Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson's Disease Affects LRRK2 Protein Levels.

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson's disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant-p.G2294R-located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient's peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features.

BACKGROUND: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified. OBJECTIVES: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation. METHODS: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [11 C]PBB3-PET to estimate regional tau loads. RESULTS: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [11 C]PBB3 binding in widespread regions from an early disease stage. CONCLUSIONS: [11 C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

COQ2 variants in Parkinson's disease and multiple system atrophy.

Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher's exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15 N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.

Myalgia caused by chronic myositis associated with plasmacytosis: a case report.

BACKGROUND: Cutaneous and systemic plasmacytosis are skin disorders characterized by cutaneous polyclonal plasma cell infiltration accompanied by polyclonal hypergammaglobulinemia. Cutaneous plasmacytosis involvement is limited to the skin, mainly on the face and trunk, while systemic plasmacytosis also involves 2 or more organ systems. However, there have been no reports of inflammatory myositis due to plasmacytosis. Here, we report a patient with plasmacytosis who developed myalgia and easy fatigability due to inflammatory myositis. CASE PRESENTATION: A 54-year-old man with cutaneous plasmacytosis on the face, chest, and back complained of a history of atypical facial and lower leg pain and easy fatigability since the age of 45 years. Muscle-strength tests revealed bilateral trivial gastrocnemius weakness with myalgia. The results of routine blood analysis, including creatine kinase and thyroid function, were normal, but levels of several inflammation markers and autoantibodies were elevated. Additionally, lower leg magnetic resonance imaging and gastrocnemius muscle biopsy revealed inflammatory myositis mimicking polymyositis. His plasmacytosis, myalgia, and lower leg weakness were ameliorated by prednisolone. CONCLUSION: The patient was diagnosed with inflammatory myositis due to plasmacytosis. Given that plasmacytosis has previously been reported to disrupt the immune status, myositis in this patient might have been associated with abnormal autoimmune inflammation. Neurologists and physicians should thus be aware that plasmacytosis might be associated with inflammatory myositis accompanied by myalgia.

Acute Hearing Loss Caused by Decreasing Anterior Inferior Cerebellar Arterial Perfusion in a Patient with Vertebral Artery Stenosis.

We report a case of bilateral hearing loss caused by decreased vascular flow in the anterior inferior cerebellar artery (AICA) territory. A 74-year-old man who experienced right hearing loss 5 months ago presented with bilateral deafness and right cerebellar ataxia; however, no ischemic lesion was detected in the bilateral AICA area. After stroke treatment, hearing loss was improved. One month later, we obtained blood flow improvement in the left AICA territory on single-photon-emission computed tomography and vertebral artery stenosis on magnetic resonance angiography. Therefore, clinicians should recognize that bilateral hearing loss may be related to stroke in the vertebrobasilar artery area.

Genotype-phenotype correlation of Parkinson's disease with PRKN variants.

To investigate the prevalence and genotype-phenotype correlations of parkin RBR E3 ubiquitin protein ligase (PRKN) variants in Parkinson's disease (PD), we first included 2,527 patients with PD. Through the defined selection, we enrolled 2,322 patients, including 1,204 with familial and 1,118 with sporadic PD. We identified 242 patients harboring PRKN variants, which were thought to be susceptibility factors, comprising 137 patients with familial and 105 with sporadic PD; among the 26 identified variants, 13 were novel. We divided our cohort into 2 groups: heterozygote (hereafter called one-allele) and homozygote or compound heterozygote (hereafter called two-allele). The patients with two-allele were significantly younger at onset than those with one-allele. Six families harbored the complex forms of one- and two-allele in different individuals of the same family. The presence of two-allele reflected more frequent normal values of [123I] metaiodobenzylguanidine myocardial scintigraphy. The log-rank test revealed an exacerbation associated with two-allele over 15 years of the disease course. The patients with PRKN variants showed specific symptoms dependent on the number of mutated alleles.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Identification of Disease-Associated Variants by Targeted Gene Panel Resequencing in Parkinson's Disease.

