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A 56-year-old man presented with right-sided headache and ptosis accompanied by a facial skin rash. He was diagnosed with herpes zoster ophthalmicus (HZO). Despite acyclovir and steroid therapy, the ocular symptoms worsened. Magnetic resonance imaging (MRI) revealed severe orbital inflammation and abnormal lesions in the right trigeminal nucleus and tract. The effects of re-administration of intravenous acyclovir and steroid pulse therapy were limited. Laser irradiation of the stellate ganglion (SGL) and high-dose oral prednisolone therapy were effective. Our experience suggests the efficacy of early multimodal treatment, including SGL, in treating ocular symptoms associated with HZO.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Intranuclear inclusions are the pathological hallmark of NIID. Previously, immunohistochemistry has revealed that intranuclear inclusions are ubiquitin-, p62-, and SUMO-1-positive, suggesting the possible alteration of the ubiquitin-proteasomal protein degradation system in the nuclei with inclusions. However, the molecular mechanisms within these nuclei remain unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in NIID with CGG repeat expansion in NOTCH2NLC to discover the proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins in the autopsy brain samples from three NIID patients was confirmed via immunofluorescence. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A3, hnRNP A2/B1, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than those without; however, they were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. These data can form the basis for understanding the pathophysiology of NIID.

Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.

Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer’s disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid β oligomers respond to hypoperfusion. BCAS accelerated amyloid β (Aβ) convergence to the aggregation seed, facilitating the growth of Aβ plaques, but without changing the total Aβ amount in the brain. Furthermore, Aβ oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aβ is in an equilibrium among monomeric, oligomeric, and aggregation forms, our data suggest that cerebral hypoperfusion after BCAS shifted this equilibrium to a state where a greater number of Aβ molecules participate in Aβ assemblies to form aggregation-prone Aβ oligomers with high molecular weight. The reduced blood flow in the cerebral arteries due to BCAS attenuated the dynamics of the interstitial fluid leading to congestion, which may have facilitated Aβ aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aβ to become aggregation-prone.

In patients with Alzheimer's disease, the brain interstitial space is an important place where amyloid-β oligomers and aggregates exist. Although tau aggregates are observed inside neurons, extracellular brain interstitial fluid tau has drawn attention because of increasing understanding of cell-to-cell propagation of tau aggregation. In this review, we summarize our current understanding of factors influencing brain interstitial fluid concentrations of amyloid-β and tau, mainly focusing on known epidemiological risk factors for Alzheimer's disease.

Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.

Background In cases with anti-glutamic acid decarboxylase (GAD) antibody-positive cerebellar ataxia, the titer of the antibody is usually very high. However, a few cases of low-titer GAD antibody-positive cerebellar ataxia patients have been described recently. In such patients, the antibody has been detected predominantly in serum, rather than in cerebrospinal fluid. Case presentation A 34-year-old man presented with subacute-onset cerebellar ataxia, and examinations revealed no abnormal findings except low-titer anti-GAD antibody in the cerebrospinal fluid at initial evaluation: the serum antibody became slightly positive in a delayed manner. Treatment with steroid and/or immunoglobulin was effective in improving symptoms, and the effect of these treatments continued for approximately 1 year. Conclusions The present case suggested a potential diagnostic pitfall, in which the examination of serum anti-GAD antibody at initial evaluation alone might be insufficient to rule out this disease. It may be indicated that the routine screening should include examination for the GAD antibody in both the serum and cerebrospinal fluid, plus additional follow-up checks for the antibody in the subsequent clinical course. Care must be taken to avoid non-detection of this disease with possibly reversible symptoms in patients with cerebellar ataxia of unknown origin.

