Pub Date : 2024-01-08DOI: 10.1093/braincomms/fcae001
Ramana V Vishnubhotla, Sidra T. Ahmad, Yi Zhao, Rupa Radhakrishnan
There has been an increase in the number of women using marijuana while pregnant. Previous studies have shown that children with prenatal marijuana exposure (PME) have developmental deficits in memory and decreased attentiveness. In this study we assess whether PME is associated with alterations in brain regional morphometry and functional and structural connectivity in adolescents. We downloaded behavioral scores and subject image files from the Adolescent Brain Cognitive DevelopmentSM (ABCD®) Study. 178 anatomical diffusion MRI files (88 PME, 90 age and gender matched controls) and 152 resting state functional MRI (rs-fMRI) files (76 PME, 76 controls) were obtained. Behavioral metrics based on the parent-reported child behavioral checklist (CBCL) were also obtained for each subject. The association of PME with 17 subscales of the CBCL was calculated. We assessed differences in brain morphometry based on voxel-based and surface-based morphometry in adolescents with PME versus controls. We also evaluated differences in structural and functional connectivity in adolescents for region-to-region connectivity and graph theoretical modeling. Interactions of PME and graph networks were assessed for impact on behavioral scores. Multiple comparison correction was performed as appropriate. Adolescents with PME had greater abnormal or borderline CBCL scores in 9 out of 17 subscales. There were no significant differences in voxel or surface-based morphometry, structural connectivity, or functional connectivity between PME and controls. However, there were significant differences in PME-graph network interactions with respect to behavioral scores. There were 3 structural PME-graph network interactions and 7 functional PME-graph network interactions that were significantly associated with behavioral scores. While this study was not able to confirm anatomical or functional differences between PME and unexposed pre-adolescent children, there were PME- brain structural and functional graph network interactions that were significantly associated with behavioral scores. This suggests that altered brain networks may underlie behavioral outcomes in adolescents with PME. More work needs to be conducted to better understand the prognostic value of brain structural and functional network measures in PME.
{"title":"Impact of prenatal marijuana exposure on adolescent brain structural and functional connectivity and behavioral outcomes","authors":"Ramana V Vishnubhotla, Sidra T. Ahmad, Yi Zhao, Rupa Radhakrishnan","doi":"10.1093/braincomms/fcae001","DOIUrl":"https://doi.org/10.1093/braincomms/fcae001","url":null,"abstract":"\u0000 There has been an increase in the number of women using marijuana while pregnant. Previous studies have shown that children with prenatal marijuana exposure (PME) have developmental deficits in memory and decreased attentiveness. In this study we assess whether PME is associated with alterations in brain regional morphometry and functional and structural connectivity in adolescents.\u0000 We downloaded behavioral scores and subject image files from the Adolescent Brain Cognitive DevelopmentSM (ABCD®) Study. 178 anatomical diffusion MRI files (88 PME, 90 age and gender matched controls) and 152 resting state functional MRI (rs-fMRI) files (76 PME, 76 controls) were obtained. Behavioral metrics based on the parent-reported child behavioral checklist (CBCL) were also obtained for each subject. The association of PME with 17 subscales of the CBCL was calculated. We assessed differences in brain morphometry based on voxel-based and surface-based morphometry in adolescents with PME versus controls. We also evaluated differences in structural and functional connectivity in adolescents for region-to-region connectivity and graph theoretical modeling. Interactions of PME and graph networks were assessed for impact on behavioral scores. Multiple comparison correction was performed as appropriate.\u0000 Adolescents with PME had greater abnormal or borderline CBCL scores in 9 out of 17 subscales. There were no significant differences in voxel or surface-based morphometry, structural connectivity, or functional connectivity between PME and controls. However, there were significant differences in PME-graph network interactions with respect to behavioral scores. There were 3 structural PME-graph network interactions and 7 functional PME-graph network interactions that were significantly associated with behavioral scores.\u0000 While this study was not able to confirm anatomical or functional differences between PME and unexposed pre-adolescent children, there were PME- brain structural and functional graph network interactions that were significantly associated with behavioral scores. This suggests that altered brain networks may underlie behavioral outcomes in adolescents with PME. More work needs to be conducted to better understand the prognostic value of brain structural and functional network measures in PME.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"42 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139447516","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}
Pub Date : 2024-01-08DOI: 10.1093/braincomms/fcae005
Irene Sintini, Nick Corriveau-Lecavalier, David T Jones, M. Machulda, J. Gunter, C. Schwarz, H. Botha, A. Carlos, Michael Kamykowski, Neha Atulkumar Singh, Ronald C. Petersen, C. R. Jack, V. Lowe, J. Graff‐Radford, K. Josephs, J. Whitwell
