{"title":"Vaccination with structurally modified fungal protein fibrils: a new treatment for synucleinopathies?","authors":"Makoto Kinoshita, Y. Kimura, Hideki Mochizuki","doi":"10.1093/brain/awae115","DOIUrl":"https://doi.org/10.1093/brain/awae115","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"13 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140666112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Blood GFAP reflects astrocyte reactivity to Alzheimer's pathology in post-mortem brain tissue.","authors":"Christian Limberger, E. Zimmer","doi":"10.1093/brain/awae104","DOIUrl":"https://doi.org/10.1093/brain/awae104","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140689829","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}
P. Sánchez-Juan, Elizabeth Valeriano-Lorenzo, Alicia Ruiz-González, A. Pastor, Hector Rodrigo Lara, Francisco López-González, M. A. Zea-Sevilla, M. Valentí, Belén Frades, Paloma Ruiz, Laura Saiz, Iván Burgueño-García, Miguel Calero, T. del Ser, A. Rábano
Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (β = 12.85; P < 0.001) that was independent of amyloid deposits (β = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (β = 3.64; P = 0.03) and argyrophilic grain disease (β = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological as
{"title":"Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.","authors":"P. Sánchez-Juan, Elizabeth Valeriano-Lorenzo, Alicia Ruiz-González, A. Pastor, Hector Rodrigo Lara, Francisco López-González, M. A. Zea-Sevilla, M. Valentí, Belén Frades, Paloma Ruiz, Laura Saiz, Iván Burgueño-García, Miguel Calero, T. del Ser, A. Rábano","doi":"10.1093/brain/awae035","DOIUrl":"https://doi.org/10.1093/brain/awae035","url":null,"abstract":"Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (β = 12.85; P < 0.001) that was independent of amyloid deposits (β = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (β = 3.64; P = 0.03) and argyrophilic grain disease (β = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological as","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":" 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686043","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}
F. Distelmaier, Abdullah Sezer, Christina Helm, Stephan Waldmüller, A. Seibt, A. Gangfuss, Heike Kölbel, Ulrike Schara-Schmidt, Deniz Yuksel, Beril Talim, Ertan Mayatepek, S. Nikolin, Joachim Weis, Andreas Roos, Tobias B. Haack
{"title":"Biallelic truncating variants in PACSIN3 cause childhood-onset myopathy with hyperCKaemia.","authors":"F. Distelmaier, Abdullah Sezer, Christina Helm, Stephan Waldmüller, A. Seibt, A. Gangfuss, Heike Kölbel, Ulrike Schara-Schmidt, Deniz Yuksel, Beril Talim, Ertan Mayatepek, S. Nikolin, Joachim Weis, Andreas Roos, Tobias B. Haack","doi":"10.1093/brain/awae099","DOIUrl":"https://doi.org/10.1093/brain/awae099","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":" 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer's dementia.","authors":"","doi":"10.1093/brain/awae103","DOIUrl":"https://doi.org/10.1093/brain/awae103","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"16 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140716305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium seeks a role in the drama of neurodegeneration.","authors":"Charles Nicholson","doi":"10.1093/brain/awae108","DOIUrl":"https://doi.org/10.1093/brain/awae108","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"275 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140723818","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 : 2023-04-11DOI: 10.1101/2023.04.11.23288391
Joshua B Tan, E. Müller, Isabella F Orlando, Natasha L. Taylor, Daniel S. Margulies, J. Szeto, S. J. Lewis, J. Shine, C. O’Callaghan
Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby abnormal communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between- functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques - diffusion-map embedding and t-distributed Stochastic Neighbour Embedding (t-SNE) - to resting state fMRI data, in order to characterise the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy controls. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default-mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions that were not apparent in the functional connectivity analysis, suggesting complex reconfigurations in functional brain network architecture as a function of the disease process. Together, the results confirm abnormal brain organisation associated with the hallucinating phenotype in Parkinson's disease, and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.
{"title":"Abnormal higher-order network interactions in Parkinson's disease visual hallucinations","authors":"Joshua B Tan, E. Müller, Isabella F Orlando, Natasha L. Taylor, Daniel S. Margulies, J. Szeto, S. J. Lewis, J. Shine, C. O’Callaghan","doi":"10.1101/2023.04.11.23288391","DOIUrl":"https://doi.org/10.1101/2023.04.11.23288391","url":null,"abstract":"Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby abnormal communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between- functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques - diffusion-map embedding and t-distributed Stochastic Neighbour Embedding (t-SNE) - to resting state fMRI data, in order to characterise the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy controls. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default-mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions that were not apparent in the functional connectivity analysis, suggesting complex reconfigurations in functional brain network architecture as a function of the disease process. Together, the results confirm abnormal brain organisation associated with the hallucinating phenotype in Parkinson's disease, and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132038200","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 : 2023-03-07DOI: 10.1101/2023.03.06.23286778
Alexander H. C. W. Agopyan-Miu, E. Merricks, Elliot H. Smith, G. Mckhann, S. Sheth, N. Feldstein, A. Trevelyan, C. Schevon
The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the seizure transition is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing while others suggest reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principles applied also in limbic structures. We analyzed simultaneous ECoG and neuronal recordings during 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, at times co-existing within seizures. 156 single-units were isolated, subclassified by cell-type, and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (p < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (p = 0.014). This study provides evidence for entrained high gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, our results of reduced neuronal firing suggest preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or if it indicates a "seizure-responsive" state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help refine surgical treatment of mesial temporal lobe epilepsy.
