Pub Date : 2023-12-07DOI: 10.1093/braincomms/fcad336
Emily Beswick, Deborah Forbes, Kay Johnson, J. Newton, Rachel Dakin, Stella Glasmcher, Sharon Abrahams, Alan Carson, Siddharthan Chandran, S. Pal
People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration, and that may significantly reduce quality of life, despite being under-recognised and evaluated in clinical practice. Non-motor symptoms explored in this population based study include: pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical, Audit, Research and Evaluation of motor neuron disease platform, the Scottish motor neuron disease register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311). 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as ‘severe’ by 54% of participants who experienced them), followed by pain and problematic saliva (51% respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease, and being a long survivor (diagnosed over 8 years ago [1]) were significantly associated with reporting more symptoms. 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care. 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.
{"title":"Non-motor symptoms in motor neuron disease: prevalence, assessment and impact","authors":"Emily Beswick, Deborah Forbes, Kay Johnson, J. Newton, Rachel Dakin, Stella Glasmcher, Sharon Abrahams, Alan Carson, Siddharthan Chandran, S. Pal","doi":"10.1093/braincomms/fcad336","DOIUrl":"https://doi.org/10.1093/braincomms/fcad336","url":null,"abstract":"\u0000 People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration, and that may significantly reduce quality of life, despite being under-recognised and evaluated in clinical practice. Non-motor symptoms explored in this population based study include: pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction.\u0000 People registered on the Clinical, Audit, Research and Evaluation of motor neuron disease platform, the Scottish motor neuron disease register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms.\u0000 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311). 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as ‘severe’ by 54% of participants who experienced them), followed by pain and problematic saliva (51% respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease, and being a long survivor (diagnosed over 8 years ago [1]) were significantly associated with reporting more symptoms. 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care. 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home.\u0000 The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"118 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138590407","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 : 2023-12-07DOI: 10.1093/braincomms/fcad331
R. Waller, Joanna J. Bury, C. Appleby-Mallinder, M. Wyles, George Loxley, Aditi Babel, Saleh Shekari, Mbombe Kazoka, Helen Wollff, Ammar Al-Chalabi, P. Heath, Pamela J Shaw, J. Kirby
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of ALS pathophysiology and could be used to monitor a patient’s response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs (miRNAs) are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding miRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as ALS. The present study aimed to investigate the transcriptomic profile (mRNA and miRNA) of lymphoblastoid cell lines (LCLs) from ALS patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (< 12 months) (n = 22) compared to those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of miRNA-mRNA interactions from LCL’s in ALS patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared to those with short survival. Understanding these particular miRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of ALS patients.
{"title":"Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival","authors":"R. Waller, Joanna J. Bury, C. Appleby-Mallinder, M. Wyles, George Loxley, Aditi Babel, Saleh Shekari, Mbombe Kazoka, Helen Wollff, Ammar Al-Chalabi, P. Heath, Pamela J Shaw, J. Kirby","doi":"10.1093/braincomms/fcad331","DOIUrl":"https://doi.org/10.1093/braincomms/fcad331","url":null,"abstract":"\u0000 Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of ALS pathophysiology and could be used to monitor a patient’s response to drugs and therapeutic agents.\u0000 Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs (miRNAs) are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding miRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as ALS.\u0000 The present study aimed to investigate the transcriptomic profile (mRNA and miRNA) of lymphoblastoid cell lines (LCLs) from ALS patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (< 12 months) (n = 22) compared to those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of miRNA-mRNA interactions from LCL’s in ALS patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared to those with short survival.\u0000 Understanding these particular miRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of ALS patients.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"28 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593336","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 : 2023-12-07DOI: 10.1093/braincomms/fcad342
P. Voruz, A. Cionca, Frédéric Assal, J. Péron