Disruption of the default mode network (DMN) is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and one-year longitudinal changes in DMN sub-systems in the visual and language variants of Alzheimer’s disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer’s disease participants diagnosed with posterior cortical atrophy (n=33) or logopenic progressive aphasia (n=28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer’s disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer’s disease participants, 26 amnestic Alzheimer’s disease participants and 40 cognitively unimpaired individuals had one follow-up fMRI approximately one to two years after the baseline scan. DMN connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral, and anterior dorsal sub-systems derived from independent component analysis. A global measure of DMN connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer’s disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer’s disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer’s disease participants had lower connectivity than the older ones, particularly in the ventral DMN. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral DMN connectivity in atypical Alzheimer’s disease. Connectivity in the ventral DMN declined over time in atypical Alzheimer’s disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal DMN connectivity, lower posterior and ventral DMN connectivity, and decline in ventral DMN connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with DMN connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer’s disease variants, and discriminated Alzheimer’s disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity, and with disruption more pronounced in younger participants. The ventral DMN declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau path
{"title":"Longitudinal default mode sub-networks in the language and visual variants of Alzheimer’s disease","authors":"Irene Sintini, Nick Corriveau-Lecavalier, David T Jones, M. Machulda, J. Gunter, C. Schwarz, H. Botha, A. Carlos, Michael Kamykowski, Neha Atulkumar Singh, Ronald C. Petersen, C. R. Jack, V. Lowe, J. Graff‐Radford, K. Josephs, J. Whitwell","doi":"10.1093/braincomms/fcae005","DOIUrl":"https://doi.org/10.1093/braincomms/fcae005","url":null,"abstract":"\u0000 Disruption of the default mode network (DMN) is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and one-year longitudinal changes in DMN sub-systems in the visual and language variants of Alzheimer’s disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer’s disease participants diagnosed with posterior cortical atrophy (n=33) or logopenic progressive aphasia (n=28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer’s disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer’s disease participants, 26 amnestic Alzheimer’s disease participants and 40 cognitively unimpaired individuals had one follow-up fMRI approximately one to two years after the baseline scan. DMN connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral, and anterior dorsal sub-systems derived from independent component analysis. A global measure of DMN connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer’s disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer’s disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer’s disease participants had lower connectivity than the older ones, particularly in the ventral DMN. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral DMN connectivity in atypical Alzheimer’s disease. Connectivity in the ventral DMN declined over time in atypical Alzheimer’s disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal DMN connectivity, lower posterior and ventral DMN connectivity, and decline in ventral DMN connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with DMN connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer’s disease variants, and discriminated Alzheimer’s disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity, and with disruption more pronounced in younger participants. The ventral DMN declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau path","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"43 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139448022","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}
Pub Date : 2024-01-05DOI: 10.1093/braincomms/fcae002
Kennedy A Josephs, Keith A. Josephs
Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative etiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical, and imaging characteristics, and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological etiology. We assessed regional involvement on 18F-fluorodeoxyglucose PET and MRI of the right and left frontal, temporal, parietal, and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C, and another with a Forkhead-box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorised as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer’s disease dementia, and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischemic and hemorrhagic), epilepsy-related, and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial-recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy, and ischemic infarcts. On 18F-fluorodeoxyglucose PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis, and mixed Alzheimer’s and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial-recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.
