This scientific commentary refers to ‘Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity’ by Ruck et al. (https://doi.org/10.1093/brain/awac064).
{"title":"Campath, clones and the cause of autoimmunity.","authors":"A. Coles","doi":"10.1093/brain/awac162","DOIUrl":"https://doi.org/10.1093/brain/awac162","url":null,"abstract":"This scientific commentary refers to ‘Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity’ by Ruck et al. (https://doi.org/10.1093/brain/awac064).","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114731562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena Vacchi, E. Lazzarini, S. Pinton, G. Chiaro, G. Disanto, F. Marchi, T. Robert, C. Staedler, S. Galati, C. Gobbi, L. Barile, A. Kaelin-Lang, G. Melli
Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). However, pathological τ has also been observed in α-synucleinopathies like Parkinson's Disease (PD) and Multiple System Atrophy (MSA). Based on the involvement of peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with PD, MSA, PSP, CBD, and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibers in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 KDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both resulted more expressed in PSP/CBD by real-time PCR. ELISA assay demonstrated significantly higher levels of total τ protein in skin lysates of PSP/CBD compared to the other groups. Multivariate regression analysis and ROC curves analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for PSP/CBD vs. PD (sensitivity 90%, specificity 69%) and PSP/CBD vs. MSA (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in PSP/CBD. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiologic and pathologic conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.
{"title":"Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.","authors":"Elena Vacchi, E. Lazzarini, S. Pinton, G. Chiaro, G. Disanto, F. Marchi, T. Robert, C. Staedler, S. Galati, C. Gobbi, L. Barile, A. Kaelin-Lang, G. Melli","doi":"10.1093/brain/awac161","DOIUrl":"https://doi.org/10.1093/brain/awac161","url":null,"abstract":"Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). However, pathological τ has also been observed in α-synucleinopathies like Parkinson's Disease (PD) and Multiple System Atrophy (MSA). Based on the involvement of peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with PD, MSA, PSP, CBD, and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibers in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 KDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both resulted more expressed in PSP/CBD by real-time PCR. ELISA assay demonstrated significantly higher levels of total τ protein in skin lysates of PSP/CBD compared to the other groups. Multivariate regression analysis and ROC curves analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for PSP/CBD vs. PD (sensitivity 90%, specificity 69%) and PSP/CBD vs. MSA (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in PSP/CBD. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiologic and pathologic conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131796945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ockham's razor, not a barber's weapon but a writer's tool.","authors":"A. Danek, Thom S. Rainer, S. Della Sala","doi":"10.1093/brain/awac159","DOIUrl":"https://doi.org/10.1093/brain/awac159","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115416172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Conejero, L. Collombier, J. López-Castromán, T. Mura, S. Alonso, E. Olié, V. Boudousq, Fabrice Boulet, C. Arquizan, Charlotte Boulet, A. Wacongne, C. Heitz, C. Castelli, S. Mouchabac, P. Courtet, M. Abbar, E. Thouvenot
Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of patients experiencing a first episode of motor functional neurological disorder with recent symptom onset, and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from 2 hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r=-0.75, p = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r=-0.81, p= 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r= -0.65, p = 0.01 and r= -0.75, p = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r=-0.81, p= 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic "state markers" associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.
运动功能性神经障碍的静息脑代谢特征尚不清楚。本研究旨在探讨一组新近出现症状的首发运动功能神经障碍患者静息脑代谢的变化及其与3个月后持续性残疾的关系。符合纳入条件的患者被诊断为首次发作的运动功能神经障碍，无双相情感障碍、物质使用障碍、精神分裂症、心因性非癫痫性发作或任何慢性或急性器质性神经障碍。排除标准包括目前有自杀意念、服用抗精神病药物和既往功能性神经障碍史。从两家医院的精神科和神经科招募了19名患者。在基线和3个月时，用18f -氟脱氧葡萄糖正电子发射计算机断层扫描测量静息脑代谢，并与23名无神经损伤的对照组进行比较。在基线和3个月时使用扩展残疾状态量表和美国国立卫生研究院卒中量表对残疾进行评分。用Spearman相关系数计算相关性。与对照组相比，患者双侧额叶区基线代谢降低，3个月后消失。与其他患者相比，扩展残疾状态量表评分改善的患者在3个月时前额叶背外侧皮层、右眶额叶皮层和双侧额极代谢的静息状态活动更高。基线时右侧膝下前扣带皮层的静息状态代谢与纳入组至3个月期间运动障碍的改善(用扩展残疾状态量表测量)呈负相关(r=-0.75, p= 0.0018)，与美国国立卫生研究院卒中量表评估的运动症状的改变呈负相关(r=-0.81, p= 0.0005)。基线时左侧亚属前扣带皮层的静息状态代谢与纳入组至3个月间扩展残疾状态量表和美国国立卫生研究院卒中量表评分的改善呈负相关(r= -0.65, p = 0.01和r= -0.75, p = 0.0021)。在多重比较校正后，基线时右侧亚属前扣带皮层脑代谢与美国国立卫生研究院卒中量表评分变化之间的负相关仍然显著(r=-0.81, p= 0.0414)。我们的研究结果表明，存在与运动障碍相关的代谢“状态标记”，以及与功能性神经障碍患者的运动恢复相关的脑标记。