{"title":"Response to: Limbic system damage following SARS-CoV2 infection","authors":"P. Voruz, A. Cionca, Frédéric Assal, J. Péron","doi":"10.1093/braincomms/fcad342","DOIUrl":"https://doi.org/10.1093/braincomms/fcad342","url":null,"abstract":"","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"51 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138591715","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 : 2023-12-07DOI: 10.1093/braincomms/fcad340
Aslihan Taskiran-Sag, Hare Yazgi
{"title":"Limbic system damage following SARS-CoV2 infection","authors":"Aslihan Taskiran-Sag, Hare Yazgi","doi":"10.1093/braincomms/fcad340","DOIUrl":"https://doi.org/10.1093/braincomms/fcad340","url":null,"abstract":"","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"47 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593849","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 : 2023-12-07DOI: 10.1093/braincomms/fcad344
Sara Regio, Gabriel Vachey, Enrique Goñi, Fábio Duarte, Margareta Rybarikova, Mélanie Sipion, Maria Rey, Maite Huarte, N. Déglon
Huntingtin-lowering strategies are central to therapeutic approaches for Huntington's disease. Recent studies reported the induction of age- and cell type-specific phenotypes by conditional huntingtin knockout, but these experimental conditions did not precisely mimic huntingtin-lowering or gene-editing conditions in terms of the cells targeted and brain distribution, and no transcriptional profiles were provided. Here, we used the adeno-associated delivery system commonly used in CNS gene therapy programs and the self-inactivating KamiCas9 gene-editing system to investigate the long-term consequences of wild-type mouse huntingtin inactivation in adult neurons and, thus, the feasibility and safety of huntingtin inactivation in these cells. Behavioral and neuropathological analyses and single-nuclei RNA sequencing indicated that huntingtin editing in 77% of striatal neurons and 16% of cortical projecting neurons in adult mice induced no behavioral deficits or cellular toxicity. Single-nuclei RNA sequencing in 11.5-month-old animals showed that huntingtin inactivation did not alter striatal-cell profiles or proportions. Few differentially expressed genes were identified and Augur analysis confirmed an extremely limited response to huntingtin inactivation in all cell types. Our results therefore indicate that wild-type huntingtin inactivation in adult striatal and projection neurons is well tolerated in the long term.
{"title":"Revisiting the outcome of adult wild-type Htt inactivation in the context of HTT-lowering strategies for Huntington’s disease","authors":"Sara Regio, Gabriel Vachey, Enrique Goñi, Fábio Duarte, Margareta Rybarikova, Mélanie Sipion, Maria Rey, Maite Huarte, N. Déglon","doi":"10.1093/braincomms/fcad344","DOIUrl":"https://doi.org/10.1093/braincomms/fcad344","url":null,"abstract":"\u0000 Huntingtin-lowering strategies are central to therapeutic approaches for Huntington's disease. Recent studies reported the induction of age- and cell type-specific phenotypes by conditional huntingtin knockout, but these experimental conditions did not precisely mimic huntingtin-lowering or gene-editing conditions in terms of the cells targeted and brain distribution, and no transcriptional profiles were provided. Here, we used the adeno-associated delivery system commonly used in CNS gene therapy programs and the self-inactivating KamiCas9 gene-editing system to investigate the long-term consequences of wild-type mouse huntingtin inactivation in adult neurons and, thus, the feasibility and safety of huntingtin inactivation in these cells. Behavioral and neuropathological analyses and single-nuclei RNA sequencing indicated that huntingtin editing in 77% of striatal neurons and 16% of cortical projecting neurons in adult mice induced no behavioral deficits or cellular toxicity. Single-nuclei RNA sequencing in 11.5-month-old animals showed that huntingtin inactivation did not alter striatal-cell profiles or proportions. Few differentially expressed genes were identified and Augur analysis confirmed an extremely limited response to huntingtin inactivation in all cell types. Our results therefore indicate that wild-type huntingtin inactivation in adult striatal and projection neurons is well tolerated in the long term.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"72 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138590822","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 : 2023-12-06DOI: 10.1093/braincomms/fcad282
Stefania Evangelisti, Sirius Boessenkool, Chris Patrick Pflanz, Romina Basting, Jill F Betts, Mark Jenkinson, Stuart Clare, K. Muhammed, Campbell LeHeron, Richard Armstrong, Johannes C Klein, Masud Husain, Andrea H Nemeth, Michele T Hu, G. Douaud
Abstract Huntington’s and Parkinson’s disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington’s and Parkinson’s disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington’s and Parkinson’s disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington’s disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson’s disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington’s and Parkinson’s disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation ‘sweet spot’—the area with maximum overall efficacy—in Parkinson’s disease. Importantly, the severity of deviation away from controls’ resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington’s and Parkinson’s disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.
