渡辺 宏久

A group of patients with coronavirus disease 2019 (COVID-19) exhibited various persistent or new systemic symptoms, including psychiatric symptoms, sleep disturbances, exercise intolerance, arthralgia, headache, cognitive decline, brain fog, and autonomic symptoms, all of which persisted long after the resolution of infectious symptoms. Several imaging studies have shown that long COVID cases present with decreased glucose metabolism and progressive brain atrophy. Although no single pathological hypothesis thoroughly explains the varied clinical presentations and timings, the following have attracted attention: 1) persistent viral infection, 2) persistent inflammation, 3) involvement of the autoimmune system, and 4) mitochondrial dysfunction. In all these hypotheses, inflammatory cytokines may be involved in orthostatic dysregulation by decreasing the expression and activity of ACE2, consequently changing the blood pressure through vagus nerve hyperactivation. Myopathy and peripheral neuropathy may also be caused by direct infection of the muscles and nerves, hypoxia, mitochondrial damage, and cytokine storm. Furthermore, multiple theories regarding the mechanisms by which systemic inflammatory findings affect the central nervous system have been postulated, including neuroinflammation caused by inflammatory cells crossing the blood-brain barrier via choroid plexus cells and the involvement of various autoantibodies. Despite these findings, no definitive consensus has been reached due to the complexity and diversity of COVID-19 pathophysiology. Thus, it is essential to understand the neurological symptoms and pathophysiology involved in long COVID.

＜文献概要＞はじめに パーキンソン病(PD)患者は,首を前方に突き出してやや下げ(頸椎の生理的後彎は保持),体幹を軽度前傾で前屈,ときに側屈させ,肘関節や膝関節が屈曲する姿勢を呈する.この姿勢異常は早期から認められるが,ドパミン系製剤に反応を示すことが多い.一方,C7-T12を中心として45度以上,もしくはL1を中心として30度以上高度に腰が前屈するcamptocormia,10〜15度以上側屈する斜め徴候(Pisa症候群),頸椎の生理的前彎が消失するほどの高度の首下がり(dropped head syndrome)など,日常生活に影響を与える重度の姿勢異常を呈する症例もある.これら高度の姿勢異常は,内科的治療にしばしば抵抗性であるため,その病態の理解に基づいた対応が必要となる.高度な姿勢異常の病態は,主には筋強剛や体軸のジストニアに伴う屈筋群と伸筋群の筋緊張のバランス障害が原因と考えられているが,それ以外にも局所性ミオパチーによる筋力低下,中枢性の固有感覚障害による身体図式障害,空間認知機能障害など,多彩な因子が関与する(図1).また,ジストニアに伴う姿勢異常から二次的な筋障害(stretch injury)をきたし,ジストニアと筋原性の病態が混在する場合も少なくない.姿勢異常が持続すると,脊椎の変形や関連する結合織の変化も助長され,ジストニアの関与がわかりづらくなる可能性もある.さらに,抗パーキンソン病薬,コリンエステラーゼ阻害薬などの追加後に発症,増悪する例もある.加えて,姿勢異常をきたす基礎疾患は多岐にわたるため,適切な鑑別が必要となる.以下,3種類の姿勢異常について,用語の由来,定義,頻度,原因疾患と病態,治療について述べるとともに,脊椎手術の位置づけについてまとめる.

Glycolipids are now known to be rapidly converted to mediators for inflammatory reactions or to signaling molecules that control inflammatory events in the nervous system. The present study aimed to explore whether disturbed glycolipids metabolism in the nervous system is present in patients with a neuroinflammatory disorder, encephalo-myelo-radiculo-neuropathy (EMRN), because most EMRN patients have been reported to exhibit autoantibodies against neutral glycolipids. Although molecular pathogenesis of this disorder remains unknown, we tried to search the immunochemical abnormalities in this disorder. ELISA for activated peripheral C5 complement and mass spectrometry analysis of cerebrospinal fluid clearly disclosed a significant upregulation of active C5 complement, C5a levels in sera as well as a significant accumulation of species-specific ceramides but not sphingomyelin in cerebrospinal fluid from EMRN patients. Furthermore, we confirmed the occurrence of anti-neutral glycolipids antibodies in all EMRN patients. Thus, the present study might indicate the pathophysiology of this disorder is the dysregulation of glycolipids metabolism and abnormal production of autoantibodies against neutral glycolipids resulting in the abnormal complement activation, although molecular basis for these sphingolipids dysregulation and the occurrence of autoantibodies against glycolipids remains to be elucidated at present. The present study implicates a new therapeutic strategy employing anti-ceramide and/or anti-complement therapy for this disorder.

