Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions.

Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.

Associations between the ALSFRS-R score and urate levels during 12 months of edaravone treatment for amyotrophic lateral sclerosis: Post hoc analysis of ALSFRS-R scores in clinical studies MCI186-16, MCI186-17, and MCI186-19.

INTRODUCTION/AIMS: In this study we examined the relationship between urate levels at baseline and functional change measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score after edaravone treatment. METHODS: Data from the edaravone trials MCI186-16, MCI186-17, and MCI186-19 were analyzed, including the following treatment sequence groups: edaravone-edaravone (EE, n = 113); edaravone-placebo (EP, n = 45); and placebo-edaravone (PE, n = 146). Subgroups were defined as low baseline urate (below the median value of 4.8 mg/dL) and high baseline urate (≥4.8 mg/dL). The differences in ALSFRS-R total score change and urate change were evaluated using the mixed model for repeated measurement for overall population, by urate-level subgroup, and by trial. RESULTS: Compared with the PE group, the EE group showed a slower decline in ALSFRS-R score, regardless of the urate baseline level, and a slower decline in urate level in the higher baseline urate subgroup. Smaller changes in ALSFRS-R score and urate were observed in patients diagnosed with "probable, laboratory-supported ALS." There was a positive correlation between changes from baseline to cycle 12 in urate levels and ALSFRS-R score. DISCUSSION: Edaravone treatment in ALS patients diagnosed with "definite ALS" or "probable ALS" showed slowing of disease progression, regardless of baseline urate level. In addition, because edaravone treatment was associated with a slower decline in urate level in the higher baseline urate subgroup and urate-level changes were associated with changes in ALSFRS-R score, urate level, and/or change may be one indicator in predicting disease progression after edaravone administration.

Associations between urate levels and amyotrophic lateral sclerosis functional score with edaravone treatment: Post hoc analysis of studies MCI186-16, MCI186-17, and MCI186-19.

INTRODUCTION/AIMS: Edaravone in amyotrophic lateral sclerosis (ALS) was analyzed in two phase 3 studies (MCI186-16 and MCI186-19). Those trials enrolled patients with Japanese ALS severity grades 1 and 2 (less severe ALS), but many patients progressed to grades 3 and 4 during the double-blind treatment period. The placebo patients who initiated edaravone treatment in the open-label periods provided an opportunity to assess the effects of edaravone in more severe ALS. This study also assessed the association between ALS Functional Rating Scale-Revised (ALSFRS-R) slope and biomarker changes after open-label edaravone initiation. METHODS: Change in ALSFRS-R slope in placebo patients before and after initiating edaravone treatment was assessed using the random coefficient model. The association of ALSFRS-R change and blood marker changes was explored by the least absolute shrinkage and selection operator (LASSO) method of machine learning. RESULTS: Twenty-four percent of patients (35/146) in the placebo-edaravone group showed ≥25% slowing of decline in the ALSFRS-R slope. Within the 25% slower-decline group, 60% (21/35) had Japanese ALS severity grades 3 or 4 at the start of edaravone treatment. The LASSO model identified serum urate as associated with the percentage change in ALSFRS-R slope. The rate of decrease in urate was smaller in the 25% slower-decline group than in the non-25% slower-decline group during edaravone treatment. DISCUSSION: This post hoc analysis indicated that ALS patients, including those with advanced ALS severity grades, may receive benefit in the group of patients whose urate levels are stable during the course of the edaravone treatment.

Krebs von den Lungen 6 decreased in the serum and muscle of GNE myopathy patients.

UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is necessary for sialic acid biosynthesis. GNE myopathy is caused by a defect in GNE, and hyposialylation is a key factor in the pathomechanism of GNE myopathy. Although candidates for evaluating hyposialylation have been reported, it is difficult to measure them in routine clinical practice. Sialylation is necessary for synthesis of various glycoproteins, including Krebs von den Lungen-6 (KL-6)/mucin 1 (MUC1). Here we report that KL-6/MUC1 is decreased in GNE myopathy. We observed that KL-6 levels were decreased in the serum of patients with GNE myopathy, and that KL-6 and MUC1-C were also decreased in muscle biopsy specimens from these patients. An immunofluorescent study revealed that KL-6 and MUC1-C were not present in the sarcolemma but were, instead, localized in rimmed vacuoles in specimens from patients with GNE myopathy. KL-6 is already used to detect lung diseases in clinical practice, and this glycoprotein may be a novel candidate for evaluating hyposialylation in GNE myopathy.

