Pub Date : 2024-03-07DOI: 10.1093/braincomms/fcae082
Christy M Kelley, Bryan Maloney, John S. Beck, S. Ginsberg, Winnie Liang, D. Lahiri, E. Mufson, S. Counts
The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer’s disease. We recently performed RNA sequencing of postmortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an antemortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to Alzheimer’s disease pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak stages III/IV compared with stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small noncoding microRNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance, and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs significantly associated (rho > 0.38, p < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation, and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak stages I-II and 47 miRNAs were associated with higher Braak stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak stages I/II vs. Braak stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau, and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and postmortem neuropathological Alzheimer’s disease diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (preclinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.
{"title":"MicroRNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders","authors":"Christy M Kelley, Bryan Maloney, John S. Beck, S. Ginsberg, Winnie Liang, D. Lahiri, E. Mufson, S. Counts","doi":"10.1093/braincomms/fcae082","DOIUrl":"https://doi.org/10.1093/braincomms/fcae082","url":null,"abstract":"\u0000 The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer’s disease. We recently performed RNA sequencing of postmortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an antemortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to Alzheimer’s disease pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak stages III/IV compared with stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small noncoding microRNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance, and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs significantly associated (rho > 0.38, p < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation, and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak stages I-II and 47 miRNAs were associated with higher Braak stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak stages I/II vs. Braak stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau, and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and postmortem neuropathological Alzheimer’s disease diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (preclinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"24 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140077241","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}
To explore the causal relationship between age and brain health (cortical atrophy, white matter integrity, white matter hyperintensities, and cerebral microbleeds in various brain regions) related multiparameter imaging features using two-sample Mendelian randomization. Age was determined as chronological age of the subject. Cortical volume, white matter micro-integrity, white matter hyperintensity volume, and cerebral microbleeds of each brain region were included as phenotypes for brain health. Age and imaging of brain health related genetic data were analyzed to determine the causal relationship using inverse-variance weighted model, validated by heterogeneity and horizontal pleiotropy variables. Age is causally related to increased volumes of white matter hyperintensities (β= 0.151). For white matter micro-integrity, fibers of the inferior cerebellar peduncle (Axial diffusivity β= -0.128, orientation dispersion index β= 0.173), cerebral peduncle (Axial diffusivity β= -0.136), superior fronto-occipital fasciculus (isotropic volume fraction β= 0.163) and fibers within the limbic system were causally deteriorated. We also detected decreased cortical thickness of multiple frontal and temporal regions (p<0.05). Microbleeds were not related with aging p＞0.05). Aging is a threaten of brain health, leading to cortical atrophy mainly in the frontal lobes, as well as the white matter degeneration especially abnormal hyperintensity and deteriorated white matter integrity around the hippocampus.
{"title":"Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization","authors":"Xinghao Wang, Qian Chen, Yawen Liu, Jing Sun, Jia Li, Pengfei Zhao, Linkun Cai, Wenjuan Liu, Zhenghan Yang, Zhenchang Wang, Han Lv","doi":"10.1093/braincomms/fcae077","DOIUrl":"https://doi.org/10.1093/braincomms/fcae077","url":null,"abstract":"\u0000 To explore the causal relationship between age and brain health (cortical atrophy, white matter integrity, white matter hyperintensities, and cerebral microbleeds in various brain regions) related multiparameter imaging features using two-sample Mendelian randomization. Age was determined as chronological age of the subject. Cortical volume, white matter micro-integrity, white matter hyperintensity volume, and cerebral microbleeds of each brain region were included as phenotypes for brain health. Age and imaging of brain health related genetic data were analyzed to determine the causal relationship using inverse-variance weighted model, validated by heterogeneity and horizontal pleiotropy variables. Age is causally related to increased volumes of white matter hyperintensities (β= 0.151). For white matter micro-integrity, fibers of the inferior cerebellar peduncle (Axial diffusivity β= -0.128, orientation dispersion index β= 0.173), cerebral peduncle (Axial diffusivity β= -0.136), superior fronto-occipital fasciculus (isotropic volume fraction β= 0.163) and fibers within the limbic system were causally deteriorated. We also detected decreased cortical thickness of multiple frontal and temporal regions (p<0.05). Microbleeds were not related with aging p＞0.05). Aging is a threaten of brain health, leading to cortical atrophy mainly in the frontal lobes, as well as the white matter degeneration especially abnormal hyperintensity and deteriorated white matter integrity around the hippocampus.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"33 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140087834","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 : 2024-03-01DOI: 10.1093/braincomms/fcae075
