Brain communications最新文献

{"title":"A compilation of reported alterations in the cerebrospinal fluid proteome in Alzheimer's disease.","authors":"Matthijs B de Geus, Angus C Nairn, Steven E Arnold, Becky C Carlyle","doi":"10.1093/braincomms/fcaf202","DOIUrl":"10.1093/braincomms/fcaf202","url":null,"abstract":"<p><p>Alzheimer's disease is a multifaceted neurodegenerative disorder, with diverse underlying pathophysiological processes extending beyond amyloid-β and tau accumulation. The heterogeneity of Alzheimer's disease necessitates the identification of a broad array of biomarkers that capture the diverse mechanisms contributing to disease onset and progression. In this study, we systematically compiled and analysed cerebrospinal fluid proteomics data from omics studies utilizing mass spectrometry, Olink, or SomaScan platforms. Systematic literature searches for each platform revealed a total of 264 studies. From this, a set of 18 studies were selected based on sample size, number of markers analysed, and open data availability. We found a total of 1,448 differentially expressed proteins between Alzheimer's disease and amyloid negative controls across these datasets, with 635 being found in more than one study. A 'top' set of 61 differentially expressed proteins were consistently reported in at least six studies. Clustering and functional enrichment analysis of the top differentially expressed proteins indicated involvement in metabolic regulation, glutathione metabolism and proteins of the 14-3-3 family, reflecting importance of reactive oxygen species (ROS) response. Synaptic signalling processes were found to generally be downregulated. We further integrated the top differentially expressed proteins with results from a study on familial Alzheimer's disease cerebrospinal fluid to assess at which stage of disease progression these proteins change, highlighting markers shared between sporadic and familial Alzheimer's disease datasets. Lastly, we examine the overlap of the top differentially expressed proteins between cerebrospinal fluid and brain tissue using a publicly available database. This analysis provides a comprehensive overview of the Alzheimer's disease cerebrospinal fluid proteomic landscape, indicating changes in key pathways and cellular processes associated with Alzheimer's disease pathology. By integrating data from different platforms, we highlight reproducible protein changes that may serve as promising candidates for further biomarker research aimed at improving patient stratification, tracking disease progression, and assessing therapeutic interventions.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf202"},"PeriodicalIF":4.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12146149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain glymphatic fluid mapping in Alzheimer's disease: a human MRI and PET study.","authors":"Liangdong Zhou, Thanh D Nguyen, Gloria C Chiang, Samantha A Keil, Xiuyuan Hugh Wang, Tsung-Wei Hu, Haoyu Lan, Ke Xi, Ana Paula Costa, Emily B Tanzi, Lidia Glodzik, Jarek Wegiel, Tracy Butler, Mony J de Leon, Yi Li","doi":"10.1093/braincomms/fcaf200","DOIUrl":"10.1093/braincomms/fcaf200","url":null,"abstract":"<p><p>Glymphatic system has been identified as a fluid exchange network in brain parenchymal for removal of toxic metabolites in Alzheimer's disease. However, a clinically feasible, accurate, and non-invasive imaging technique for mapping global glymphatic fluid distribution throughout the entire brain and monitoring its dysfunction in Alzheimer's disease is currently lacking. This cross-sectional retrospective study aims to compare three MRI-based measures of the glymphatic system structural alterations, a novel multi-echo T2 relaxometry-based parenchymal CSF (pCSF) mapping, T2 weighted-based segmented perivascular space burden, and diffusion tensor imaging-based free-water mapping. We evaluated their cross-correlation and investigated their respective association with PET measured beta-amyloid deposition using ¹¹C-PiB PET. A total of 29 subjects (18 Female, age: 70.07 ± 8.73 years old), among them, 16 were cognitively normal and 13 were mild cognitive impairment or Alzheimer's disease, underwent both MRI and ¹¹C-PiB PET scans. Parenchymal CSF mapping, diffusion-based free-water mapping and perivascular spaces burden were generated from their respective MRI. Age and sex effects and group differences of these biomarkers were evaluated. The associations among these measures and Aβ deposition on ¹¹C-PiB PET were analysed and compared. Our analysis demonstrated moderate correlations between pCSF, diffusion-based free-water mapping and perivascular space burden, suggesting these biomarkers capture overlapping yet distinct aspects of glymphatic fluid distribution. Importantly, linear regression analyses revealed that pCSF exhibited a significantly stronger positive