{"title":"Prosopagnosia: face blindness and its association with neurological disorders","authors":"Kennedy A Josephs, Keith A. Josephs","doi":"10.1093/braincomms/fcae002","DOIUrl":"https://doi.org/10.1093/braincomms/fcae002","url":null,"abstract":"\u0000 Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative etiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical, and imaging characteristics, and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological etiology. We assessed regional involvement on 18F-fluorodeoxyglucose PET and MRI of the right and left frontal, temporal, parietal, and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C, and another with a Forkhead-box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorised as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer’s disease dementia, and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischemic and hemorrhagic), epilepsy-related, and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial-recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy, and ischemic infarcts. On 18F-fluorodeoxyglucose PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis, and mixed Alzheimer’s and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial-recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139384041","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}
Pub Date : 2024-01-05DOI: 10.1093/braincomms/fcae003
A. Çakar, R. Maroofian, Y. Parman, Mary M Reilly, Henry Houlden
{"title":"Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies","authors":"A. Çakar, R. Maroofian, Y. Parman, Mary M Reilly, Henry Houlden","doi":"10.1093/braincomms/fcae003","DOIUrl":"https://doi.org/10.1093/braincomms/fcae003","url":null,"abstract":"","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"82 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381513","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}
Pub Date : 2024-01-03DOI: 10.1093/braincomms/fcad355
K. Lau, Ngoc T. Nguyen, Jaideep C Kesavan, E. Langa, Kevin Fanning, G. Brennan, A. Sanz‐Rodriguez, Javier Villegas-Salmerón, Yan Yan, M. Venø, James D Mills, Felix Rosenow, S. Bauer, Jørgen Kjems, D. Henshall
MicroRNAs have emerged as important regulators of the gene expression landscape in temporal lobe epilepsy. The mechanisms that control microRNA levels and influence target choice remain, however, poorly understood. RNA editing is a post-transcriptional mechanism mediated by the adenosine acting on RNA (ADAR) family of proteins that introduces base modification that diversifies the gene expression landscape. RNA editing has been studied for the mRNA landscape but the extent to which microRNA editing occurs in human temporal lobe epilepsy is unknown. Here we used small RNA sequencing data to characterise the identity and extent of microRNA editing in human temporal lobe epilepsy brain samples. This detected low-to-high editing in over 40 of the identified microRNAs. Among microRNA exhibiting the highest editing was miR-376a-3p, which was edited in the seed region and this was predicted to significantly change the target pool. The edited form was expressed at lower levels in human temporal lobe epilepsy samples. We modelled the shift in editing levels of miR-376a-3p in human induced pluripotent stem cell-derived neurons. Reducing levels of the edited form of miR-376a-3p using antisense oligonucleotides resulted in extensive gene expression changes, including upregulation of mitochondrial and metabolism-associated pathways. Together, these results show that differential editing of microRNAs may re-direct targeting and result in altered functions relevant to the pathophysiology of temporal lobe epilepsy and perhaps other disorders of neuronal hyperexcitability.
{"title":"Differential microRNA editing may drive target pathway switching in human temporal lobe epilepsy","authors":"K. Lau, Ngoc T. Nguyen, Jaideep C Kesavan, E. Langa, Kevin Fanning, G. Brennan, A. Sanz‐Rodriguez, Javier Villegas-Salmerón, Yan Yan, M. Venø, James D Mills, Felix Rosenow, S. Bauer, Jørgen Kjems, D. Henshall","doi":"10.1093/braincomms/fcad355","DOIUrl":"https://doi.org/10.1093/braincomms/fcad355","url":null,"abstract":"\u0000 MicroRNAs have emerged as important regulators of the gene expression landscape in temporal lobe epilepsy. The mechanisms that control microRNA levels and influence target choice remain, however, poorly understood. RNA editing is a post-transcriptional mechanism mediated by the adenosine acting on RNA (ADAR) family of proteins that introduces base modification that diversifies the gene expression landscape. RNA editing has been studied for the mRNA landscape but the extent to which microRNA editing occurs in human temporal lobe epilepsy is unknown. Here we used small RNA sequencing data to characterise the identity and extent of microRNA editing in human temporal lobe epilepsy brain samples. This detected low-to-high editing in over 40 of the identified microRNAs. Among microRNA exhibiting the highest editing was miR-376a-3p, which was edited in the seed region and this was predicted to significantly change the target pool. The edited form was expressed at lower levels in human temporal lobe epilepsy samples. We modelled the shift in editing levels of miR-376a-3p in human induced pluripotent stem cell-derived neurons. Reducing levels of the edited form of miR-376a-3p using antisense oligonucleotides resulted in extensive gene expression changes, including upregulation of mitochondrial and metabolism-associated pathways. Together, these results show that differential editing of microRNAs may re-direct targeting and result in altered functions relevant to the pathophysiology of temporal lobe epilepsy and perhaps other disorders of neuronal hyperexcitability.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"24 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139388467","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}