M. Kubota, H. Endo, K. Takahata, K. Tagai, Hisaomi Suzuki, M. Onaya, Yasunori Sano, Yasuharu Yamamoto, Shin Kurose, K. Matsuoka, C. Seki, H. Shinotoh, K. Kawamura, Ming‐Rong Zhang, Y. Takado, H. Shimada, Makoto Higuchi
Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of FTD at an individual level have hitherto not been successful. Here, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607, 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer’s disease as well as in non-Alzheimer’s disease tauopathies. Twenty-six patients with FTD, 15 with behavioral variant FTD and 11 with other FTD phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the behavioral variant FTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = three); 2) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = four); 3) amyloid and tau accumulations consistent with Alzheimer’s disease (n = four); 4) no overt amyloid and tau pathologies (n = four). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioral variant FTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with FTD on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.
{"title":"In vivo PET classification of tau pathologies in patients with frontotemporal dementia","authors":"M. Kubota, H. Endo, K. Takahata, K. Tagai, Hisaomi Suzuki, M. Onaya, Yasunori Sano, Yasuharu Yamamoto, Shin Kurose, K. Matsuoka, C. Seki, H. Shinotoh, K. Kawamura, Ming‐Rong Zhang, Y. Takado, H. Shimada, Makoto Higuchi","doi":"10.1093/braincomms/fcae075","DOIUrl":"https://doi.org/10.1093/braincomms/fcae075","url":null,"abstract":"\u0000 Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of FTD at an individual level have hitherto not been successful. Here, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607, 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer’s disease as well as in non-Alzheimer’s disease tauopathies. Twenty-six patients with FTD, 15 with behavioral variant FTD and 11 with other FTD phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the behavioral variant FTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = three); 2) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = four); 3) amyloid and tau accumulations consistent with Alzheimer’s disease (n = four); 4) no overt amyloid and tau pathologies (n = four). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioral variant FTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with FTD on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"120 28","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140088256","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 : 2024-02-18DOI: 10.1093/braincomms/fcae051
Robson C Lillo Vizin, C. Kopruszinski, Paula M Redman, Hisakatsu Ito, Jill Rau, D. Dodick, E. Navratilova, Frank Porreca
Migraine and sleep disorders are common comorbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following implantation of EEG/EMG electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e., nocturnal awake period). Neither single nor repeated nitroglycerin affected total sleep time, non-rapid eye movement sleep, rapid-eye movement sleep, sleep depth, or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of EEG/EMG electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behavior. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e., daylight) or active (i.e., night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.
{"title":"Unraveling the directional relationship of sleep and migraine-like pain","authors":"Robson C Lillo Vizin, C. Kopruszinski, Paula M Redman, Hisakatsu Ito, Jill Rau, D. Dodick, E. Navratilova, Frank Porreca","doi":"10.1093/braincomms/fcae051","DOIUrl":"https://doi.org/10.1093/braincomms/fcae051","url":null,"abstract":"\u0000 Migraine and sleep disorders are common comorbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following implantation of EEG/EMG electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e., nocturnal awake period). Neither single nor repeated nitroglycerin affected total sleep time, non-rapid eye movement sleep, rapid-eye movement sleep, sleep depth, or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of EEG/EMG electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behavior. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e., daylight) or active (i.e., night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"5 50","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139959134","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 : 2024-02-15DOI: 10.1093/braincomms/fcae048
Nadieh Drenth, Suzanne E. van Dijk, J. Foster-Dingley, A. Bertens, N. Rius Ottenheim, R. van der Mast, Serge A R B Rombouts, S. van Rooden, Jeroen van der Grond
Although past research has established a relationship between functional connectivity and cognitive function, less is known about which cognitive domains are associated with which specific functional networks. This study investigated associations between functional connectivity and global cognitive function and performance in the domains of memory, executive function and psychomotor speed in 166 older adults aged 75-91 years (mean=80.3 ± 3.8) with minor cognitive deficits (mini mental state examination scores between 21 and 27). Functional connectivity was assessed within ten standard large-scale resting state networks and on a finer spatial resolution between 300 nodes in a functional connectivity matrix. No domain-specific associations with mean functional connectivity within large-scale resting state networks were found. Node-level analysis revealed that associations between functional connectivity and cognitive performance differed across cognitive functions in strength, location and direction. Specific subnetworks of functional connections were found for each cognitive domain in which higher connectivity between some nodes but lower connectivity between other nodes were related to better cognitive performance. Our findings add to a growing body of literature showing differential sensitivity of functional connections to specific cognitive functions and may be a valuable resource for hypothesis generation of future studies aiming to investigate specific cognitive dysfunction with resting state functional connectivity in people with beginning cognitive deficits.