Background: Recent advanced technologies, such as high-throughput sequencing, have enabled the identification of a broad spectrum of variants. Using targeted-gene-panel resequencing for Parkinson's disease (PD)-associated genes, we have occasionally found several single-nucleotide variants (SNVs), which are thought to be disease-associated, in PD patients. To confirm the significance of these potentially disease-associated variants, we performed genome association analyses, using next-generation target resequencing, to evaluate the associations between the identified SNVs and PD. Methods: We obtained genomic DNA from 766 patients, who were clinically diagnosed with PD, and 336 healthy controls, all of Japanese origin. All data were analyzed using Ion AmpliSeq panel sequences, with 29 PD- or dementia-associated genes in a single panel. We excluded any variants that did not comply with the Hardy-Weinberg equilibrium in the control group. Variant frequencies in the PD and control groups were compared using PLINK. The identified variants were confirmed to a frequency difference of P < 0.05, after applying the Benjamini-Hochberg procedure using Fisher's exact test. The pathogenicity and prevalence of each variant were estimated based on a public gene database. Results: We identified three rare variants that were significantly associated with PD: rs201012663/rs150500694 in SYNJ1 and rs372754391 in DJ-1, which are intronic variants, and rs7412 in ApoE, which is an exonic variant. The variants in SYNJ1 and ApoE were frequently identified in the control group, and rs201012663/rs150500694 in SYNJ1 may play a protective role against PD. The DJ-1 variant was frequently identified in the PD group, with a high odds ratio of 2.2. Conclusion: The detected variants may represent genetic modifiers or disease-related variants in PD. Targeted-gene-panel resequencing may represent a useful method for detecting disease-causing variants and genetic association studies in PD.

Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder.

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.

GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Deep cerebral venous thrombosis mimicking influenza-associated acute necrotizing encephalopathy: a case report.

BACKGROUND: Acute necrotizing encephalopathy is one of the most devastating neurological complications of influenza virus infection. Acute necrotizing encephalopathy preferentially affects the thalamus bilaterally, as does deep cerebral venous thrombosis, which can lead to misdiagnosis. CASE PRESENTATION: A 52-year-old Japanese woman infected with seasonal influenza B virus presented to the emergency care unit in our hospital with progressive alteration of her level of consciousness. Bilateral thalamic lesions were demonstrated by magnetic resonance imaging, leading to a tentative diagnosis of acute necrotizing encephalopathy. However, she had deep cerebral venous thrombosis, and the presence of diminished signal and enlargement of deep cerebral veins on T2*-weighted imaging contributed to a revised diagnosis of deep cerebral venous thrombosis. Anticoagulant therapy was initiated, leading to her gradual recovery, with recanalization of the deep venous system and straight sinus. CONCLUSIONS: To the best of our knowledge, these results represent the first report of deep cerebral venous thrombosis associated with influenza infection. It is clinically important to recognize that deep cerebral venous thrombosis, although rare, might be one of the neurological complications of influenza infection. In the presence of bilateral thalamic lesions in patients with influenza infection, deep cerebral venous thrombosis should be considered in addition to acute necrotizing encephalopathy. Delays in diagnosis and commencement of anticoagulant therapy can lead to unfavorable outcomes.

Anti-NMDA receptor encephalitis due to large-cell neuroendocrine carcinoma of the uterus.

A 44-year-old woman presented with a large-cell neuroendocrine carcinoma and uterine endometrioid carcinoma with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Following the diagnosis of uterine cancer, the patient suddenly developed psychosis with abnormal behaviors, delusions, irritability, and forgetfulness. The cerebrospinal fluid tested positive for anti-NMDAR antibodies (encoding the NR1 subunit). The patient was diagnosed with paraneoplastic limbic encephalitis due to uterine cancer. Histology of multiple abdominal metastatic samples revealed a neuroendocrine tumor. Her consciousness improved temporarily after tumor resection and comprehensive immunomodulatory therapy. On day 104 after admission, the patient died of multiple organ failure. The autopsy revealed a perivascular infiltration of inflammatory cells in the amygdala and NMDAR-positive cells in the primary uterine cancer. Our findings demonstrated that neuroendocrine tumors can induce anti-NMDAR encephalitis, which is consistent with three previous reports. A comprehensive treatment with resection of the carcinoma, immunoglobulins, and plasma exchange can induce a partial improvement of the symptoms.

Transient hemiparesis due to a ruptured cerebral aneurysm in the prehospital setting.

A 67-year-old woman developed a sudden onset headache and left hemiparesis. Emergency medical technicians found that she was conscious, but had left hemiparesis. On arrival, she had an isolated headache without any neurological deficits, however, suddenly became comatose during a head CT examination, which demonstrated a subarachnoid haemorrhage. The head CT angiography on the second day revealed a cerebral aneurysm at the right middle cerebral artery, which was clipped on the same day. The patient demonstrated left haemiplegia and total aphasia after the operation, however, the neurological deficit gradually subsided and discharged on foot in 4 months without any deficits. Some patients with a subarachnoid haemorrhage may demonstrate transient neurological deficits, like those occurring during an ischaemic stroke, so emergency medical technicians and physicians should pay attention to treat such patients gently to avoid the re-rupture of a cerebral aneurysm, especially if the patient has headache symptoms.