association with beta-amyloid deposition (white matter: <i>t</i> = 3.536, <i>P</i> = 0.002, <i>R</i> ² = 0.446; Alzheimer's disease-related meta regions: <i>t</i> = 4.510, <i>P</i> < 0.001, <i>R</i> ² = 0.541), compared with diffusion-based free-water mapping in white matter (<i>t</i> = 0.843, <i>P</i> = 0.407, <i>R</i> ² = 0.191) and perivascular space burden (<i>t</i> = 0.422, <i>P</i> = 0.677, <i>R</i> ² = 0.174), after adjusting for age and sex. This study identifies pCSF mapping, derived from multi-echo T2 data with clinically feasible 5 mins scan FAST-T2 sequence, as a potential non-invasive imaging biomarker for assessing glymphatic dysfunction in Alzheimer's disease. The superior sensitivity of pCSF mapping arises from its direct quantification of glymphatic fluid at the water molecular level based on free CSF-specific T2 relaxation properties. These results suggest that pCSF could be useful in the monitoring of Alzheimer's disease progression as beta-amyloid accumulating and predicting response to anti-amyloid therapies, potentially leading to better diagnostic strategies and therapeutic interventions of Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf200"},"PeriodicalIF":4.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence that minocycline treatment confounds the interpretation of neurofilament as a biomarker.","authors":"Juliana E Gentile, Christina N Heiss, Taylor L Corridon, Meredith A Mortberg, Stefanie Fruhwürth, Kenia Guzman, Lana Grötschel, Laia Montoliu-Gaya, Kwan Chan, Neil C Herring, Timothy Janicki, Rajaa Nhass, Janani Manavala Sarathy, Brian Erickson, Ryan Kunz, Alison Erickson, Craig Braun, Katherine T Henry, Lynn Bry, Steven E Arnold, Eric Vallabh Minikel, Henrik Zetterberg, Sonia M Vallabh","doi":"10.1093/braincomms/fcaf175","DOIUrl":"10.1093/braincomms/fcaf175","url":null,"abstract":"<p><p>Neurofilament light (NfL) concentration in CSF and blood serves as an important biomarker in neurology drug development. Changes in NfL are generally assumed to reflect changes in neuronal damage, while little is known about the clearance of NfL from biofluids. In a study of asymptomatic individuals at risk for prion disease, both blood and CSF NfL spiked in one participant following a 6-week course of minocycline, absent any other biomarker changes and without subsequent onset of symptoms. We subsequently observed high NfL after minocycline treatment in discarded clinical plasma samples from inpatients, in mouse plasma and in conditioned media from neuron-microglia co-cultures. The specificity and kinetics of NfL response lead us to hypothesize that minocycline does not cause or exacerbate neuronal damage, but instead affects NfL by inhibiting its clearance, posing a potential confounder for the interpretation of this important biomarker.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf175"},"PeriodicalIF":4.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitivity of diffusion tensor imaging to regional mixed cerebrovascular pathology.","authors":"Jennifer K Ferris, Julia Dahlby, Shie Rinat, Brian Greeley, Joel Ramirez, Sandra E Black, Lara A Boyd","doi":"10.1093/braincomms/fcaf193","DOIUrl":"10.1093/braincomms/fcaf193","url":null,"abstract":"<p><p>Diffusion tensor imaging is a candidate biomarker in cerebrovascular disease. Yet, little is known about the sensitivity of diffusion tensor imaging to mixed forms of cerebrovascular pathology: stroke and white matter hyperintensities. We evaluated the sensitivity of diffusion tensor imaging to regional lesion load, considering both stroke and white matter hyperintensity lesions. 65 older adults and 39 individuals with chronic stroke underwent diffusion tensor imaging and comprehensive cerebrovascular lesion segmentation. We tested relationships between fractional anisotropy or mean diffusivity and cerebrovascular lesions with linear mixed effects regression. In older adults, tract microstructure related to white matter hyperintensity lesion load (fractional anisotropy: <i>b</i> = -0.003, <i>P</i> = 0.003; mean diffusivity: <i>b</i> = 0.071 × 10^-4, <i>P</i> < 0.001). In individuals with chronic stroke, tract microstructure related to stroke lesion load (fractional anisotropy: <i>b</i> = -0.041, <i>P</i> < 0.001; mean diffusivity: <i>b</i> = 1.460 × 10^-4, <i>P</i> < 0.001), with a significant interaction between stroke and white matter hyperintensity lesion load (fractional anisotropy: <i>b</i> = 0.019, <i>P</i> < 0.001; mean diffusivity: <i>b</i> = -0.727 × 10^-4, <i>P</i> < 0.001). Among both groups, whole-brain normal appearing white matter microstructure did not relate to whole-brain lesion volumes. Our findings provide foundational evidence for the use and interpretation of diffusion tensor imaging as a biomarker in cerebrovascular disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf193"},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiating sporadic frontotemporal dementia from late-onset primary psychiatric disorders.","authors":"Sterre C M de Boer, Lina Riedl, Simon Braak, Chiara Fenoglio, David Foxe, James Carrick, Ramón Landin-Romero, Sophie Matis, Zac Chatterton, Ishana Rue, Marie-Paule E van Engelen, Jay L P Fieldhouse, Mardien Oudega, Sigfried N T M Schouws, Welmoed A Krudop, Argonde C van Harten, Flora H Duits, Sven J van der Lee, Daniela Galimberti, Janine Diehl-Schmid, Glenda M Halliday, Simon Ducharme, Yolande A L Pijnenburg, Olivier Piguet","doi":"10.1093/braincomms/fcaf199","DOIUrl":"10.1093/braincomms/fcaf199","url":null,"abstract":"<p><p>Sporadic behavioural variant frontotemporal dementia (bvFTD) is often misdiagnosed as late-onset primary psychiatric disorder (PPD) due to overlapping symptoms and lack of biomarkers. We aimed to identify clinical features that distinguish sporadic bvFTD from PPD. Multi-centre baseline data were retrospectively retrieved and categorized into neuropsychological domains. Logistic regression models and receiver operating characteristic curves were conducted to determine discriminators. Data from 508 sporadic bvFTD and 152 PPD cases were included. Higher scores in cognitive screening [odds ratio (OR): 1.23], facial emotion processing (OR: 1.69), episodic memory (OR: 1.09), animal fluency (OR: 1.17), working memory (OR: 1.18), letter fluency (OR: 1.17) and depressive symptoms (OR: 7.41) were significantly associated with PPD (all <i>P</i>s ≤ 0.010). Within a combined model, higher scores of letter fluency (OR: 1.47), cognitive screening (OR: 1.72) and lower attention (OR: 0.77) were significantly (all <i>P</i>s ≤ 0.05) associated with PPD (area under the curve = 0.771). Neuropsychological measurements-letter fluency, cognitive screening and attention-can help distinguish sporadic bvFTD from late-onset PPD. Depressive symptoms and facial emotion processing emerged as potential discriminators, warranting further exploration.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf199"},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delineating network integration and segregation in the pathophysiology of functional neurological disorder.","authors":"Christiana Westlin, Andrew J Guthrie, Cristina Bleier, Sara A Finkelstein, Julie Maggio, Jessica Ranford, Julie MacLean, Ellen Godena, Daniel Millstein, Sara Paredes-Echeverri, Jennifer Freeburn, Caitlin Adams, Christopher D Stephen, Ibai Diez, David L Perez","doi":"10.1093/braincomms/fcaf195","DOIUrl":"10.1093/braincomms/fcaf195","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Functional neurological disorder (FND) is a neuropsychiatric condition that is framed as a multi-network brain problem. Despite this conceptualization, studies have generally focused on specific regions or connectivity features, under-characterizing the complex and nuanced role of resting-state networks in FND pathophysiology. This study employed three complementary graph theory analyses to delineate the functional network architecture in FND. Specifically, we investigated whole-brain weighted-degree, isocortical integration and isocortical segregation extracted from resting-state functional MRI data prospectively collected from 178 participants: 61 individuals with mixed FND; 58 psychiatric controls matched on age, sex, depression, anxiety and post-traumatic stress disorder severity; and 59 age- and sex-matched healthy controls. All analyses were adjusted for age, sex and antidepressant use and focused on differences between FND versus psychiatric controls, with individual-subject maps normalized to healthy controls. Compared to psychiatric controls, patients with mixed FND exhibited increased weighted-degree in the right dorsal anterior cingulate and superior frontal gyrus and the left inferior frontal gyrus and supplementary motor area. Isocortical integration analyses revealed increased &lt;i&gt;between-network&lt;/i&gt; connectivity for somatomotor network areas, with widespread heightened connections to regions of the default mode, frontoparietal and salience networks. Isocortical segregation analyses revealed increased &lt;i&gt;within-network&lt;/i&gt; connectivity for the frontoparietal network. Secondary analyses of functional motor disorder (&lt;i&gt;n&lt;/i&gt; = 46) and functional seizure (&lt;i&gt;n&lt;/i&gt; = 23) subtypes (versus psychiatric controls) revealed both shared and unique patterns of altered connectivity across subtypes, including increased weighted-degree and integrated connectivity in the left posterior insula and anterior/mid-cingulate in functional motor disorder and increased segregated connectivity in the right angular gyrus for functional seizures. In &lt;i&gt;post hoc&lt;/i&gt; between-group analyses, findings remained significant adjusting for depression, anxiety and post-traumatic stress disorder severity, as well as