{"title":"Distinct functional subnetworks of cognitive domains in older adults with minor cognitive deficits","authors":"Nadieh Drenth, Suzanne E. van Dijk, J. Foster-Dingley, A. Bertens, N. Rius Ottenheim, R. van der Mast, Serge A R B Rombouts, S. van Rooden, Jeroen van der Grond","doi":"10.1093/braincomms/fcae048","DOIUrl":"https://doi.org/10.1093/braincomms/fcae048","url":null,"abstract":"\u0000 Although past research has established a relationship between functional connectivity and cognitive function, less is known about which cognitive domains are associated with which specific functional networks. This study investigated associations between functional connectivity and global cognitive function and performance in the domains of memory, executive function and psychomotor speed in 166 older adults aged 75-91 years (mean=80.3 ± 3.8) with minor cognitive deficits (mini mental state examination scores between 21 and 27). Functional connectivity was assessed within ten standard large-scale resting state networks and on a finer spatial resolution between 300 nodes in a functional connectivity matrix. No domain-specific associations with mean functional connectivity within large-scale resting state networks were found. Node-level analysis revealed that associations between functional connectivity and cognitive performance differed across cognitive functions in strength, location and direction. Specific subnetworks of functional connections were found for each cognitive domain in which higher connectivity between some nodes but lower connectivity between other nodes were related to better cognitive performance. Our findings add to a growing body of literature showing differential sensitivity of functional connections to specific cognitive functions and may be a valuable resource for hypothesis generation of future studies aiming to investigate specific cognitive dysfunction with resting state functional connectivity in people with beginning cognitive deficits.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"30 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139962764","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 : 2024-02-15DOI: 10.1093/braincomms/fcae046
Sita N Shah, Maria-Eleni Dounavi, Paresh Malhotra, Brian Lawlor, L. Naci, Ivan Koychev, Craig Ritchie, Karen Ritchie, John T. O'Brien
A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer’s disease, mild cognitive impairment, and asymptomatic individuals with risk factors for early-onset Alzheimer’s disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. 700 participants aged 40-59 years were recruited into the PREVENT-Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using Freesurfer 7.1.0. Thalamic nuclei were grouped into six regions; 1) Anterior, 2) Lateral, 3) Ventral, 4) Intralaminar, 5) Medial and 6) Posterior. Cognitive performance was evaluated using the computerised assessment of information processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate (FDR) correction for multiple comparisons. We did not find significant volumetric differences of the thalamus or its subregions, that survived FDR correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without dementia family history. A larger volume of the mediodorsal medial nucleus (pFDR = 0.019) was associated with a faster processing speed in those without dementia family history. Larger volumes of the thalamus (p = 0.016) and posterior thalamus (pFDR = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences of thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without dementia family history but have little effect in those with dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.