{"title":"Subthalamic nucleus shows opposite functional connectivity pattern in Huntington’s and Parkinson’s disease","authors":"Stefania Evangelisti, Sirius Boessenkool, Chris Patrick Pflanz, Romina Basting, Jill F Betts, Mark Jenkinson, Stuart Clare, K. Muhammed, Campbell LeHeron, Richard Armstrong, Johannes C Klein, Masud Husain, Andrea H Nemeth, Michele T Hu, G. Douaud","doi":"10.1093/braincomms/fcad282","DOIUrl":"https://doi.org/10.1093/braincomms/fcad282","url":null,"abstract":"Abstract Huntington’s and Parkinson’s disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington’s and Parkinson’s disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington’s and Parkinson’s disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington’s disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson’s disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington’s and Parkinson’s disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation ‘sweet spot’—the area with maximum overall efficacy—in Parkinson’s disease. Importantly, the severity of deviation away from controls’ resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington’s and Parkinson’s disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"54 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138597505","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 : 2023-12-05DOI: 10.1093/braincomms/fcad328
B. Edlow, M. Massimini
This scientific commentary refers to ‘Functional hub disruption emphasizes consciousness recovery in severe traumatic brain injury’, by Oujamaa et al. (https://doi.org/10.1093/braincomms/fcad319)
{"title":"Are disorders of consciousness disconnection or dysconnection syndromes?","authors":"B. Edlow, M. Massimini","doi":"10.1093/braincomms/fcad328","DOIUrl":"https://doi.org/10.1093/braincomms/fcad328","url":null,"abstract":"This scientific commentary refers to ‘Functional hub disruption emphasizes consciousness recovery in severe traumatic brain injury’, by Oujamaa et al. (https://doi.org/10.1093/braincomms/fcad319)","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"113 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138599578","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 : 2023-12-03DOI: 10.1093/braincomms/fcad333
Lianlian Du, Bruce P. Hermann, E. Jonaitis, K. Cody, L. Rivera-Rivera, Howard Rowley, Aaron Field, Laura Eisenmenger, Bradley T Christian, T. Betthauser, Bret Larget, Rick Chappell, S. Janelidze, Oskar Hansson, Sterling C. Johnson, Rebecca Langhough
Cognitive decline in Alzheimer’s disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally-based random slope and change point parameter estimates from a Preclinical Alzheimer’s disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer’s disease and vascular disease varied across these cognitive clusters. Data were drawn from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer’s disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with >= 3 cognitive visits were included in trajectory modeling (n=1068). The following biomarker data were available for subsets: positron emission tomography (PET) amyloid (Amyloid: n = 367; [C-11]PiB: Global PiB distribution volume ratio); PET tau (Tau: n = 321; [F-18]MK-6240: primary regions of interest Meta-Temporal composite); MRI neurodegeneration (Neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2-FLAIR MRI white matter ischemic lesion volumes (Vascular: White matter hyperintensities; n=419); and plasma pTau217 (n=165). Posterior median estimate person-level change points, slopes pre- and post- change point, and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modeling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify Amyloid/Tau/Neurodegeneration/Vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and Amyloid/Tau/Neurodegeneration/Vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, Chi-square, and Fisher’s exact tests. Mean(SD) baseline and last cognitive assessment ages were 58.4(6.4) and 66.6(6.6) years, respectively. Cluster analysis identified 3 cognitive trajectory groups representing Steep: n = 77(7.2%); Intermediate: n = 446(41.8%); and Minimal: n = 545(51.0%) cognitive decline. The Steep decline group was older, had more females, APOE e4 carriers, and Mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher Amyloid, Tau, Neurodegeneration and White matter hyperintensities positive proportions at last visit. Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on etiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and Amyloid/Tau/Neurodegeneration/Va
{"title":"Harnessing cognitive trajectory clusterings to examine subclinical decline risk factors","authors":"Lianlian Du, Bruce P. Hermann, E. Jonaitis, K. Cody, L. Rivera-Rivera, Howard Rowley, Aaron Field, Laura Eisenmenger, Bradley T Christian, T. Betthauser, Bret Larget, Rick Chappell, S. Janelidze, Oskar Hansson, Sterling C. Johnson, Rebecca Langhough","doi":"10.1093/braincomms/fcad333","DOIUrl":"https://doi.org/10.1093/braincomms/fcad333","url":null,"abstract":"\u0000 Cognitive decline in Alzheimer’s disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally-based random slope and change point parameter estimates from a Preclinical Alzheimer’s disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer’s disease and vascular disease varied across these cognitive clusters.\u0000 Data were drawn from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer’s disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with >= 3 cognitive visits were included in trajectory modeling (n=1068). The following biomarker data were available for subsets: positron emission tomography (PET) amyloid (Amyloid: n = 367; [C-11]PiB: Global PiB distribution volume ratio); PET tau (Tau: n = 321; [F-18]MK-6240: primary regions of interest Meta-Temporal composite); MRI neurodegeneration (Neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2-FLAIR MRI white matter ischemic lesion volumes (Vascular: White matter hyperintensities; n=419); and plasma pTau217 (n=165). Posterior median estimate person-level change points, slopes pre- and post- change point, and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modeling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify Amyloid/Tau/Neurodegeneration/Vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and Amyloid/Tau/Neurodegeneration/Vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, Chi-square, and Fisher’s exact tests.