渡辺 宏久

『An Essay on the Shaking Palsy』の発表以後、運動症状はパーキンソン病(PD)の診断と治療の中核である。近年、Movement Disorder Society-Unified Parkinson's Disease Rating Scale(MDS-UPDRS)において振戦、運動緩慢、筋強剛、姿勢保持障害、前傾姿勢、すくみ足の定義が明確化された。これまでの研究から、運動症状の発現に黒質神経細胞脱落と線条体のドパミン低下が関与することは間違いない。しかし、レボドパは運動症状を改善しても健常レベルまでは回復できず、レボドパ抵抗性の症状も少なくない。近年の研究の進歩は運動野、連合野、小脳などの運動症状への関与を明らかにし、運動症状の子細な分類も可能とした。人工知能(AI)とデジタルヘルステクノロジーを組み合わせた運動症状の客観的測定法開発もめざましい。新機軸で運動症状を"解剖"する時代に突入している。(著者抄録)

INTRODUCTION: This study aimed to evaluate whether novel individual voxel-based morphometry adjusting covariates (iVAC), such as age, sex, and total intracranial volume, could increase the accuracy of a diagnosis of multiple system atrophy (MSA) and enable the differentiation of MSA from Parkinson's disease (PD). METHODS: We included 53 MSA patients (MSA-C: 33, MSA-P: 20), 53 PD patients, and 189 healthy controls in this study. All participants underwent high-resolution T1-weighted imaging (WI) and T2-WI with a 3.0-T MRI scanner. We evaluated the occurrence of significant atrophic findings in the pons/middle cerebellar peduncle (MCP) and putamen on iVAC and compared these findings with characteristic changes on T2-WI. RESULTS: On iVAC, abnormal findings were observed in the pons/MCP of 96.2% of MSA patients and in the putamen of 80% of MSA patients; however, on T2-WI, they were both observed at a frequency of 60.4% in MSA patients. On iVAC, all but one MSA-P patient (98.1%) showed significant atrophic changes in the pons/MCP or putamen. By contrast, 69.8% of patients with MSA showed abnormal signal changes in the pons/MCP or putamen on T2-WI. iVAC yielded 95.0% sensitivity and 96.2% specificity for differentiating MSA-P from PD. CONCLUSION: iVAC enabled us to recognize the morphological characteristics of MSA visually and with high accuracy compared to T2-WI, indicating that iVAC is a potential diagnostic screening tool for MSA.

INTRODUCTION: The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD. METHODS: Patients with PD and ≥1 NMS and 'wearing-off' with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model. RESULTS: Overall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score. CONCLUSION: NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs.

The pathophysiology of neuralgic amyotrophy (NA) remains to be elucidated. However, high-resolution magnetic resonance imaging and ultrasound sonography have provided new insights into the mechanism underlying the development of NA and its diagnosis. We report a case of idiopathic distal NA with hyperintensity and thickening in the inferior trunk extending to the posterior and medial fasciculus of the left brachial plexus, which was detected by magnetic resonance neurography (MRN) with diffusion-weighted whole-body imaging with background body signal suppression (DWIBS). The abnormal signal intensity diminished after the improvement of symptoms following corticosteroid treatment. MRN with DWI can help diagnose distal NA and evaluate the post-therapeutic response.