Pub Date : 2024-01-02DOI: 10.1093/braincomms/fcad356
A. Houldsworth
Neurological disorders include a variety of conditions, Alzheimer’s disease, Motor Neuron disease, and Parkinson’s disease, affecting longevity and quality of life and their pathogenesis is associated with oxidative stress. Several of the chronic neurodegenerative pathologies of the central nervous system share some common features, such as, oxidative stress, inflammation, synapse dysfunctions, protein misfolding, and defective autophagia. Neuroinflammation can involve the activation of mast cells, contributing to oxidative stress, in addition other the sources of reactive oxygen species. Antioxidants can powerfully neutralise reactive oxygen species and free radicals, decreasing oxidative damage. Antioxidant genes, like manganese superoxide dismutase enzyme, can undergo epigenetic changes that reduce their expression, thus increasing oxidative stress in tissue. Alternatively, DNA can be altered by free radical damage. The epigenetic landscape of these genes can change antioxidant function and may result in neurodegenerative disease. This imbalance of free radical production and antioxidant function increases the reactive oxygen species that cause cell damage in neurons and is often observed as an age-related event. Increased antioxidant expression in mice is protective against reactive oxygen species in neurons as is the exogenous supplementation of antioxidants. Manganese superoxide dismutase requires manganese for its enzymic function. Antioxidant therapy is considered for age-related neurodegenerative diseases and new mimetic of a manganese superoxide dismutase, Avasopasem Manganese is described and suggested as putative treatment to reduce the oxidative stress that causes neurodegenerative disease. The aim of this narrative review is to explore the evidence that oxidative stress causes neurodegenerative damage and the role of antioxidant genes in inhibiting reactive oxygen species damage. Can the neuronal environment of oxidative stress, causing neuroinflammation and neurodegeneration, be reduced or reversed?
{"title":"Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants","authors":"A. Houldsworth","doi":"10.1093/braincomms/fcad356","DOIUrl":"https://doi.org/10.1093/braincomms/fcad356","url":null,"abstract":"\u0000 Neurological disorders include a variety of conditions, Alzheimer’s disease, Motor Neuron disease, and Parkinson’s disease, affecting longevity and quality of life and their pathogenesis is associated with oxidative stress. Several of the chronic neurodegenerative pathologies of the central nervous system share some common features, such as, oxidative stress, inflammation, synapse dysfunctions, protein misfolding, and defective autophagia. Neuroinflammation can involve the activation of mast cells, contributing to oxidative stress, in addition other the sources of reactive oxygen species. Antioxidants can powerfully neutralise reactive oxygen species and free radicals, decreasing oxidative damage. Antioxidant genes, like manganese superoxide dismutase enzyme, can undergo epigenetic changes that reduce their expression, thus increasing oxidative stress in tissue. Alternatively, DNA can be altered by free radical damage. The epigenetic landscape of these genes can change antioxidant function and may result in neurodegenerative disease. This imbalance of free radical production and antioxidant function increases the reactive oxygen species that cause cell damage in neurons and is often observed as an age-related event. Increased antioxidant expression in mice is protective against reactive oxygen species in neurons as is the exogenous supplementation of antioxidants. Manganese superoxide dismutase requires manganese for its enzymic function. Antioxidant therapy is considered for age-related neurodegenerative diseases and new mimetic of a manganese superoxide dismutase, Avasopasem Manganese is described and suggested as putative treatment to reduce the oxidative stress that causes neurodegenerative disease.\u0000 The aim of this narrative review is to explore the evidence that oxidative stress causes neurodegenerative damage and the role of antioxidant genes in inhibiting reactive oxygen species damage. Can the neuronal environment of oxidative stress, causing neuroinflammation and neurodegeneration, be reduced or reversed?","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"78 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139390450","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}
Pub Date : 2024-01-02DOI: 10.1093/braincomms/fcad358
M. Wandall-Holm, Rolf Pringler Holm, Alex Heick, Annika Langkilde, M. Magyari
Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting Multiple Sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting Multiple Sclerosis, and two MRIs performed respectively within one year before and after discontinuing fingolimod. The included patients were compared to those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration, and relapse rate. The main outcome was the presence of new T2-lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T2-lesions. Of 1.324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion (mean age [SD], years, 41 [10]; 552 females [73%]; median Expanded Disability Status Scale [Q1-Q3], 2.5 [2.0-3.5]; mean disease duration [SD], years, 12 [8]). Of 2.044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 [17%] had 1-2 new T2-lesions, and 124 [17%] had ≥3 new T2-lesions compared to 114 [12%] and 45 [5%], respectively for those discontinuing dimethyl fumarate, corresponding to odds ratios [95% CI] of 1.8 [1.3-2.3] and 4.4 [3.1-6.3]. The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T2-lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T2-lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.