{"title":"Dementia risk and thalamic nuclei volumetry in healthy midlife adults: The prevent-dementia study","authors":"Sita N Shah, Maria-Eleni Dounavi, Paresh Malhotra, Brian Lawlor, L. Naci, Ivan Koychev, Craig Ritchie, Karen Ritchie, John T. O'Brien","doi":"10.1093/braincomms/fcae046","DOIUrl":"https://doi.org/10.1093/braincomms/fcae046","url":null,"abstract":"\u0000 A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer’s disease, mild cognitive impairment, and asymptomatic individuals with risk factors for early-onset Alzheimer’s disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition.\u0000 700 participants aged 40-59 years were recruited into the PREVENT-Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using Freesurfer 7.1.0. Thalamic nuclei were grouped into six regions; 1) Anterior, 2) Lateral, 3) Ventral, 4) Intralaminar, 5) Medial and 6) Posterior. Cognitive performance was evaluated using the computerised assessment of information processing battery.\u0000 Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate (FDR) correction for multiple comparisons.\u0000 We did not find significant volumetric differences of the thalamus or its subregions, that survived FDR correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without dementia family history. A larger volume of the mediodorsal medial nucleus (pFDR = 0.019) was associated with a faster processing speed in those without dementia family history. Larger volumes of the thalamus (p = 0.016) and posterior thalamus (pFDR = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers.\u0000 We did not find significant volumetric differences of thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without dementia family history but have little effect in those with dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"20 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139963419","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 : 2024-02-15DOI: 10.1093/braincomms/fcae049
J. Vohryzek, Joana Cabral, Louis-David Lord, Henrique M. Fernandes, L. Roseman, David J Nutt, Robin L. Carhart-Harris, G. Deco, Morten L. Kringelbach
Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-Hydroxytryptamine 2a and 5-Hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.
{"title":"Brain dynamics predictive of response to psilocybin for treatment-resistant depression","authors":"J. Vohryzek, Joana Cabral, Louis-David Lord, Henrique M. Fernandes, L. Roseman, David J Nutt, Robin L. Carhart-Harris, G. Deco, Morten L. Kringelbach","doi":"10.1093/braincomms/fcae049","DOIUrl":"https://doi.org/10.1093/braincomms/fcae049","url":null,"abstract":"\u0000 Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-Hydroxytryptamine 2a and 5-Hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"11 22","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139962560","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 : 2024-02-15DOI: 10.1093/braincomms/fcae045
A. Errante, S. Ferraro, G. Demichelis, C. Pinardi, Mario Stanziano, D. Sattin, D. Rossi Sebastiano, Stefano Rozzi, Ludovico D’Incerti, Eleonora Catricalà, Matilde Leonardi, M. Bruzzone, L. Fogassi, A. Nigri
In the past two decades several attempts have been made to promote a correct diagnosis and possible restorative interventions in patients suffering from Disorders of Consciousness (DOC). Sensory stimulation has been proved to be useful in sustaining the level of arousal/awareness and to improve behavioral responsiveness with a significant effect on oro-motor functions. Recently, action observation has been proposed as a stimulation strategy in DOC patients, based on neurophysiological evidence that the motor cortex can be activated not only during action execution, but also when actions are merely observed in the absence of motor output, or during listening to action sounds and speech. This mechanism is provided by the activity of mirror neurons. In the present study, a group of patients with DOC (11 males, 4 females; median age: 55 years; age range 19-74 years) underwent task-based functional MRI in which they had, in one condition, to observe and listen to the sound of mouth actions, in another condition, to listen to verbs with motor or abstract content. In order to verify the presence of residual activation of the mirror neuron system, brain activations of patients were compared with that of a group of healthy individuals (7 males, 8 females; median age: 33.4 years; age range: 24-65 years) preforming the same tasks. The results show that brain activations were lower in DOC patients compared with controls, except for primary auditory areas. During the audiovisual task, 5 out of 15 DOC patients showed only residual activation of low-level visual and auditory areas. Activation of high-level parieto-premotor areas was present in 6 patients. During the listening task, 3 patients showed only low-level activations, and 6 patients activated also high-level areas. Interestingly, in both tasks, one patient with a clinical diagnosis of vegetative state showed activations of high-level areas. Region of interest analysis on Blood Oxygen Level Dependent (BOLD) signal change in temporal, parietal and premotor cortex revealed a significant linear relation with the level of clinical functioning, assessed with Coma Recovery Scale-Revised. We propose a classification of the patient’s response based on the presence of low-level and high-level activations, combined with patient’s functional level. These findings support the use of action observation and listening as possible stimulation strategies in DOC patients and highlight the relevance of combined methods based on functional assessment and brain imaging to provide more detailed neuroanatomical specificity about residual activated areas at both cortical and subcortical levels.