The full spectrum of human herpesviruses (HHV)-associated neuroinfectious diseases in immunocompetent adults remains unclear. Hence, we sought to elucidate the epidemiology and clinical features of these diseases. The study subjects were patients over 16 years old suspected of neuroinfectious diseases who underwent spinal tap performed by neurologists in our university hospital between April 2013 and March 2018. The presence of seven HHV DNAs in cerebrospinal fluid (CSF) was determined by real-time PCR. HHV DNAs were detected in 33 (10.2%) of the 322 patients. The most frequently detected herpesvirus was varicella zoster virus (VZV) (19 patients), followed by HHV-6 (four patients), herpes simplex virus (HSV)-1 (three patients), HSV-2 (three patients), and Epstein-Barr virus (two patients). HHV DNAs were detected in CSF collected from patients with various neuroinfectious diseases, including myelitis, peripheral neuritis, encephalitis, and meningitis. All patients with HSV-1 DNA had encephalitis, whereas all patients with HSV-2 DNA had meningitis. Eleven of the 19 patients with VZV DNA had meningitis. Patients with VZV-associated encephalitis (median age, 80 years) were significantly older than non-encephalitis patients (median age, 60.5 years) (P = 0.046). Although post-herpetic neuralgia was observed in seven (54%) of the 13 patients with VZV and without encephalitis, no such neurological sequela was observed in the four encephalitis patients. In conclusion, HHVs were associated with approximately 10% of neuroinfectious diseases in this cohort. VZV was the most common pathogen, probably due to the large number of VZV meningitis patients. In addition, patients with VZV-associated meningitis were significantly younger than patients with VZV-associated encephalitis.

BACKGROUND AND PURPOSE: To clarify the relationship between fiber-specific white matter changes in amyotrophic lateral sclerosis (ALS) and clinical signs of upper motor neuron (UMN) involvement, we performed a fixel-based analysis (FBA), a novel framework for diffusion-weighted imaging analysis. METHODS: We enrolled 96 participants, including 48 nonfamilial ALS patients and 48 age- and sex-matched healthy controls (HCs), in this study and conducted whole-brain FBA and voxel-based morphometry analysis. We compared the fiber density (FD), fiber morphology (fiber cross-section [FC]), and a combined index of FD and FC (FDC) between the ALS and HC groups. We performed a tract-of-interest analysis to extract FD values across the significant regions in the whole-brain analysis. Then, we evaluated the associations between FD values and clinical variables. RESULTS: The bilateral corticospinal tracts (CSTs) and the corpus callosum (CC) showed reduced FD and FDC in ALS patients compared with HCs (p < 0.05, familywise error-corrected), and the comparison of FCs revealed no region that was significantly different from another. Voxel-based morphometry showed cortical volume reduction in the regions, including the primary motor area. Clinical scores showed correlations with FD values in the CSTs (UMN score: rho = -0.530, p < 0.001; central motor conduction time [CMCT] in the upper limb: rho = -0.474, p = 0.008; disease duration: rho = -0.383, p = 0.007; ALS Functional Rating Scale-Revised: rho = 0.340, p = 0.018). In addition, patients whose CMCT was not calculated due to unevoked waves also showed FD reduction in the CSTs. CONCLUSIONS: Our findings suggest that FD values in the CST estimated via FBA can be potentially used in evaluating UMN impairments.

＜文献概要＞TDP-43は主に核内に存在し,RNAの生合成をはじめ様々なプロセスに関与する.TDP-43の核内局在の喪失と異常な翻訳後修飾を受けた不溶化TDP-43の存在を特徴とする一群は,TDP-43proteinopathyと呼ばれ,筋萎縮性側索硬化症と前頭側頭葉変性症が代表的な疾患である.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, alpha-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of alpha-blocker with immunotherapy may ameliorate dysautonomia.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, α-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of α-blocker with immunotherapy may ameliorate dysautonomia.

Nemaline myopathy (NM) is a rare muscle disease with various clinical types. In some cases, NM can lead to type 2 respiratory failure and right heart failure. We herein report a patient with congenital NM with nebulin gene mutation who presented with acute right heart failure and type 2 respiratory failure due to respiratory muscle paralysis after upper respiratory tract infection, needing a permanent ventilator for assistance. However, the limb and trunk muscle strengths were within normal limits. This case showed that NM should be considered as a cause of right heart failure and type 2 respiratory failure.