{"title":"Risk of T2-lesions when discontinuing fingolimod: a nationwide predictive and comparative study","authors":"M. Wandall-Holm, Rolf Pringler Holm, Alex Heick, Annika Langkilde, M. Magyari","doi":"10.1093/braincomms/fcad358","DOIUrl":"https://doi.org/10.1093/braincomms/fcad358","url":null,"abstract":"Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting Multiple Sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting Multiple Sclerosis, and two MRIs performed respectively within one year before and after discontinuing fingolimod. The included patients were compared to those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration, and relapse rate. The main outcome was the presence of new T2-lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T2-lesions. Of 1.324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion (mean age [SD], years, 41 [10]; 552 females [73%]; median Expanded Disability Status Scale [Q1-Q3], 2.5 [2.0-3.5]; mean disease duration [SD], years, 12 [8]). Of 2.044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 [17%] had 1-2 new T2-lesions, and 124 [17%] had ≥3 new T2-lesions compared to 114 [12%] and 45 [5%], respectively for those discontinuing dimethyl fumarate, corresponding to odds ratios [95% CI] of 1.8 [1.3-2.3] and 4.4 [3.1-6.3]. The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T2-lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T2-lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"5 31","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139124887","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}
Pub Date : 2023-12-11DOI: 10.1093/braincomms/fcad334
{"title":"Correction to: Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations","authors":"","doi":"10.1093/braincomms/fcad334","DOIUrl":"https://doi.org/10.1093/braincomms/fcad334","url":null,"abstract":"","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"9 49","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138584442","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}
Pub Date : 2023-12-08DOI: 10.1093/braincomms/fcad341
Cynthia K. Thompson, Matthew Walenski
This scientific commentary refers to ‘Cerebral perfusion in post-stroke aphasia and its relationship to residual language abilities’, by Ivanova et al. (https://doi.org/10.1093/braincomms/fcad252).
{"title":"Measurement matters for assessing the role of chronically altered perfusion in post-stroke aphasia","authors":"Cynthia K. Thompson, Matthew Walenski","doi":"10.1093/braincomms/fcad341","DOIUrl":"https://doi.org/10.1093/braincomms/fcad341","url":null,"abstract":"This scientific commentary refers to ‘Cerebral perfusion in post-stroke aphasia and its relationship to residual language abilities’, by Ivanova et al. (https://doi.org/10.1093/braincomms/fcad252).","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"10 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138587700","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}
Pub Date : 2023-12-08DOI: 10.1093/braincomms/fcad345
Divya A. Chari, Maimuna Ahmad, Susan King, Anissa Boutabla, Cameron Fattahi, Alexander S Panic, F. Karmali, Richard F Lewis
Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually-barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed which either activated dynamic idiothetic cues (dynamic task, navigate by turning, walking in place) or eliminated them (static task, navigate with key-presses, head stationary). For both protocols, we employed a standard “triangle completion task” in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear accuracy (derived from response error) and precision (derived from response variability) were calculated. Comparing performance within tasks, navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance between tasks, normal men performed better on the dynamic than the static paradigm while vestibular deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.
{"title":"Vestibular damage affects the precision and accuracy of navigation in a virtual visual environment","authors":"Divya A. Chari, Maimuna Ahmad, Susan King, Anissa Boutabla, Cameron Fattahi, Alexander S Panic, F. Karmali, Richard F Lewis","doi":"10.1093/braincomms/fcad345","DOIUrl":"https://doi.org/10.1093/braincomms/fcad345","url":null,"abstract":"\u0000 Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually-barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed which either activated dynamic idiothetic cues (dynamic task, navigate by turning, walking in place) or eliminated them (static task, navigate with key-presses, head stationary). For both protocols, we employed a standard “triangle completion task” in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear accuracy (derived from response error) and precision (derived from response variability) were calculated. Comparing performance within tasks, navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance between tasks, normal men performed better on the dynamic than the static paradigm while vestibular deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"26 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138589173","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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