{"title":"Brain activation during processing of mouth actions in patients with disorders of consciousness","authors":"A. Errante, S. Ferraro, G. Demichelis, C. Pinardi, Mario Stanziano, D. Sattin, D. Rossi Sebastiano, Stefano Rozzi, Ludovico D’Incerti, Eleonora Catricalà, Matilde Leonardi, M. Bruzzone, L. Fogassi, A. Nigri","doi":"10.1093/braincomms/fcae045","DOIUrl":"https://doi.org/10.1093/braincomms/fcae045","url":null,"abstract":"\u0000 In the past two decades several attempts have been made to promote a correct diagnosis and possible restorative interventions in patients suffering from Disorders of Consciousness (DOC). Sensory stimulation has been proved to be useful in sustaining the level of arousal/awareness and to improve behavioral responsiveness with a significant effect on oro-motor functions. Recently, action observation has been proposed as a stimulation strategy in DOC patients, based on neurophysiological evidence that the motor cortex can be activated not only during action execution, but also when actions are merely observed in the absence of motor output, or during listening to action sounds and speech. This mechanism is provided by the activity of mirror neurons. In the present study, a group of patients with DOC (11 males, 4 females; median age: 55 years; age range 19-74 years) underwent task-based functional MRI in which they had, in one condition, to observe and listen to the sound of mouth actions, in another condition, to listen to verbs with motor or abstract content. In order to verify the presence of residual activation of the mirror neuron system, brain activations of patients were compared with that of a group of healthy individuals (7 males, 8 females; median age: 33.4 years; age range: 24-65 years) preforming the same tasks. The results show that brain activations were lower in DOC patients compared with controls, except for primary auditory areas. During the audiovisual task, 5 out of 15 DOC patients showed only residual activation of low-level visual and auditory areas. Activation of high-level parieto-premotor areas was present in 6 patients. During the listening task, 3 patients showed only low-level activations, and 6 patients activated also high-level areas. Interestingly, in both tasks, one patient with a clinical diagnosis of vegetative state showed activations of high-level areas. Region of interest analysis on Blood Oxygen Level Dependent (BOLD) signal change in temporal, parietal and premotor cortex revealed a significant linear relation with the level of clinical functioning, assessed with Coma Recovery Scale-Revised. We propose a classification of the patient’s response based on the presence of low-level and high-level activations, combined with patient’s functional level. These findings support the use of action observation and listening as possible stimulation strategies in DOC patients and highlight the relevance of combined methods based on functional assessment and brain imaging to provide more detailed neuroanatomical specificity about residual activated areas at both cortical and subcortical levels.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"7 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139962725","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 : 2024-02-14DOI: 10.1093/braincomms/fcae041
G. Beecher, R. Gavrilova, J. Mandrekar, E. Naddaf
Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum, and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings, and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-2021). We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. Most common phenotypes included: multisystem disorder (n=30), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (14), limb myopathy (13), chronic progressive external ophthalmoplegia (12), and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. 69% had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17), however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, were identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%), and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibers (5.1%) then ragged-blue (1.4%) and ragged-red fibers (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality (hazard ratio 2.36 [1.05, 5.29]). There was no difference in survival based on genotype or phenotype. Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multi-organ involvement and high mortality.
