渡辺 宏久

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end.

Recent studies have demonstrated that connector hubs, regions considered critical for the flow of information across neural systems, are mostly involved in neurodegenerative dementia. Considering that aging can significantly affect the brain's intrinsic connectivity, identifying aging's impact on these regions' overall connection strength is important to differentiate changes associated with healthy aging from neurodegenerative disorders. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of 175 healthy volunteers aging from 21 to 86 years old, we computed an intrinsic connectivity contrast (ICC) metric, which quantifies a region's overall connectivity strength, for whole brain, short-range, and long-range connections and examined age-related changes of this metric over the adult lifespan. We have identified a limited number of hub regions with ICC values that showed significant negative relationship with age. These include the medial precentral/midcingulate gyri and insula with both their short-range and long-range (and thus whole-brain) ICC values negatively associated with age, and the angular, middle frontal, and posterior cingulate gyri with their long-range ICC values mainly involved. Seed-based connectivity analyses further confirmed that these regions are connector hubs with connectivity profile that strongly overlapped with multiple large-scale brain networks. General cognitive performance was not associated with these hubs' ICC values. These findings suggest that even healthy aging could negatively impact the efficiency of regions critical for facilitating information transfer among different functional brain networks. The extent of the regions involved, however, was limited.

Cerebellar ataxia-predominant multiple system atrophy (MSA-C) and cortical cerebellar atrophy are representative diseases of adult-onset sporadic degenerative ataxia. Both diseases are distinctly different because of α-synuclein pathology. However, it takes approximately 2 years for cerebellar ataxia to progress to concomitant severe autonomic dysfunction in patients with MSA-C. The period of only cerebellar ataxia (mono system atrophy) may extend to more than 10 years. Understanding mono system atrophy is vital for the early diagnosis and drug development for MSA. In this review, we discuss mono system atrophy focusing on the concept and natural history and the possibility of the of early diagnosis and disease-modifying therapy for MSA.

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

パーキンソン病(PD)では、明確なパーキンソニズムを認める前に、軽微なパーキンソニズムを呈する時期(prodromal PD)のあることが明らかとなり、その病態を説明しうるBraak仮説や伝播仮説を理論的基盤として、2015年にBergらによりprodromal PDの研究診断基準が提唱された。1)prodromal PD研究診断基準の理論的基盤、2)prodromal PD研究診断基準の有用性と課題、3)PDの超早期診断へ向けた課題、などについて概説した。

Background:Nonmotor symptoms (NMSs) of Parkinson's disease (PD) impair health-related quality of life. Objectives:To identify changes in NMSs during 52 weeks in Japanese PD patients exhibiting motor fluctuations. Methods:In PD patients with ≥1 NMS and wearing-off, changes in total/subscore of the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part I and 8-item PD Questionnaire were assessed. Group-based trajectory models were used to characterize longitudinal patterns of MDS-UPDRS Part I. Results:Data from 996 patients were analyzed. MDS-UPDRS Part I subscores for cognitive function decreased linearly over time. Total and subscores for apathy and lightheadedness on standing significantly deteriorated with fluctuations, whereas other subscores fluctuated without significant deterioration. Changes in the MDS-UPDRS Part I total score correlated with changes in the 8-item PD Questionnaire total score. Based on group-based trajectory models, longitudinal pattern analysis of MDS-UPDRS Part I scores yielded the following 3 separate groups: unchanged (63.8%), deteriorated (20.1%), and improved (16.2%). The improved group had significantly more NMSs at baseline, significantly higher MDS-UPDRS Part I/8-item PD Questionnaire total scores, and modified Hoehn and Yahr scores, and had received treatment for NMSs. The multivariate analysis revealed significant associations between severe motor disability and receiving any treatment for NMSs at baseline and improvement of MDS-UPDRS Part I total scores. Conclusions:Changes in MDS-UPDRS Part I scores were variable and related to changes in health-related quality of life in PD patients with motor fluctuations.

<title>Abstract</title> Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the <italic>ACSL5</italic> locus (top SNP <italic>p</italic> = 2.97 × 10⁻⁸). We validated the association with <italic>ACSL5</italic> in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP <italic>p</italic> = 1.82 × 10⁻⁴). In the combined meta-analysis, the intronic <italic>ACSL5</italic> SNP rs3736947 showed the strongest association (<italic>p</italic> = 7.81 × 10⁻¹¹). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: <italic>ERGIC1</italic>, <italic>RAPGEF5</italic>, <italic>FNBP1</italic>, and <italic>ATXN3</italic>. These results advance our understanding of the genetic basis of sporadic ALS.

