Asymptomatic Acute Cerebral Infarction in a Patient with Hemoglobin Köln.

Congenital hemoglobin disorders typically present as hemolytic anemia, but there are also numerous reports of thrombotic complications in these diseases, suggesting an associated hypercoagulative state. In hemoglobin Köln, the most common type of unstable hemoglobinopathy worldwide, there have not been many reports of such thrombotic phenomena. We herein describe the case of a patient with hemoglobin Köln demonstrating acute cerebral infarction. His father, who also had hemolytic anemia, presumably hemoglobin Köln, had a history of cerebral infarction. This case suggests that hemoglobin Köln, among other congenital hemoglobin disorders, may be a precipitating factor of thrombotic events.

Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease.

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. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate 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 was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. 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 A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID.

Successful Treatment of Herpes Zoster Ophthalmicus Complicated by Intense Orbital Inflammation Using Laser Irradiation over the Stellate Ganglion.

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.

Two Cases of Severe Type 2 Respiratory Failure Associated with Diffuse Idiopathic Skeletal Hyperostosis.

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory process characterized by hyperostosis at tendon insertions and around joint capsules and ossification of the anterior longitudinal ligament of the spine. The flexibility of the spinal column is reduced in DISH and affects the movement of the thorax, leading to restrictive ventilatory function. In this report, we describe the first two cases of severe type 2 (hypercapnic) respiratory failure associated with DISH. Two older men presented with histories of shortness of breath. Radiography of the spine revealed DISH with coexisting ankylosis of the costovertebral joints. The patients' thoracic motion was severely restricted, reducing the mechanism of lung expansion to diaphragm contraction only. Both patients required non-invasive positive-pressure ventilation therapy to cope with their conditions. Our report sheds light on the risk of potentially life-threatening respiratory manifestations of DISH among older adults.

[Factors Influencing Brain Interstitial Fluid Concentrations of Amyloid ß and Tau].

In patients with Alzheimer's disease, the brain interstitial space is an important place where amyloid-ß 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-ß and tau, mainly focusing on known epidemiological risk factors for Alzheimer's disease.

A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia.

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.

Chronic cerebral hypoperfusion shifts the equilibrium of amyloid ß oligomers to aggregation-prone species with higher molecular weight.

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 ß oligomers respond to hypoperfusion. BCAS accelerated amyloid ß (Aß) convergence to the aggregation seed, facilitating the growth of Aß plaques, but without changing the total Aß amount in the brain. Furthermore, Aß oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aß 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 Aß molecules participate in Aß assemblies to form aggregation-prone Aß 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 Aß aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aß to become aggregation-prone.

Optic neuropathy and decorticate-like posture as presenting symptoms of Bickerstaff's brainstem encephalitis: A case report and literature review.

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.

Methylation changes and aberrant expression of FGFR3 in Lewy body disease neurons.

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.

Cilostazol alleviates white matter degeneration caused by chronic cerebral hypoperfusion in mice: Implication of its mechanism from gene expression analysis.

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<0.01) genes showed that majority of the genes were related to cell development processes. Among the validated genes, expression of Btg2 was significantly promoted in the corpus callosum of BCAS mice by administration of cilostazol. Results of this study suggest that activation of Btg2 may be one of the key pharmacological effects of cilostazol towards the white matter during chronic ischemia.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) 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 Aß. 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 Aß 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.

Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing.

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.

Anti-NMDA receptor encephalitis associated with transient cerebral dyschromatopsia, prosopagnosia, and lack of stereopsis.

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.