{"title":"Mitochondrial myopathies diagnosed in adulthood: clinico-genetic spectrum and long-term outcomes","authors":"G. Beecher, R. Gavrilova, J. Mandrekar, E. Naddaf","doi":"10.1093/braincomms/fcae041","DOIUrl":"https://doi.org/10.1093/braincomms/fcae041","url":null,"abstract":"\u0000 Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum, and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings, and survival.\u0000 We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-2021).\u0000 We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. Most common phenotypes included: multisystem disorder (n=30), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (14), limb myopathy (13), chronic progressive external ophthalmoplegia (12), and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. 69% had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17), however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, were identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%), and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibers (5.1%) then ragged-blue (1.4%) and ragged-red fibers (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality (hazard ratio 2.36 [1.05, 5.29]). There was no difference in survival based on genotype or phenotype.\u0000 Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multi-organ involvement and high mortality.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"118 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139963625","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 : 2024-01-09DOI: 10.1093/braincomms/fcae004
Tony Feng, Phoebe Makiello, Benjamin Dunwoody, Felix Steckler, J. Symonds, S. Zuberi, L. Dorris, A. Brunklaus
Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. SCN1A mutation-positive Dravet syndrome patients were prospectively followed-up in the United Kingdom from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children. 68/113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, p<0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (p=0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] vs 30% [17/57], X2=19.9, p<0.001), behavioural problems (81% [46/57] vs 38% [23/60], X2=14.1, p<0.001) and motor/mobility problems (80% [51/64] vs 41% [24/59], X2=16.9, p<0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (p<0.001), more severe baseline epilepsy severity (p=0.003) and a worse SCN1A genetic score (p=0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities. Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasises the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies while the potential impact of newer anti-seizure medications requires further study.
德雷维综合征是一种与钠通道α1亚基基因SCN1A突变有关的严重婴儿发病性发育和癫痫性脑病。有关长期发育和临床结果的前瞻性数据非常有限；本研究旨在评估德拉沃综合征 10 年来的临床过程，并确定发育结果的预测因素。从2010年到2020年，英国对SCN1A突变呈阳性的德雷维综合征患者进行了前瞻性随访。护理人员填写了有关临床特征和疾病负担的结构化问卷、癫痫与学习障碍生活质量问卷、适应行为评估系统-3和儿童睡眠障碍量表。68/113名护理人员（60%）返回了张贴的调查问卷。与基线（2.9 [SD 1.1]，中度认知障碍，p<0.001）相比，随访时的发育结果恶化（4.45 [SD 0.65]，极度认知障碍），而10年随访时的癫痫严重程度似乎较轻（p=0.042）。10年随访结果中合并症更为明显，包括自闭症特征增加（77% [48/62] vs 30% [17/57]，X2=19.9，p<0.001）、行为问题（81% [46/57] vs 38% [23/60]，X2=14.1，p<0.001）和运动/行动问题（80% [51/64] vs 41% [24/59]，X2=16.9，p<0.001）。亚组分析表明，与年龄较大的患者相比，年龄较小的患者合并症的增加更为显著。长期发展结果较差的预测因素包括较差的基线语言能力（p<0.001）、较严重的基线癫痫严重程度（p=0.003）和较差的SCN1A基因评分（p=0.027）。35%的参与者（24/68）未与医务人员讨论过癫痫猝死问题。超过 90% 的照顾者表示，这对他们自身的健康和职业机会产生了负面影响。我们的研究发现了预测德雷维综合征发育结果的重要因素和潜在生物标志物，并强调了疾病给照顾者带来的沉重负担。基线时的癫痫严重程度对长期发育结果的负面影响凸显了早期实施重点治疗的重要性，而新型抗癫痫药物的潜在影响则需要进一步研究。
{"title":"Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome","authors":"Tony Feng, Phoebe Makiello, Benjamin Dunwoody, Felix Steckler, J. Symonds, S. Zuberi, L. Dorris, A. Brunklaus","doi":"10.1093/braincomms/fcae004","DOIUrl":"https://doi.org/10.1093/braincomms/fcae004","url":null,"abstract":"\u0000 Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome.\u0000 SCN1A mutation-positive Dravet syndrome patients were prospectively followed-up in the United Kingdom from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children.\u0000 68/113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, p<0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (p=0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] vs 30% [17/57], X2=19.9, p<0.001), behavioural problems (81% [46/57] vs 38% [23/60], X2=14.1, p<0.001) and motor/mobility problems (80% [51/64] vs 41% [24/59], X2=16.9, p<0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (p<0.001), more severe baseline epilepsy severity (p=0.003) and a worse SCN1A genetic score (p=0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities.\u0000 Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasises the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies while the potential impact of newer anti-seizure medications requires further study.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"99 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139444476","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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