{"title":"Association between brain metabolism and clinical course of motor functional neurological disorders.","authors":"I. Conejero, L. Collombier, J. López-Castromán, T. Mura, S. Alonso, E. Olié, V. Boudousq, Fabrice Boulet, C. Arquizan, Charlotte Boulet, A. Wacongne, C. Heitz, C. Castelli, S. Mouchabac, P. Courtet, M. Abbar, E. Thouvenot","doi":"10.1093/brain/awac146","DOIUrl":"https://doi.org/10.1093/brain/awac146","url":null,"abstract":"Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of patients experiencing a first episode of motor functional neurological disorder with recent symptom onset, and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from 2 hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r=-0.75, p = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r=-0.81, p= 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r= -0.65, p = 0.01 and r= -0.75, p = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r=-0.81, p= 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic \"state markers\" associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"46 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114069708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Something interesting is happening in the world of clinical trials that is likely to have a profound impact on how we evaluate new therapies for brain disorders. It is the advent of novel designs that often integrate adaptive clinical trial methodology andmaster protocols within platform trials to allowmultiple treatment arms to run concurrently. While standard trial designs are ballistic creatures (once launched, they follow a predefined trajectory), adaptive trials allow for interim analyses that permit a range of decisions to be made on the subsequent course of the trial. Master protocols within platform trials provide unified study protocols that cover several sub-studies, with different interventions often being compared to a single control group, thereby reducing numbers of patients who receive only placebo or standard treatment. Compared to some specialties, neurology has, at least until now, lagged behind in developing innovative trial methodologies that can answer questions rapidly. We have instead been wedded to conventional, large scale randomized controlled trials that take many years to complete. Most of them conclude that a drug that was promising in an animal model actually does not seem to have a significant impact on the disease in humans. Sadly, neurology is littered with an array of such ‘failed’ and costly trials. Our patients—and Pharma—have understandably become frustrated at the lack of progress in some areas. Althoughwe can point to a few great successes, for example in multiple sclerosis and epilepsy, the field that has been most challenging to crack has been that of neurodegenerative diseases. Here, many fingers have been burned and much money spent to very little avail. Some important considerations have become apparent over the course of many disappointments. First, traditional trial designs are unwieldy, cumbersome and costly. One solution might be to deploy relatively small-scale human trials that provide investigators—and Pharma—confidence to decide whether to take a compound into expensive, larger scale randomized trials. However, for such Go/NoGo trials to succeed, they are, almost by definition, going to have to be unconventional. One possibility is to use novel outcome measures: not ones currently approved by regulatory agencies, but nevertheless having the potential to be more sensitive to changes in disease state. They might be fluid or tissue biomarkers; genomic, proteomic or metabolomic profile; brain imaging (PET or MRI) or neurophysiological signals; cognitive measures; or even indices of gait. But the key point is that, whatever the outcome measure used, it has to have far more dynamic range and sensitivity than conventional ones. In summary, the metrics simply have to be better. Second, one of the big issues that has likely had a huge impact on the outcome of many clinical trials is patient heterogeneity. This confounding factor has probably been appreciated best in oncology where it has become clear tha
{"title":"Smarter adaptive platform clinical trials in neurology.","authors":"Masud Husain","doi":"10.1093/brain/awac005","DOIUrl":"https://doi.org/10.1093/brain/awac005","url":null,"abstract":"Something interesting is happening in the world of clinical trials that is likely to have a profound impact on how we evaluate new therapies for brain disorders. It is the advent of novel designs that often integrate adaptive clinical trial methodology andmaster protocols within platform trials to allowmultiple treatment arms to run concurrently. While standard trial designs are ballistic creatures (once launched, they follow a predefined trajectory), adaptive trials allow for interim analyses that permit a range of decisions to be made on the subsequent course of the trial. Master protocols within platform trials provide unified study protocols that cover several sub-studies, with different interventions often being compared to a single control group, thereby reducing numbers of patients who receive only placebo or standard treatment. Compared to some specialties, neurology has, at least until now, lagged behind in developing innovative trial methodologies that can answer questions rapidly. We have instead been wedded to conventional, large scale randomized controlled trials that take many years to complete. Most of them conclude that a drug that was promising in an animal model actually does not seem to have a significant impact on the disease in humans. Sadly, neurology is littered with an array of such ‘failed’ and costly trials. Our patients—and Pharma—have understandably become frustrated at the lack of progress in some areas. Althoughwe can point to a few great successes, for example in multiple sclerosis and epilepsy, the field that has been most challenging to crack has been that of neurodegenerative diseases. Here, many fingers have been burned and much money spent to very little avail. Some important considerations have become apparent over the course of many disappointments. First, traditional trial designs are unwieldy, cumbersome and costly. One solution might be to deploy relatively small-scale human trials that provide investigators—and Pharma—confidence to decide whether to take a compound into expensive, larger scale randomized trials. However, for such Go/NoGo trials to succeed, they are, almost by definition, going to have to be unconventional. One possibility is to use novel outcome measures: not ones currently approved by regulatory agencies, but