\u0000 Mean(SD) baseline and last cognitive assessment ages were 58.4(6.4) and 66.6(6.6) years, respectively. Cluster analysis identified 3 cognitive trajectory groups representing Steep: n = 77(7.2%); Intermediate: n = 446(41.8%); and Minimal: n = 545(51.0%) cognitive decline. The Steep decline group was older, had more females, APOE e4 carriers, and Mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher Amyloid, Tau, Neurodegeneration and White matter hyperintensities positive proportions at last visit.\u0000 Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on etiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and Amyloid/Tau/Neurodegeneration/Va","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"91 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138606252","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 : 2023-12-03DOI: 10.1093/braincomms/fcad320
N. Rubido, Gernot Riedel, Vesna Vuksanović
Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer’s disease are still largely unexplored. Understanding the association between gene expression in the brain and functional networks may provide useful information about the molecular processes underlying variations in impaired brain function. Given the potential of dynamic functional connectivity to uncover brain states associated with Alzheimer’s disease, it is interesting to ask: How does gene expression associated with Alzheimer’s disease map onto the dynamic functional brain connectivity? If genetic variants associated with neurodegenerative processes involved in Alzheimer’s disease are to be correlated with brain function, it is essential to generate such a map. Here, we investigate how the relation between gene expression in the brain and dynamic functional connectivity arises from nodal interactions, quantified by their role in network centrality (i.e., the drivers of the metastability), and the principal component of genetic co-expression across the brain. Our analyses include genetic variations associated with Alzheimer’s disease and also genetic variants expressed within the cholinergic brain pathways. Our findings show that contrasts in metastability of functional networks between Alzheimer’s and healthy individuals can in part be explained by the two combinations of genetic co-variations in the brain with the confidence interval between 72% and 92%. The highly central nodes, driving the brain aberrant metastable dynamics in Alzheimer’s disease, highly correlate with the magnitude of variations from two combinations of genes expressed in the brain. These nodes include mainly the white matter, parietal and occipital brain regions, each of which (or their combinations) are involved in impaired cognitive function in Alzheimer’s disease. In addition, our results provide evidence of the role of genetic associations across brain regions in asymmetric changes in ageing. We validated our findings on the same cohort using alternative brain parcellation methods. This work demonstrates how genetic variations underpin aberrant dynamic functional connectivity in Alzheimer’s disease.
{"title":"Genetic basis of anatomical asymmetry and aberrant dynamic functional networks in Alzheimer’s disease","authors":"N. Rubido, Gernot Riedel, Vesna Vuksanović","doi":"10.1093/braincomms/fcad320","DOIUrl":"https://doi.org/10.1093/braincomms/fcad320","url":null,"abstract":"\u0000 Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer’s disease are still largely unexplored. Understanding the association between gene expression in the brain and functional networks may provide useful information about the molecular processes underlying variations in impaired brain function. Given the potential of dynamic functional connectivity to uncover brain states associated with Alzheimer’s disease, it is interesting to ask: How does gene expression associated with Alzheimer’s disease map onto the dynamic functional brain connectivity? If genetic variants associated with neurodegenerative processes involved in Alzheimer’s disease are to be correlated with brain function, it is essential to generate such a map. Here, we investigate how the relation between gene expression in the brain and dynamic functional connectivity arises from nodal interactions, quantified by their role in network centrality (i.e., the drivers of the metastability), and the principal component of genetic co-expression across the brain. Our analyses include genetic variations associated with Alzheimer’s disease and also genetic variants expressed within the cholinergic brain pathways. Our findings show that contrasts in metastability of functional networks between Alzheimer’s and healthy individuals can in part be explained by the two combinations of genetic co-variations in the brain with the confidence interval between 72% and 92%. The highly central nodes, driving the brain aberrant metastable dynamics in Alzheimer’s disease, highly correlate with the magnitude of variations from two combinations of genes expressed in the brain. These nodes include mainly the white matter, parietal and occipital brain regions, each of which (or their combinations) are involved in impaired cognitive function in Alzheimer’s disease. In addition, our results provide evidence of the role of genetic associations across brain regions in asymmetric changes in ageing. We validated our findings on the same cohort using alternative brain parcellation methods. This work demonstrates how genetic variations underpin aberrant dynamic functional connectivity in Alzheimer’s disease.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"45 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138605419","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 : 2023-11-22DOI: 10.1093/braincomms/fcad319