Histone deacetylase 10 knockout activates chaperone-mediated autophagy and accelerates the decomposition of its substrate.

Histone deacetylase (HDAC) 10 is a member of class IIb HDACs, but its deacetylation targets and functions are poorly characterized. Recent investigation has proposed that HDAC10 deacetylates heat shock cognate protein 70 kDa (HSC70) after interaction. HSC70 plays an important role in chaperone-mediated autophagy (CMA), binding CMA substrates and transporting them to lysosomes. However, it has not been clarified whether HDAC10 is involved in CMA. In this study, we established the HDAC10 knockout HeLa cell line and evaluated its CMA activity to determine whether HDAC10 participates in regulating CMA. In HDAC10 knockout cells, lysosome-associated protein type 2A (LAMP2A) protein level increased and LAMP2A-positive lysosomes accumulated around the nucleus. Moreover, GAPDH, which is a well-known CMA substrate, was delivered to LAMP2A-positive lysosomes and degraded in HDAC10 knockout cells more efficiently than in wild type HeLa cells. These results suggest that CMA is activated in HDAC10 knockout cells. Meanwhile, turnover assay using LC3 and p62, which are macroautophagy markers, indicated that autophagic flux was fully functioning in HDAC10 knockout cells as well as in wild type HeLa cells. In conclusion, HDAC10 participated in regulating CMA, and HDAC10 knockout activated CMA and accelerated degradation of a CMA substrate.

HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.

Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses. Here, we showed that hypoxia treatment could induce interaction between HDAC6 and MFN2, thus protecting mitochondrial connectivity. Mechanistically, we demonstrated that a mitochondrial ubiquitin ligase MARCH5/MITOL was responsible for hypoxia-induced MFN2 degradation in HDAC6 deficient cells. Notably, genetic abolition of HDAC6 in amyotrophic lateral sclerosis model mice showed MFN2 degradation with MARCH5 induction. Our results indicate that HDAC6 is a critical regulator of MFN2 degradation by MARCH5, thus protecting mitochondrial connectivity from hypoxic stress.

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles.

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 [PtdIns(4,5)P2], in AD and other neurodegenerative disorders. METHODS: We compared PtdIns(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 PtdIns(4,5)P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for PtdIns(4,5)P2 was also evident in NFTs composed of hyperphosphorylated tau, PtdIns(4,5)P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, PtdIns(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 PtdIns(4,5)P2 play a role in the formation of both GVD bodies and NFTs.

Efficacy and safety of inebilizumab in Asian participants with neuromyelitis optica spectrum disorder: Subgroup analyses of the N-MOmentum study.

BACKGROUND: Inebilizumab, an anti-CD19 B cell-depleting antibody, reduced the risk of a neuromyelitis optica spectrum disorder (NMOSD) attack, disability worsening, magnetic resonance imaging (MRI) lesion activity, and disease-related hospitalizations in participants with NMOSD in the N-MOmentum study (NCT02200770). However, the efficacy and safety outcomes of inebilizumab specific to an Asian population were not fully reported. Therefore, subgroup analyses of the N-MOmentum study were conducted post hoc to evaluate the efficacy and safety of inebilizumab in Asian participants with NMOSD. METHODS: The N-MOmentum study was a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial with an open-label extension period (OLP). In the subgroup analyses, data from Asian participants from the N-MOmentum study were compared with those of non-Asian participants. Eligible participants were randomly allocated (3:1) to receive 300 mg intravenous (IV) inebilizumab or placebo on Days 1 and 15. Participants who had an NMOSD attack or completed the randomized controlled period (RCP) could enter the OLP, where they received inebilizumab for ≥2 years. All participants who entered the OLP received inebilizumab 300 mg IV every 6 months. RESULTS: Overall, 230 participants received treatment (174 received inebilizumab and 56 received placebo), of whom 47 were Asian (39 received inebilizumab and 8 received placebo). Baseline characteristics were similar between the Asian and non-Asian subgroups, except for disease duration, annualized relapse rate prior to randomization in this study, and previous maintenance therapy. In the Asian subgroup, the risk of NMOSD attacks was reduced with inebilizumab versus placebo (hazard ratio, 0.202) and the attack-free rate at 28 weeks was 82.1% with inebilizumab versus 37.5% with placebo, in the 6-month RCP. NMOSD attack rates were comparable between the Asian and non-Asian subgroups. In the Asian subgroup, the rates of Expanded Disability Status Scale worsening from baseline, active MRI lesions, and disease-related hospitalizations tended to be lower in the inebilizumab group than in the placebo group; similar results were shown in the non-Asian subgroup. For long-term efficacy and safety (RCP and OLP), the annualized adjudicated NMOSD attack rate in Asian participants treated with inebilizumab was reduced (0.096) compared with that at baseline (1.04), with a mean follow-up period of inebilizumab treatment of 3.38 years, which was consistent with the results in the non-Asian subgroup. The risk of NMOSD attack decreased with prolonged duration of treatment in both the inebilizumab/inebilizumab and placebo/inebilizumab groups in the Asian and non-Asian subgroups. The incidence of treatment-emergent adverse events (TEAEs) was similar between the Asian and non-Asian subgroups. In the Asian and non-Asian subgroups, 15.2% and 35.2% of participants, respectively, had at least one serious TEAE and/or Grade ≥3 TEAE during long-term therapy. No deaths occurred in the Asian subgroup whereas three deaths occurred in the non-Asian subgroup. CONCLUSION: Inebilizumab reduced the risk of an NMOSD attack, progression of disability, MRI lesion activity, and disease-related hospitalizations in Asian participants with NMOSD. The efficacy of inebilizumab in reducing NMOSD attacks continued without any unexpected safety signals or concerns during long-term use in Asian participants.

Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson's disease model cells by inhibiting ROS production and apoptosis.

Synphilin-1, a cytoplasmic protein, interacts with α-synuclein which is one of the main constituents of Lewy bodies and plays an important role in the pathology of Parkinson's disease (PD), in neurons. This interaction indicates that synphilin-1 may also play a central role in PD. However, the biological functions of synphilin-1 are not fully understood, and whether synphilin-1 is neurotoxic or neuroprotective remains controversial. This study examined the function of synphilin-1 in a PD model in vitro. We used an inhibitor of mitochondrial complex I, 1-methyl-4-phenylpyridinium (MPP+). We established human neuroblastoma SH-SY5Y cell lines that stably expressed human synphilin-1. We found that overexpression of synphilin-1 increased SH-SY5Y cell viability after MPP+ treatment. We further found that synphilin-1 significantly suppressed apoptotic changes in nuclei, including nuclear condensation and fragmentation, after MPP+ treatment. We showed that synphilin-1 significantly decreased MPP+-induced cleaved caspase-3 and cleaved poly-ADP-ribose polymerase levels by using western blotting. Production of reactive oxygen species (ROS) induced by MPP+ was significantly reduced in cells expressing synphilin-1 compared to those expressing empty vector. Synphilin-1 inhibited MPP+-induced cytochrome c release from mitochondria into the cytosol. These data suggested that synphilin-1 may function to protect against dopaminergic cell death by preserving mitochondrial function and inhibiting early steps in the intrinsic apoptotic pathway. Taken together, our results indicated that synphilin-1 may play neuroprotective roles in PD pathogenesis by inhibiting ROS production and apoptosis.

[Case of rheumatoid meningitis: findings on diffusion-weighted image versus FLAIR image].

We report a 63-year-old man with rheumatoid meningitis. At 47-years-old, he developed rheumatoid vasculitis causing arthralgia and skin ulcer. Although the patient had been treated with prednisolone and cyclosporine A, headache and recurrent focal seizures of the right upper limb and generalized seizures developed. Brain magnetic resonance imaging showed high signal intensity lesions on FLAIR MRI and associated abnormal enhancement of the leptomeninges. Part of the lesions also showed patchy high signal intensity on diffusion-weighted imaging (DWI). This features may be useful for differentiating rheumatoid meningitis from subdural empyema, because the extent of the lesions on DWI matches the lesion on FLAIR imaging in patients with subdural empyema. Cerebrospinal fluid analysis revealed monocytic pleocytosis and negative findings for infection or malignancy. After intravenous administration of methylprednisolone (1,000 mg/day for 3 days), the patient showed improvements in headache, cerebrospinal fluid findings and abnormal hyperintensity on DWI. Rheumatoid meningitis is an extremely rare neurological manifestation, but careful attention should be paid even in the inactive stage of rheumatoid arthritis. This disease tends to present with unilateral supratentorial lesions. In this case, serial diffusion-weighted and FLAIR MRI was useful for following the leptomeningeal lesions.

Interactions of Synphilin-1 with phospholipids and lipid membranes.

Synphilin-1 is an alpha-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.

Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression.