{"title":"Cell-type specific and multiscale dynamics of human focal seizures in limbic structures","authors":"Alexander H. C. W. Agopyan-Miu, E. Merricks, Elliot H. Smith, G. Mckhann, S. Sheth, N. Feldstein, A. Trevelyan, C. Schevon","doi":"10.1101/2023.03.06.23286778","DOIUrl":"https://doi.org/10.1101/2023.03.06.23286778","url":null,"abstract":"The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the seizure transition is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing while others suggest reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principles applied also in limbic structures. We analyzed simultaneous ECoG and neuronal recordings during 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, at times co-existing within seizures. 156 single-units were isolated, subclassified by cell-type, and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (p < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (p = 0.014). This study provides evidence for entrained high gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, our results of reduced neuronal firing suggest preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or if it indicates a \"seizure-responsive\" state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help refine surgical treatment of mesial temporal lobe epilepsy.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"13 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126819103","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 : 2022-12-22DOI: 10.1101/2022.12.21.22283728
A. Dilliott, Seulki Kwon, G. Rouleau, S. Iqbal, S. Farhan
Background: Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3,864 individuals with ALS and 7,839 controls) and Project MinE ALS Sequencing Consortium (4,366 individuals with ALS and 1,832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. Results: Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in {beta}-sheets and -helices, as well as in core, buried, or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and protein-protein interaction regions are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses to determine whether individual genes were driving the enrichment signal. A case study is presented for SOD1 to demonstrate proof of concept of how enriched features may aid in defining variant pathogenicity. Conclusions: Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.
{"title":"Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes","authors":"A. Dilliott, Seulki Kwon, G. Rouleau, S. Iqbal, S. Farhan","doi":"10.1101/2022.12.21.22283728","DOIUrl":"https://doi.org/10.1101/2022.12.21.22283728","url":null,"abstract":"Background: Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3,864 individuals with ALS and 7,839 controls) and Project MinE ALS Sequencing Consortium (4,366 individuals with ALS and 1,832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. Results: Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in {beta}-sheets and -helices, as well as in core, buried, or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and protein-protein interaction regions are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses to determine whether individual genes were driving the enrichment signal. A case study is presented for SOD1 to demonstrate proof of concept of how enriched features may aid in defining variant pathogenicity. Conclusions: Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"9 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116776777","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 : 2022-12-21DOI: 10.1101/2022.12.20.22283430
Shenghong He, F. Baig, Anca Merla, F. Torrecillos, A. Perera, C. Wiest, Jean Debarros, Moaad Benjaber, M. Hart, L. Ricciardi, F. Morgante, H. Hasegawa, M. Samuel, M. Edwards, T. Denison, A. Pogosyan, K. Ashkan, E. Pereira, H. Tan
Subthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) in people with Parkinson's disease (PD) with less energy delivered to the brain and less stimulation induced side-effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over time periods of 400ms or longer in most previous ADBS studies. A shorter smoothing period could have the advantage of being more sensitive to changes in beta power which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400ms and a shorter 200ms smoothing window during reaching movements. Results from 13 people with PD showed that STN beta-triggered ADBS is effective in improving motor performance during reaching movements as it better preserves gamma oscillation than CDBS in people with PD, and that shortening the smoothing window does not result in any additional behavioural benefit. ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. When developing ADBS systems for PD, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.
{"title":"Beta-triggered adaptive deep brain stimulation during reaching movement in Parkinson's disease","authors":"Shenghong He, F. Baig, Anca Merla, F. Torrecillos, A. Perera, C. Wiest, Jean Debarros, Moaad Benjaber, M. Hart, L. Ricciardi, F. Morgante, H. Hasegawa, M. Samuel, M. Edwards, T. Denison, A. Pogosyan, K. Ashkan, E. Pereira, H. Tan","doi":"10.1101/2022.12.20.22283430","DOIUrl":"https://doi.org/10.1101/2022.12.20.22283430","url":null,"abstract":"Subthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) in people with Parkinson's disease (PD) with less energy delivered to the brain and less stimulation induced side-effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over time periods of 400ms or longer in most previous ADBS studies. A shorter smoothing period could have the advantage of being more sensitive to changes in beta power which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400ms and a shorter 200ms smoothing window during reaching movements. Results from 13 people with PD showed that STN beta-triggered ADBS is effective in improving motor performance during reaching movements as it better preserves gamma oscillation than CDBS in people with PD, and that shortening the smoothing window does not result in any additional behavioural benefit. ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. When developing ADBS systems for PD, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"104 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132755970","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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