Objective: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by motor neuron involvement. Although olfactory dysfunction has been described in ALS, clinicoradiological features associated with the olfactory dysfunction remain poorly understood. Methods: We enrolled 30 patients with ALS and age- and sex-matched 53 healthy controls (HCs). All participants underwent the odor stick identification test for Japanese (OSIT-J) and clinical assessments, including disease duration, ALSFRS-R, site of onset, forced vital capacity, and cognitive examinations that reflected the general, executive, memory and language function. We investigated the associations between OSIT-J score and clinical features and examined atrophic changes by voxel-based morphometry (VBM) analysis to MRI. Results: The OSIT-J score was significantly lower in ALS patients than HCs (6.9 ± 3.2 vs. 9.8 ± 1.9, p < 0.001). In ALS, there were significant relationships between OSIT-J score and age at examination, frontal assessment battery, word fluencies, digit span forward, and ADAS-Jcog recognition, but not education, disease type, duration, ALSFRS-R and, %VC. Multiple regression analysis with stepwise method showed the only ADAS-Jcog recognition substantially predicted OSIT-J score. VBM analysis with age, sex, total intracranial volume, and ADAS-Jcog recognition as covariates showed OSIT-J scores were substantially correlated with atrophic changes of left orbital cortex consisting of gyrus rectus and medial orbital gyrus and right hippocampus in ALS. Conclusion: ALS patients could show substantial olfactory dysfunction in association with orbital cortex and hippocampus involvements. The olfactory examination could be a useful marker for screening of frontotemporal alteration in 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.

Purpose: Maintenance of cognitive performance is important for healthy aging. This study aims to elucidate the relationship between brain networks and cognitive function in subjects maintaining relatively good cognitive performance. Methods: A total of 120 subjects, with equal number of participants from each age group between 20 and 70 years, were included in this study. Only participants with Addenbrooke's Cognitive Examination - Revised (ACE-R) total score greater than 83 were included. Anatomical T1-weighted MR images and resting-state functional MR images (rsfMRIs) were taken from all participants using a 3-tesla MRI scanner. After preprocessing, several factors associated with age including the ACE-R total score, scores of five domains, sub-scores of ACE-R, and brain volumes were tested. Morphometric changes associated with age were analyzed using voxel based morphometry (VBM) and changes in resting state networks (RSNs) were examined using dual regression analysis. Results: Significant negative correlations with age were seen in the total gray matter volume (GMV, r = -0.58), and in the memory, attention, and visuospatial domains. Among the different sub-scores, the score of the delayed recall (DR) showed the highest negative correlation with age (r = -0.55, p < 0.001). In VBM analysis, widespread regions demonstrated negative correlation with age, but none with any of the cognitive scores. Quadratic approximations of cognitive scores as functions of age showed relatively delayed decline compared to total GMV loss. In dual regression analysis, some cognitive networks, including the dorsal default mode network, the lateral dorsal attention network, the right / left executive control network, the posterior salience network, and the language network, did not demonstrate negative correlation with age. Some regions in the sensorimotor networks showed positive correlation with the DR, memory, and fluency scores. Conclusion: Some domains of the cognitive test did not correlate with age, and even the highly correlated sub-scores such as the DR score, showed delayed decline compared to the loss of total GMV. Some RSNs, especially involving cognitive control regions, were relatively maintained with age. Furthermore, the scores of memory, fluency, and the DR were correlated with the within-network functional connectivity values of the sensorimotor network, which supported the importance of exercise for maintenance of cognition.

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer's disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

BACKGROUND: No studies have examined the associations between adult height and ischemic stroke subtypes. METHODS: We conducted a population-based case-control study that included 2,451 thrombotic and 687 embolic stroke cases, as well as 1,623 intracerebral and 768 subarachnoid hemorrhage cases without history of stroke aged 40-79 years, and the same number of sex- and age-matched controls. Cases and controls were grouped according to the quintile cut-off values of height in controls, and the third quintile, which was approximately the average height group, was used as the reference group. Height was also examined as a continuous variable as divided by one standard deviation of height in controls. The analyses were carried out separately for participants aged 40-59 years and 60-79 years. RESULTS: In both younger and older men, continuous height was linearly inversely associated with total and thrombotic strokes, and the shortest quintile compared to the reference was associated with increased risks of these strokes. Although height was linearly inversely associated with embolic stroke and intracerebral hemorrhage in younger men, the shortest quintile did not show increased risks of these strokes. Height did not seem to be associated with total stroke and any stroke subtypes in younger women. In contrast, the tallest quintile was significantly associated with increased risks of total stroke and intracerebral hemorrhage, and height tended to be positively associated with these strokes in older women. CONCLUSIONS: We reported the associations between adult height and ischemic stroke subtypes for the first time, which differed according to sex and age-group.