PURPOSE: The estimation of functional connectivity (FC) measures using resting state functional MRI (fMRI) is often affected by head motion during functional imaging scans. Head motion is more common in the elderly than in young participants and could therefore affect the evaluation of age-related changes in brain networks. Thus, this study aimed to investigate the influence of head motion in FC estimation when evaluating age-related changes in brain networks. METHODS: This study involved 132 healthy volunteers divided into 3 groups: elderly participants with high motion (OldHM, mean age (±SD) = 69.6 (±5.31), N = 44), elderly participants with low motion (OldLM, mean age (±SD) = 68.7 (±4.59), N = 43), and young adult participants with low motion (YugLM, mean age (±SD) = 27.6 (±5.26), N = 45). Head motion was quantified using the mean of the framewise displacement of resting state fMRI data. After preprocessing all resting state fMRI datasets, several resting state networks (RSNs) were extracted using independent component analysis (ICA). In addition, several network metrics were also calculated using network analysis. These FC measures were then compared among the 3 groups. RESULTS: In ICA, the number of voxels with significant differences in RSNs was higher in YugLM vs. OldLM comparison than in YugLM vs. OldHM. In network analysis, all network metrics showed significant (P < 0.05) differences in comparisons involving low vs. high motion groups (OldHM vs. OldLM and OldHM vs. YugLM). However, there was no significant (P > 0.05) difference in the comparison involving the low motion groups (OldLM vs. YugLM). CONCLUSION: Our findings showed that head motion during functional imaging could significantly affect the evaluation of age-related brain network changes using resting state fMRI data.

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, and the cognitive status fluctuates over time. However, individual changes in longitudinal cognitive performance in PD are not fully understood. We evaluated three visual indices (visuoperception, visuoconstruction, and visuospatial ability) and four cognitive domains (attention/working memory, executive function, memory, and language) at baseline (Time1) and at 1-year follow-up (Time2) in 36 patients with PD and 32 healthy controls (HCs). To explore the magnitude and frequency of cognitive changes, we analyzed data using the simple difference method and the standardized regression-based method. We also explored the correlations between changes in test scores and several clinical predictors, using logistic regression analysis. At 1 year, patients with PD showed higher rates of change in scores on several cognitive tests, especially the Incomplete Letters test of visuoperception, compared to HCs. After adjusting for demographic variables, the visuoperceptual change was 61.1% overall, with the largest effect size. The changes in scores of visuoperception correlated with those of memory (r = 0.672, p < 0.001), language (r = 0.389, p < 0.05), and visuospatial ability (r = 0.379, p < 0.05). The severity of olfactory disturbance, the MDS-UPDRS Part I score, and younger PD onset predicted the significant changes observed in the Incomplete Letters test scores. Visuoperception changed more in non-demented PD patients than in HCs at 1-year follow-up. The changes in visuoperception could relate to involvement of the ventral occipitotemporal pathway, the more widespread temporal lobe, and brain reserve in PD.

多系統萎縮症(MSA)は,病理学的にglial cytoplasmic inclusionの出現を特徴とする進行性の神経変性疾患で,パーキンソニズム,小脳失調,自律神経不全,錐体路徴候を経過中に種々の程度で認める.孤発性が圧倒的に多い.パーキンソニズムが優位な臨床病型はMSA-P,小脳失調が優位な臨床病型はMSA-Cと呼ばれる.欧米ではMSA-Pが多く,日本ではMSA-Cが多い.平均発症年齢は55〜60歳で,若年発症例や,75歳を超える高齢発症例もある.診断には運動機能異常(パーキンソン症状もしくは小脳性運動失調)と自律神経不全の存在が必須で,両系統の症状が揃うまでの期間の中央値は2年である.早期からのディサースリアや嚥下障害をはじめとするRed flagsサイン(診断を支持する特徴)にも留意する.頭部MRIのほか,Tilt試験,ウロダイナミックスタディ,123 I-metaiodobenzylguanidine(MIBG)心筋シンチグラフィーなどが補助検査として有用である.予後は6年から10年で,突然死が多いことが特徴であり,高度な自律神経不全は予後不良因子である.従来は稀と考えられていた認知症の合併をはじめ,多様な臨床病型を呈する一群のあることも明らかとなっている.(著者抄録)

＜文献概要＞68歳,男性。10日前に発症した左上肢帯状疱疹に対してバラシクロビルの内服で治療開始した。5日前より左上肢挙上困難となり,当科を紹介受診した。左上肢の筋力低下があり,MRIで脳・脊髄炎の所見はなかったが,髄液を用いたRT-PCR法によりvaricella-zoster virus(VZV)-DNAが検出された。以上の所見より帯状疱疹による運動神経障害と診断し,ステロイドパルス療法とアシクロビル20mg/kg/日の点滴静注を行い,治療2週間後には髄液中VZV-DNAが陰性化し,症状も徐々に改善,48週で完治した。自験例の経験より,運動神経障害を伴う重症な帯状疱疹においては,早期に診断し抗ウイルス薬の点滴投与で治療することが重要と考えた。