The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathological changes from those associated with the normal human aging process. Using longitudinal MRI data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter were 2,497.5 mm3 per year and 2,579.8 mm3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, and caudate, whereas the pallidum showed an increasing volume with age. Overall, regions maturing late in development (frontal, parietal) are more vulnerable to longitudinal decline, whereas those that fully mature in the early stage (temporal, occipital) are mainly affected by cross sectional changes in healthy older cohort. This may suggest that, for a successful healthy aging, the former needs to be maximally developed at an earlier age to compensate for the longitudinal decline later in life and the latter to remain relatively preserved even in old age, consistent with both concepts of reserve and brain maintenance.Significance StatementAging is associated with gray matter (GM) decline, yet some individuals tend to remain cognitively healthy even in advanced age. What differentiates the brains of "healthy agers" from those individuals who are prone to faster cognitive decline still remains unclear. Using longitudinal MRI data from a carefully selected cohort, we examined the brain aging characteristics of healthy agers. Our findings showed that, even in this population, frontal-parietal regions have faster longitudinal rate of GM decline, whereas some temporal-occipital regions appeared relatively preserved. These findings may suggest that, for a successful healthy aging, frontal-parietal regions need to be maximally developed to compensate for the longitudinal decline later in life and the temporal-occipital regions to remain relatively preserved even in old age.

INTRODUCTION: The impact of deep brain stimulation (DBS) on speech rhythm and its mechanism remains unclear. We investigated speech rhythm characteristics of patients with Parkinson's disease (PD) treated with subthalamic nucleus (STN) DBS to understand the underlying pathophysiology better. METHODS: We enrolled a total of 105 participants and evaluated speech rhythm performances among patients with PD who had undergone STN-DBS (the PD-DBS group), patients with PD treated only with medication (the PD-Med group), patients with cerebellar ataxia (the CA group), and healthy controls (the HC group). Each participant was asked to repeat the syllable/pa/at a comfortable self-chosen steady pace. A widely-used software (the Motor Speech Profile) program performed an acoustic analysis. RESULTS: Compared to the PD-Med and HC groups, speech rate instability (DDKjit) was significantly higher in the PD-DBS and CA groups (p < 0.01). However, after DBS was turned off, the DDKjit of the PD-DBS group improved to a level comparable to that of the PD-Med and HC groups. In contrast to the significantly higher variability of speech volume (DDKcvi) in the CA group, the PD-DBS group showed similar DDKcvi to the PD-Med and HC groups. CONCLUSIONS: STN-DBS affects the speech rate stability of patients with PD. Speech rhythm disorders caused by STN-DBS were phenotypically similar to that in CA in terms of interval variability but different regarding amplitude variability. Further studies are warranted to elucidate the underlying pathophysiology of speech rhythm disorders in PD patients treated with DBS.

DNAJC7 has recently been identified as an amyotrophic lateral sclerosis (ALS) gene via large-scale exome analysis, and its involvement in ALS is still unclear in various populations. This study aimed to determine the frequencies and characteristics of the DNAJC7 variants in a Japanese ALS cohort. A total of 807 unrelated Japanese patients with sporadic ALS were screened via exome analysis. In total, we detected six rare missense variants and one splice-site variant of the DNAJC7 gene, which are not reported in the Japanese public database. Furthermore, the missense variants are located around the TPR domain, which is important for the function of DNAJC7. The total frequency of the DNAJC7 variants in Japanese ALS patients was estimated at 0.87%. Collectively, these results suggest that variants of DNAJC7 are rare cause of Japanese patients with sporadic ALS.

The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this document, the general part is 1) What is neurological disease? 2) Current status of neurological disease overcoming research, 3) Significance and necessity of neurological disease overcoming research, 4) Research promotion system for overcoming neurological disease, 5) the roadmap for overcoming neuromuscular diseases, 6) a summary version of these recommendations are explained using figures that are easy for the general public to understand.

安静時機能的MRIは非侵襲的で比較的短時間で撮像できるため、多くの研究で利用をされている。その情報には空間情報に加え時系列情報も入っているため、その解析は複雑で多くの解析手法が存在する。一方で、その時系列情報により脳内の離れた場所においても同期して活動する脳領域を抽出でき、これまで可視化することが難しかった脳内の機能的なネットワークを明らかにできるようになった。今回、我々が開発した新たな解析手法やこれまで明らかにしてきた加齢による脳内ネットワーク変化や神経変性疾患での変化などを中心に紹介する。(著者抄録)

The thalamus is critical for the brain's integrative hub functions; however, the localization and characterization of the different thalamic hubs remain unclear. Using a voxel-level network measure called functional connectivity overlap ratio (FCOR), we examined the thalamus' association with large-scale resting-state networks (RSNs) to elucidate its connector hub roles. Connections to the core-neurocognitive networks were localized in the anterior and medial parts, such as the anteroventral and mediodorsal nuclei areas. Regions functionally connected to the sensorimotor network were distinctively located around the lateral pulvinar nucleus but to a limited extent. Prominent connector hubs include the anteroventral, ventral lateral, and mediodorsal nuclei with functional connections to multiple RSNs. These findings suggest that the thalamus, with extensive connections to most of the RSNs, is well placed as a critical integrative functional hub and could play an important role for functional integration facilitating brain functions associated with primary processing and higher cognition.