川畑 和也

The olfactory nerve possesses unique anatomical features, including direct central nervous system (CNS) projection and continuous regeneration. Scientific advances have elucidated mechanisms such as combinatorial receptor coding and signal amplification. This review summarizes these foundations and examines olfactory dysfunction in COVID-19 and Parkinson's disease (PD). In COVID-19, evidence suggests that SARS-CoV-2 targets sustentacular cells rather than olfactory neurons, causing gene downregulation and parosmia attributed to incomplete peripheral filtering, while direct CNS invasion remains rare. In PD, olfactory loss is a prodromal feature. However, seed amplification assays reveal that alpha-synuclein aggregation in the nasal mucosa does not fully correlate with olfactory dysfunction, as reflected by differences between PD and Multiple System Atrophy. This, together with correlations with cardiac sympathetic denervation, challenges simple pathogen propagation hypotheses. We propose that PD-related hyposmia reflects a systemic vulnerability involving deficits in energy metabolism and neural network organization, rather than solely peripheral protein aggregation. Understanding these pathologies requires a multifaceted approach beyond anatomical lesions.

Abstract Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains an REM sleep centre, the sublaterodorsal nucleus (SLD), which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume (GMV) using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 postmortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical measures, including autonomic functions. VBM revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared to controls with a moderate effect size (Cohen’s d = 0.46, Bonferroni-corrected p = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinson’s Disease-Autonomic dysfunction (SCOPA-AUT) scores (partial r = -0.237, p = 0.019 and partial r = -0.236, p = 0.019, respectively). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homolog of the murine SLD, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for _α -synucleinopathies.

OBJECTIVE: About 30%-50% of patients with amyotrophic lateral sclerosis (ALS) show cognitive impairment ranging from mild dysexecutive syndrome to frontotemporal dementia. We aimed to develop a brief cognitive test, convenient auditory-based language and executive function test (CABLET), for rapid detection of cognitive impairment in ALS, with reduced load on motor function. METHOD: The CABLET comprises two tests using auditory verbal stimuli: Test 1, assessing word repetition and lexical judgment, and Test 2, evaluating verbal short-term memory and semantics knowledge. The administration time of Test 1 and Test 2 was 1 and 3-5 min, respectively. Overall, 61 patients with ALS and 46 age-, sex-, and education-matched healthy controls participated in this study. All participants underwent existing neuropsychological tests and the CABLET. We investigated the applicability of the CABLET to detect ALS with cognitive impairment (ALSci) from normal cognition. RESULTS: Receiver operating characteristic analyses showed that both the CABLET total and Test 2 had good diagnostic accuracy (area under the curve [AUC]: total = 0.894, Test 2 = 0.893). Test 2 had the highest sensitivity (100% sensitivity and 71.4% specificity). No significant difference existed in the AUC between the analyses with and without age, education, and disease severity as covariates. Correlations were observed between the CABLET and established neuropsychological tests, supporting its good convergent validity. CONCLUSIONS: Our findings indicated that the CABLET could be useful in identifying ALSci quickly without adjusting for confounding factors. Further validation is required to evaluate it in larger groups and compare with ALS-specific cognitive screen.

INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. METHODS: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG. RESULTS: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score. CONCLUSION: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

Cognitive and movement processes involved integration of several large-scale brain networks. Central to these integrative processes are connector hubs, brain regions characterized by strong connections with multiple networks. Growing evidence suggests that many neurodegenerative and psychiatric disorders are associated with connector hub dysfunctions. Using a network metric called functional connectivity overlap ratio, we investigated connector hub alterations in Parkinson's disease. Resting-state functional MRI data from 99 patients (male/female = 44/55) and 99 age- and sex-matched healthy controls (male/female = 39/60) participating in our cross-sectional study were used in the analysis. We have identified two sets of connector hubs, mainly located in the sensorimotor cortex and cerebellum, with significant connectivity alterations with multiple resting-state networks. Sensorimotor connector hubs have impaired connections primarily with primary processing (sensorimotor, visual), visuospatial, and basal ganglia networks, whereas cerebellar connector hubs have impaired connections with basal ganglia and executive control networks. These connectivity alterations correlated with patients' motor symptoms. Specifically, values of the functional connectivity overlap ratio of the cerebellar connector hubs were associated with tremor score, whereas that of the sensorimotor connector hubs with postural instability and gait disturbance score, suggesting potential association of each set of connector hubs with the disorder's two predominant forms, the akinesia/rigidity and resting tremor subtypes. In addition, values of the functional connectivity overlap ratio of the sensorimotor connector hubs were highly predictive in classifying patients from controls with an accuracy of 75.76%. These findings suggest that, together with the basal ganglia, cerebellar and sensorimotor connector hubs are significantly involved in Parkinson's disease with their connectivity dysfunction potentially driving the clinical manifestations typically observed in this disorder.