nevertheless having the potential to be more sensitive to changes in disease state. They might be fluid or tissue biomarkers; genomic, proteomic or metabolomic profile; brain imaging (PET or MRI) or neurophysiological signals; cognitive measures; or even indices of gait. But the key point is that, whatever the outcome measure used, it has to have far more dynamic range and sensitivity than conventional ones. In summary, the metrics simply have to be better. Second, one of the big issues that has likely had a huge impact on the outcome of many clinical trials is patient heterogeneity. This confounding factor has probably been appreciated best in oncology where it has become clear tha","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133134386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bobby Fischer and the delusions of a king of logic.","authors":"E. Fernandez-Egea, T. Robbins","doi":"10.1093/brain/awac140","DOIUrl":"https://doi.org/10.1093/brain/awac140","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132979565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi-Hong Liu, Ying-Tsen Chou, Fu‐Pang Chang, Wei‐Ju Lee, Yuh-Cherng Guo, Cheng-Ta Chou, Hui-Chun Huang, T. Mizuguchi, C. Chou, Hsiang-Yu Yu, K. Yu, Hsiu-Mei Wu, P. Tsai, N. Matsumoto, Yi-Chung Lee, Y. Liao
Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum, and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsy from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patents presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%, 4/34), and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesion on diffusion weighted imaging (DWI) was the best biomarker to diagnose NIID with high specificity (98.4%) and sensitivity (88.2%). However, such DWI abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, presence of white matter hyperintensity lesions (WMH) either in paravermis or middle cerebellar peduncles also favored the diagnosis of NIID with a specificity of 85.3% and a sensitivity of 76.5%. Among the ten patients' MRI performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical DWI hyperintense lesions and two revealed focal brain edema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients ever developed encephalitis-like episodes with restricted diffusion in the cortical regions at the acute stage DWI. Corticomedullary junction hyperintense lesions, WMH in paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnose NIID.
{"title":"Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy.","authors":"Yi-Hong Liu, Ying-Tsen Chou, Fu‐Pang Chang, Wei‐Ju Lee, Yuh-Cherng Guo, Cheng-Ta Chou, Hui-Chun Huang, T. Mizuguchi, C. Chou, Hsiang-Yu Yu, K. Yu, Hsiu-Mei Wu, P. Tsai, N. Matsumoto, Yi-Chung Lee, Y. Liao","doi":"10.1093/brain/awac135","DOIUrl":"https://doi.org/10.1093/brain/awac135","url":null,"abstract":"Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum, and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsy from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patents presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%, 4/34), and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesion on diffusion weighted imaging (DWI) was the best biomarker to diagnose NIID with high specificity (98.4%) and sensitivity (88.2%). However, such DWI abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, presence of white matter hyperintensity lesions (WMH) either in paravermis or middle cerebellar peduncles also favored the diagnosis of NIID with a specificity of 85.3% and a sensitivity of 76.5%. Among the ten patients' MRI performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical DWI hyperintense lesions and two revealed focal brain edema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients ever developed encephalitis-like episodes with restricted diffusion in the cortical regions at the acute stage DWI. Corticomedullary junction hyperintense lesions, WMH in paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnose NIID.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128876739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amélie Descheemaeker, H. Poras, M. Wurm, P. Luccarini, T. Ouimet, R. Dallel
The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from their rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioral testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naive rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears as an innovative approach to treat migraine.
{"title":"Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.","authors":"Amélie Descheemaeker, H. Poras, M. Wurm, P. Luccarini, T. Ouimet, R. Dallel","doi":"10.1093/brain/awac139","DOIUrl":"https://doi.org/10.1093/brain/awac139","url":null,"abstract":"The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from their rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioral testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naive rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears as an innovative approach to treat migraine.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124798452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Broca's legacy: fame not shame.","authors":"James R. Wright","doi":"10.1093/brain/awac131","DOIUrl":"https://doi.org/10.1093/brain/awac131","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123226817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunali Padhi, Surjyapratap Sarangi, Nisha S. Nayak, Abhijit Pati, A. K. Panda
{"title":"OAS1 rs1131454 genetic variant is associated with Alzheimer's disease: an epidemiological analysis.","authors":"Sunali Padhi, Surjyapratap Sarangi, Nisha S. Nayak, Abhijit Pati, A. K. Panda","doi":"10.1093/brain/awac132","DOIUrl":"https://doi.org/10.1093/brain/awac132","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124146285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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