The small G protein RhoA and its downstream effector Rho-kinase/ROCK2 play an important role in regulation of various vasculature cellular functions. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important mediator of vascular homeostasis and cerebral blood flow. Using the human endothelial cell line HUVEC, the present study investigated the role of RhoA and Rho-kinase in endothelial eNOS protein expression under hypoxic conditions as an in vitro model of ischemia. RhoA protein levels in HUVEC were low under normoxic conditions, but were significantly increased after 5h of hypoxia. Endothelial Rho-kinase expression was not detected until after 3h of hypoxia; such expression remained significantly increased after 5h. On the other hand, endothelial eNOS expression was similar after 3h of hypoxia, but was significantly decreased after 5h. The hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of RhoA and significantly inhibited by suppression of RhoA expression by small interfering RNA. The hypoxia-induced decrease in eNOS expression was significantly inhibited when endogenous Rho-kinase activation was inhibited by Rho-binding domain expression. Furthermore, the hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of Rho-kinase. Since expression and activation of RhoA and Rho-kinase inhibit eNOS expression in endothelial cells, attempts to down-regulate RhoA and Rho-kinase by multiple drugs, such as statins or Rho-kinase inhibitors, might provide endothelial and cardiovascular benefits through upregulation of eNOS.

Radiation Effects on Cognitive Function Among Atomic Bomb Survivors Exposed at or After Adolescence.

BACKGROUND: The objective of this study was to investigate radiation effects on longitudinal pre-dementia cognitive decline among participants who developed dementia as well as on those who did not develop dementia during follow-up. METHODS: Measuring cognitive function with the Cognitive Abilities Screening Instrument approximately every 2 years, we followed 1844 atomic bomb survivors participating in the Adult Health Study of the Radiation Effects Research Foundation from 1992 to 2011. Participants were adolescents or older when exposed to between 0 and 4 Gy. Approximately 15% and 40% of participants were exposed to ≥1 Gy and <5 mGy, respectively. At study start, participants were dementia-free and between 60 and 80 years old. Three-quarters of the participants returned after baseline, averaging 8.4 years of follow-up. During follow-up, 313 developed dementia. We used cognitive scores before dementia onset for analysis and a mixed-effects model to estimate radiation effects on longitudinal change of cognition, adjusting for dementia occurrence, age, sex, and education. RESULTS: Cognition level was significantly associated with age, education, and dementia occurrence but not with radiation dose or sex. Cognitive decline accelerated with increasing age, especially among participants who developed dementia. Neither radiation nor education was significantly associated with the degree of deterioration with age. Radiation did not modify the different cognitive decline by dementia occurrence. CONCLUSIONS: Radiation did not significantly affect cognition among atomic bomb survivors exposed at or after adolescence.

Trajectories of cognitive function in dementia-free subjects: Radiation Effects Research Foundation Adult Health Study.

OBJECTIVES: To investigate associations between age, sex, education, and birth cohort and global cognitive decline among a population that would most likely not progress to dementia. METHODS: A total of 1538 dementia-free subjects aged 60 to 80years in 1992 were followed up through 2011 without dementia occurrence. We assessed cognitive function using the Cognitive Ability Screening Instrument (CASI). Using stepwise-like model selection procedure, we built mixed-effects models for initial cognition and longitudinal cognition. RESULTS: Initial CASI scores for younger age and more years of formal education were higher than those for older and less education. Sex did not show a significant effect. In the longitudinal analysis, cognitive decline became more rapid with increasing age. Sex and education did not modify the degree of deterioration with age. CASI scores were higher for younger cohorts and men due to differences in education levels. CONCLUSION: Among dementia-free subjects, age is an important predictor of cognitive function level and cognitive decline. Education level affects cognitive function level, but did not affect cognitive decline. The results have implications not only for elucidation of the aging process, but also for reference in dementia screening.

Activation of Pyk2/RAFTK induces tyrosine phosphorylation of alpha-synuclein via Src-family kinases.

alpha-Synuclein (alpha S) 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 alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125. Pyk2/RAFTK-mediated phosphorylation of alpha S was primarily achieved with Src-family kinases. In addition, osmotic stress-induced phosphorylation of alpha S 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 alpha S.