Lewy body disease (LBD) is characterized by accumulation of aggregated α-synuclein in the central nervous system as eosinophilic cytoplasmic inclusions called Lewy bodies. According to their distribution pattern, it is classified into brainstem LBD, limbic LBD and diffuse neocortical LBD. It has been reported that α-synuclein affects various points in the MAPK cascade but its relationship with FGF receptors, which are the most upstream of the pathway, has not been previously investigated. We discovered that among the four FGFRs, FGFR3 showed neuronal upregulation in LBD brains histopathologically. Further examination using neuron-specific methylome analysis revealed that the gene body of FGFR3 was hypermethylated in LBD, suggesting its increased transcription. Altered methylation was not observed in the non-neuronal genome. Altered methylation status was associated with the severity of α-synuclein pathology.

A 72-year-old woman with a 10-day history of bilateral visual impairment after respiratory tract infection showed decorticate-like posture and progressive deterioration of consciousness leading to coma. Ophthalmoplegia was also noted and anti-GQ1b antibodies were positive, consistent with Bickerstaff's brainstem encephalitis. After intravenous immunoglobulin and steroid pulse therapy, her consciousness gradually improved. However, severe visual impairment at the level of hand motion was noticed, which gradually normalized after second steroid pulse therapy. Atypical findings including optic neuropathy and decorticate-like posture can be seen in patients with Bickerstaff's brainstem encephalitis, and early diagnosis is essential for adequate management.

Significance To extract critical information from Alzheimer’s disease (AD) postmortem brains that may otherwise be lost, we chose to screen epigenetic signatures. Epigenome analysis is a robust methodology in terms of its cell type and gene specificity, suitability for high-throughput analysis, and resistance to postmortem degradation. Analysis of the neuron-specific methylome revealed a variety of differentially methylated genes, including BRCA1. We demonstrate the pathogenic relevance of compromised genomic integrity by analyzing the neuroprotective function of BRCA1 against amyloid β (Aβ)-induced DNA double-strand breaks. Furthermore, insolubility of BRCA1 under the presence of aggregated tau suggested the reason for its dysfunction despite enhanced expression. We provide insight into the pathomechanism of AD and demonstrate the potential of screening neuron-specific methylome to reveal new pathogenic contributors., Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Cilostazol is known to alleviate white matter demyelination due to chronic cerebral hypoperfusion in rodent models, although their pharmacological mechanisms remain unclear. In this study, we investigated the protective effect of cilostazol in relation to gene expression profile. Bilateral common carotid artery stenosis (BCAS) mice were treated with oral administration of cilostazol or placebo starting from a week after the surgery. Demyelination of the cingulum was compared between the 2 groups 2, 6, and 10 weeks after initial drug administration. Also, to examine temporal gene expression change during demyelination, DNA microarray analysis was conducted using samples from the corpus callosum of 2nd and 6th week BCAS mice. For genes that showed more than 2-fold up-regulation, their increase was validated by qPCR. Finally, to determine the effect of cilostazol towards those genes, their expression in the corpus callosum of 6-week placebo-treated and cilostazol-treated BCAS mice was compared by qPCR. Amelioration of myelin loss was observed in cilostazol-treated group, showing significant difference with those observed in placebo group after 10-week treatment. Gene ontology analysis of the 17 up-regulated (FDR

d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood.

The present report describes the case of a 57-year-old male patient with spinal dural arteriovenous fistula (AVF). During the diagnostic examination, intravenous steroid therapy was implemented. The next day, the patient's symptoms were mildly improved and magnetic resonance imaging showed that the spinal cord swelling was markedly reduced. After the angiographic diagnosis of spinal dural AVF fed from the radicular artery originating from the sixth intercostal artery, the shunts were surgically interrupted by cutting the drainage vein. Clinical deterioration after steroid therapy was reported in several previous papers on this disorder. Based on the present case, however, we propose the possibility that intravenous steroid therapy is a viable option for presurgical management.

A 20-year-old woman suffered from anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and was treated with removal of an ovarian teratoma and retroperitoneal ganglioneuroma in addition to immunotherapy. She was incapable of face recognition, had difficulty with object recognition, and lacked color sensation and stereo perception during recovery. These symptoms were transient and completely resolved over 4 months. Our report documents additional aspects of visual impairment associated with anti-NMDAR encephalitis and suggests that the disease can lead to diffuse cerebral dysfunction including the cortical visual system.