 family. Although irp94 mRNA was constitutively expressed in the normal hippocampus, it was clearly enhanced 4-24 h after ischemia for 10 (1.9-fold increase) and 15 min (3.4-fold increase). These changes mainly occurred in neuronal cells, as judged by the localization of irp94 mRNA using in situ hybridization histochemistry. On the other hand, hyperthermic stress did not enhance irp94 mRNA expression, suggesting that irp94 expression was enhanced under ischemic stress and not related to the heat shock signaling mechanism. Our study suggested that irp94, a novel member of the HSP110 family, might play an important role in the environment altering neuronal functions, especially after transient forebrain ischemia. [ABSTRACT FROM AUTHOR]

This report concerns a 65-year-old right-handed woman with cerebral hemorrhage who presented with mild right-sided hemiparesis. Computed tomography (CT) revealed hematoma in the left thalamus and compression of the posterior limb of the internal capsule by a brain edema surrounding the lesion. 99mTc-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) images obtained 4 days after onset showed hypoperfusion in the left thalamus containing a hematoma as well as contralateral cerebellar hypoperfusion to the supratentorial lesion, which is well recognized as crossed cerebellar diaschisis (CCD) after stroke. CT 14 days after the onset revealed reduction of the brain edema of the posterior limb of the internal capsule accompanied by gradual neurological improvement. SPECT obtained 14 and 28 days later showed that CCD had disappeared. In this case report, the authors discuss the disappearance of CCD due to transient edematous compression of the internal capsule following thalamic hemorrhage on serial 99mTc-HMPAO SPECT scans. CCD was possibly caused by the lesion confined to the posterior limb of the internal capsule, which anatomically constitutes the cerebropontocerebellar pathway. [ABSTRACT FROM AUTHOR]

Background Past reports suggested that total-body irradiation at 0.5 to 1.0 Gy could be responsible for atherosclerosis. Peripheral artery disease ( PAD ) is a manifestation of systematic atherosclerosis. Whether the consequences of a low-to-moderate dose of radiation include increased risk of PAD remains to be determined. The purpose of this study was to examine the association between radiation exposure and prevalence of PAD among Japanese atomic bomb survivors. Methods and Results Radiation exposure from the atomic bombing was assessed in 3476 participants (41.1% men, mean age 74.8 years with SD 6.4 years) with a cross-sectional survey in 2010 to 2014. Left- and right-side ankle-brachial indexes and upstroke time ( UT ) were obtained using oscillometric VP -2000. PAD was defined as an ankle-brachial index of 1.0 or less or a prior history related to revascularization. UT was considered a sensitive marker of early-stage PAD . Association between radiation exposure and PAD or UT was assessed using multivariable regression analyses with adjustment for potential confounding factors. Of 3476 participants, 79 (2.3%) were identified as having prevalent PAD . Multivariate logistic regression analysis indicated that radiation dose was unrelated to PAD prevalence (odds ratio, 0.83; 95% confidence interval [0.57-1.21]). UT appeared to increase with radiation dose, but the increase was not statistically significant (1.09 ms/Gy; 95% confidence interval [-0.17 to 2.36]). Conclusions We found no clear association of radiation dose with PAD , but it remains to be determined whether UT is associated with radiation dose.

In addition to advanced stenosis, earlier stages of carotid atherosclerosis are associated with the risk for stroke. Based on a recent report, this review will focus on the associations between carotid atherosclerosis and stroke subtypes. The authors report increased severity of carotid atherosclerosis in atherothrombotic and lacunar infarction patients, compared to nonstroke patients. However, the severity was similar between nonstroke patients and those with cardioembolic infarction and cerebral hemorrhage. By receiver operating characteristic curve analyses, although evaluation of carotid atherosclerosis appears to help for risk assessment of atherothrombotic and lacunar infarction, the potential for benefit may be greater for atherothrombotic. Large prospective studies are still necessary to establish the link between earlier carotid atherosclerosis and the future risk for specific stroke subtypes., (Copyright 2003 CHF, Inc.)