Tyrosine 125 of alpha-synuclein plays a critical role for dimerization following nitrative stress.

alpha-Synuclein is a major component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusions in multiple system atrophy. Increasing evidence suggests that the nitration of tyrosine residues in alpha-synuclein induced by oxidative injury is involved in the formation of inclusions characteristic to these synucleinopathies. Exposure of alpha-synuclein to peroxynitrite induces nitration of tyrosine residues, thereby forming alpha-synuclein oligomers. However, the contribution of tyrosine residues to either the nitration or the oligomerization is currently unknown. The present study used recombinant wild-type and mutant alpha-synuclein proteins to investigate the role of each alpha-synuclein tyrosine residue in the in vitro formation of alpha-synuclein oligomers under nitrative stress. Confocal microscopic analysis revealed that wild-type alpha-synuclein protein was able to accumulate and form an inclusion-like structure in the cytoplasm of living cells upon introduction by streptolysin O. Authentic peroxynitrite induced nitration of tyrosine residues in alpha-synuclein protein, as well as dimerization of alpha-synuclein. The formation of both SDS- and heat-stable dimers suggests cross-linking between nitrated tyrosine residues. Nonetheless, dimerization of alpha-synuclein proteins lacking tyrosine 125 was significantly decreased compared with alpha-synuclein proteins lacking tyrosine residues at positions 39, 133, or 136. Presumably, tyrosine 125 plays a critical role for alpha-synuclein dimerization under nitrative stress.

Dural arteriovenous fistula presenting with progressive dementia and parkinsonism.

We report a rare case of progressive parkinsonism and cognitive dysfunction due to dural arteriovenous fistula (DAVF). A 69-year-old man, with a history of hypertension and diabetes, was admitted to our hospital because of parkinsonism and dementia. Susceptibility-weighted imaging (SWI) revealed a thrombus in the superior sagittal sinus (SSS) and marked dilation of the medullary vein suggestive of the presence of comorbid DAVF. A single-photon emission CT (SPECT) showed widespread hypoperfusion in the bilateral frontal lobes. Selective cerebral angiography revealed a DAVF in SSS. These symptoms were significantly ameliorated following transvenous embolisation of the venous sinus at the shunting point. Reversible parkinsonism and dementia after embolisation was correlated with decreased dilation of medullary vein on SWI and improved cerebral blood flow on SPECT in the frontal lobes. Differentiation of parkinsonian and dementia symptoms due to DAVF from those associated with neurodegenerative disease is of great importance because DAVF-associated deficits may be reversed by endovascular therapy.

Characterization and distribution of adaptor protein containing a PH domain, PTB domain and leucine zipper motif (APPL1) in Alzheimer's disease hippocampus: an immunohistochemical study.

Adaptor protein containing a PH domain, PTB domain and leucine zipper motif (APPL1) is emerging as a critical regulator of various cellular processes in non-neuronal cells as well as in neurons where it localizes to dendritic spines and synapses. It regulates the development of these structures in hippocampal neurons. Although memory impairment in Alzheimer's disease (AD) has been attributed to disruption of synaptic plasticity, there is scant information on this protein in the human brain. In the present study, we immunohistochemically characterized the localization of APPL1 in AD and control brains. APPL1 accumulated perisomatically as granules around neurons within vulnerable sectors of the hippocampus (CA1 and subiculum) in AD brain, whilst APPL1-positive granules were rarely identified in control brains derived from elderly individuals with no known cognitive impairment. Interestingly, in the AD hippocampus, APPL1 also co-localized with perisomatic granules (non-plaque dystrophic dendrites) expressing glutamate receptor 2 and ubiquitin, suggesting the possible involvement of APPL1 in the synaptic modifications in AD. Thus, the immunohistochemical distribution of APPL1 in AD brain was distinct from that in non-AD control brains, suggesting that signaling via APPL1 might play a critical role in the memory impairment in AD.

Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy.

Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p < 0.01). However, the nerve sizes of CNR were not significantly different between patients with either disease. When we evaluated ESN of four selected sites for screening from the intermediate region, the sensitivity and specificity to distinguish between demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP.

Elevated urinary ß2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy.

Here we report what is to our knowledge the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. The index case is a 52-year-old man with almost 40years of progressive proximal muscle weakness. High urinary ß2 microglobulin, normal serum ß2 microglobulin, autophagic vacuoles with sarcolemmal features, and a hemizygous c.164-7T>G mutation in the VMA21 gene were found. His two maternal uncles had similar clinicopathological findings. High urinary ß2 microglobulin without obvious renal dysfunction might result from decreased urine acidification in the distal convoluted tubules caused by the VMA21 gene mutation. These findings might prove to be useful as a preliminary marker suggestive of X-linked myopathy with excessive autophagy.