The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T.

<jats:title>Abstract</jats:title><jats:p>Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.</jats:p>

Background: As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson’s disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. Objective: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. Methods: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. Results: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. Conclusion: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

Clioquinol has been implicated as a causative agent for subacute myelo-optico-neuropathy (SMON) in humans, although the mechanism remains to be elucidated. In this study, we utilized astrocyte-derived cell line, KT-5 cells to explore its potential cytotoxicity on glial cells. KT-5 cells were exposed in vitro to a maximum of 50 μM clioquinol for up to 24 h. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte trazolium bromide (MTT) assay of the cells revealed that clioquinol induced significant cell damage and death. We also found that clioquinol caused accumulation of microtubule-associated protein light chain-3 (LC3)-II and sequestosome-1 (p62) in a dose- and time-dependent manner, suggesting the abnormality of autophagy-lysosome pathway. Consistent with these findings, an exposure of 20 μM clioquinol induced the accumulation of cellular autophagic vacuoles. Moreover, an exposure of 20 μM clioquinol provoked a statistically significant reduction of intracellular lysosomal acid hydrolases activities but no change in lysosomal pH. It also resulted in a significant decline of intracellular ATP levels, enhanced cellular levels of reactive oxygen species, and eventually cell death. This cell death at least did not appear to occur via apoptosis. 10 μM Chloroquine, lysosomal inhibitor, blocked the autophagic degradation and augmented clioquinol-cytotoxicity, whereas rapamycin, an inducer of autophagy, rescued clioquinol-induced cytotoxicity. Thus, our present results strongly suggest clioquinol acts as a potentially cytotoxic agent to glial cells. For future clinical application of clioquinol on the treatment of neurological and cancer disorders, we should take account of this type of cell death mechanism.

＜文献概要＞はじめに 日常臨床において,脊髄小脳路を侵す疾患を意識しながら診療をする場面は決して多くない.その理由を考えてみると,まず脊髄小脳路の重要な役割は筋紡錘や腱器官などから固有感覚を小脳へと伝えることにあるが,体性感覚の中でも,意識に上る表在感覚や,位置覚や振動覚など意識に上る深部感覚と違い,意識に上らない固有感覚の評価は,一般的な神経学的診察で困難であるため,固有感覚と密接に関連する脊髄小脳路病変を意識する機会が限られていることが挙げられる.次に,脊髄小脳路を正しく評価できる補助診断指標が日常臨床で十分に使えないことが挙げられる.脊髄小脳路の周囲には,皮質脊髄路,後索,後根を含めてさまざまな構造物があるため,固有感覚の障害による症状であるのか,ほかの運動系や感覚系の障害による症状であるのかを判断するためには画像検査が重要となるが,日常臨床においてMRIを用いて正確に脊髄小脳路と周囲の構造物とを明確に区別することは容易ではない.一方,体幹や下肢の運動失調の発現は後索の単独病変では生じず,後根や後根神経節,さらには脊髄小脳路などの障害が必要とする報告があること,姿勢の調節には下肢からの固有知覚信号が必要であることなどを踏まえると,脊髄小脳路病変を伴う疾患を知り,その臨床像を見直すことは重要である.そこで本稿では,ここで扱う脊髄小脳路の走行を簡単に整理したうえで,まず脊髄小脳路を侵す疾患として,物理的に脊髄小脳路を圧排した転移性脊髄腫瘍の臨床像や,比較的純粋な脊髄小脳路病変をみていると考えられる下部延髄外側梗塞症例の臨床像を整理する.さらに,脊髄小脳路を侵すことが報告されている非変性疾患と変性疾患について,誌面の許す範囲で整理し,今後の課題について考えてみる.