Lydia Oujamaa, C. Delon-Martin, Chloé Jaroszynski, Maite Termenon, Stein Silva, Jean-François Payen, S. Achard
Severe traumatic brain injury can lead to transient or even chronic disorder of consciousness. To increase diagnosis and prognosis accuracy of disorder of consciousness, functional neuroimaging is recommended one month post injury. Here, we investigated brain networks remodelling on longitudinal data between one- and three-months post severe traumatic brain injury related to change of consciousness. Thirty-four severe traumatic brain injured patients were included in a cross sectional and longitudinal clinical study and their MRI data were compared to those of twenty healthy subjects. Long duration resting-state functional MRI were acquired in minimally conscious and conscious patients at two time points after their brain injury. The first time corresponds to the exit from Intensive Care Unit and the second one to the discharge from post intensive care rehabilitation ward. Brain networks data were extracted using graph analysis and metrics at each node quantifying local (Clustering) and global (Degree) connectivity characteristics. Comparison with brain networks of healthy subjects revealed patterns of hyper- and hypo- connectivity that characterize brain networks reorganization through the hub disruption index, a value quantifying the functional disruption in each individual severe traumatic brain injury graph. At discharge from intensive care unit, twenty-four patients’ graphs (nine minimally conscious and fifteen conscious) were fully analysed and demonstrated significant network disruption. Clustering and Degree nodal metrics, respectively related to segregation and integration properties of the network, were relevant to distinguish minimally conscious and conscious groups. At discharge from post intensive care rehabilitation unit, fifteen patients’ graphs (two minimally conscious, thirteen conscious) were fully analysed. The conscious-group still presented a significant difference with healthy subjects. Using mixed effects models, we showed that consciousness state, rather than time, explained the Hub disruption index differences between minimally conscious and conscious-groups. While severe traumatic brain injured patients recovered full consciousness, regional functional connectivity evolved towards a healthy pattern. More specifically the restoration of a healthy brain functional segregation could be necessary for consciousness recovery after severe traumatic brain injury. For the first time, extracting the Hub disruption index directly from each patient’s graph, we were able to track the clinical alteration and subsequent recovery of consciousness during the first three months following a severe traumatic brain injury.
{"title":"Functional hub disruption emphasizes consciousness recovery in severe traumatic brain injury","authors":"Lydia Oujamaa, C. Delon-Martin, Chloé Jaroszynski, Maite Termenon, Stein Silva, Jean-François Payen, S. Achard","doi":"10.1093/braincomms/fcad319","DOIUrl":"https://doi.org/10.1093/braincomms/fcad319","url":null,"abstract":"Severe traumatic brain injury can lead to transient or even chronic disorder of consciousness. To increase diagnosis and prognosis accuracy of disorder of consciousness, functional neuroimaging is recommended one month post injury. Here, we investigated brain networks remodelling on longitudinal data between one- and three-months post severe traumatic brain injury related to change of consciousness. Thirty-four severe traumatic brain injured patients were included in a cross sectional and longitudinal clinical study and their MRI data were compared to those of twenty healthy subjects. Long duration resting-state functional MRI were acquired in minimally conscious and conscious patients at two time points after their brain injury. The first time corresponds to the exit from Intensive Care Unit and the second one to the discharge from post intensive care rehabilitation ward. Brain networks data were extracted using graph analysis and metrics at each node quantifying local (Clustering) and global (Degree) connectivity characteristics. Comparison with brain networks of healthy subjects revealed patterns of hyper- and hypo- connectivity that characterize brain networks reorganization through the hub disruption index, a value quantifying the functional disruption in each individual severe traumatic brain injury graph. At discharge from intensive care unit, twenty-four patients’ graphs (nine minimally conscious and fifteen conscious) were fully analysed and demonstrated significant network disruption. Clustering and Degree nodal metrics, respectively related to segregation and integration properties of the network, were relevant to distinguish minimally conscious and conscious groups. At discharge from post intensive care rehabilitation unit, fifteen patients’ graphs (two minimally conscious, thirteen conscious) were fully analysed. The conscious-group still presented a significant difference with healthy subjects. Using mixed effects models, we showed that consciousness state, rather than time, explained the Hub disruption index differences between minimally conscious and conscious-groups. While severe traumatic brain injured patients recovered full consciousness, regional functional connectivity evolved towards a healthy pattern. More specifically the restoration of a healthy brain functional segregation could be necessary for consciousness recovery after severe traumatic brain injury. For the first time, extracting the Hub disruption index directly from each patient’s graph, we were able to track the clinical alteration and subsequent recovery of consciousness during the first three months following a severe traumatic brain injury.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139247949","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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