OBJECTIVE: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in ET patients by analyzing resting-state networks (RSNs). METHODS: Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and HCs. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. RESULTS: Preoperatively, ET patients showed a significant decrease in FC in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in FC in the SMN correlated with the severity of tremor. After MRgFUS thalamotomy, ET patients still exhibited a significant decrease in FC in a small area of the SMN, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post-MRgFUS patients, the FC in the SMN and the VSN significantly increased after treatment. Quantitative evaluation of the FCs in these three groups showed that the SMN and VSN increased postoperatively and demonstrated a trend toward those of HCs. CONCLUSIONS: The SMN and CN, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in ET patients compared with HCs, tended to normalize postoperatively. This could be related to the hypothesis that visual feedback is involved in tremor severity in ET patients. Overall, the analysis of the RSNs by rsfMRI reflected the pathophysiology with the intervention of MRgFUS thalamotomy in ET patients and demonstrated a possibility of a biomarker for successful treatment.

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.

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.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is known to cause not only respiratory but also neuropsychiatric symptoms, which are assumed to be derived from a cytokine storm and its effects on the central nervous systems. Patients with COVID-19 who develop severe respiratory symptoms are known to show severe neuropsychiatric symptoms such as cerebrovascular disease and encephalopathy. However, the detailed clinical courses of patients with neuropsychiatric symptoms caused by mild or asymptomatic COVID-19 remain poorly understood. Here, we present a case of COVID-19 who presented with severe and prolonged neuropsychiatric symptoms subsequent to mild respiratory symptoms. CASE PRESENTATION: A 55-year-old female with COVID-19 accompanied by mild respiratory symptoms showed delusion, psychomotor excitement, and poor communication ability during quarantine outside the hospital. Considering her diminished respiratory symptoms, her neuropsychiatric symptoms were initially regarded as psychogenic reactions. However, as she showed progressive disturbance of consciousness accompanied by an abnormal electroencephalogram, she was diagnosed with post-COVID-19 encephalopathy. Although her impaired consciousness and elevated cytokine level improved after steroid pulse therapy, several neuropsychiatric symptoms, including a loss of concentration, unsteadiness while walking, and fatigue, remained. CONCLUSIONS: This case suggests the importance of both recognizing that even apparently mild COVID-19-related respiratory symptoms can lead to severe and persistent neuropsychiatric symptoms, and elucidating the mechanisms, treatment, and long-term course of COVID-19-related neuropsychiatric symptoms in the future.

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.

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.

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.

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: 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.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder associated with motor impairment and behavioral/cognitive involvement. We examined decision-making features and changes in the neural hub network in patients with ALS using a probabilistic reversal learning task and resting-state network analysis, respectively. METHODS: Ninety ALS patients and 127 cognitively normal participants performed this task. Data from 62 ALS patients and 63 control participants were fitted to a Q-learning model. RESULTS: ALS patients had anomalous decision-making features with little shift in choice until they thought the value of the two alternatives had become equal. The quantified parameters (Pαβ) calculated by logistic regression analysis with learning rate and inverse temperature well represented the unique choice pattern of ALS patients. Resting-state network analysis demonstrated a strong correlation between Pαβ and decreased degree centrality in the anterior cingulate gyrus and frontal pole. INTERPRETATION: Altered decision-making in ALS patients may be related to the decreased hub function of medial prefrontal areas.