for childhood maltreatment. &lt;i&gt;Post hoc&lt;/i&gt; correlations revealed significant relationships between connectivity metrics in several of these regions and somatic symptom severity across FND and psychiatric control participants. Notably, individual connectivity values were predominantly within the range of healthy controls (with patients with FND generally showing tendencies for increased connectivity and psychiatric controls showing tendencies towards decreased connectivity), indicating subtle shifts in the network architecture rather than gross abnormalities. This study provides novel mechanistic insights (i.e. increased somatomotor integration) and specificity regarding the neurobiology of FND, highlighting both shared mechanisms across subtypes and ","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf195"},"PeriodicalIF":4.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma α-synuclein domain profiles across α-synucleinopathies.","authors":"Marie-Laure Pons, Pablo Mohaupt, Jérôme Vialaret, Etienne Mondesert, Margaux Vignon, Salomé Coppens, Moreau Stéphane, Sylvain Lehmann, Christophe Hirtz","doi":"10.1093/braincomms/fcaf189","DOIUrl":"10.1093/braincomms/fcaf189","url":null,"abstract":"<p><p>The differential diagnosis of α-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), remains challenging due to overlapping clinical features and the absence of reliable biomarkers. We developed a targeted mass spectrometry assay to profile α-synuclein peptides in plasma from Parkinson's disease (<i>n</i> = 82), DLB (<i>n</i> = 32), MSA (<i>n</i> = 8) and controls (<i>n</i> = 21). We hypothesized that disease-specific truncations or post-translational modifications would alter levels of non-modified α-synuclein peptides across α-synucleinopathies. The assay quantified non-modified peptides derived from the N-terminus and non-amyloid component (NAC) domain, regions implicated in aggregate formation. Although peptide levels were consistent across disease groups, a distinct NAC domain pattern observed in MSA may reflect unique pathological processes. This study presents the first blood-based profiling of α-synuclein peptides in these disorders, offering a basis for further investigation into disease mechanisms. Refinement of the assay to include post-translational modifications could enhance understanding of α-synucleinopathies and support future biomarker development.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf189"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significant underascertainment in Huntington's disease.","authors":"Sujin Lee, Ben Weisburd, Jiwoo Lee, Kevin Correia, Sophia Zeng, Seri S Park, Jun Wan Shin, Doo Eun Choi, Kyung-Hee Kim, Jae-Hyun Jang, Tammy Gillis, Heidi L Rehm, James F Gusella, Marcy E MacDonald, Jong-Min Lee","doi":"10.1093/braincomms/fcaf194","DOIUrl":"10.1093/braincomms/fcaf194","url":null,"abstract":"<p><p>While Huntington's disease (HD), a Mendelian disorder caused by an expanded CAG repeat in <i>HTT</i>, is considered rare, the true prevalence could be significantly higher due to substantial underascertainment. Given inherent biases in empirically assessing disease prevalence, we performed mathematical modelling and validation analyses to estimate the frequency of expanded CAG repeats in the general population to better understand the disease prevalence. We developed an exponential decay model after confirming that the logarithmic decrease in frequency of CAG repeats extends into the pathogenic range (CAG > 35). The model was further refined by incorporating HD onset and mortality probabilities to estimate the clinical ascertainment rate. Our age-adjusted exponential decay model estimated one expanded repeat in 325 people and further showed that the frequency of expanded repeats decreases with age due to the early mortality associated with HD, which was validated by All of Us and UK Biobank data. Importantly, our data suggest that approximately half of symptomatic HD individuals aged 30-70 are not clinically ascertained/diagnosed. Our data, showing higher frequencies of expanded repeats in the general population and significant underascertainment rates, imply that HD prevalence could be twice as high as current estimates.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf194"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ending nuclear weapons, before they end us ^†.","authors":"Kamran Abbasi, Parveen Ali, Virginia Barbour, Marion Birch, Inga Blum, Peter Doherty, Andy Haines, Ira Helfand, Richard Horton, Kati Juva, Jose F Lapena, Robert Mash, Olga Mironova, Arun Mitra, Carlos Monteiro, Elena N Naumova, David Onazi, Tilman Ruff, Peush Sahni, James Tumwine, Carlos Umaña, Paul Yonga, Chris Zielinski","doi":"10.1093/braincomms/fcaf154","DOIUrl":"10.1093/braincomms/fcaf154","url":null,"abstract":"","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf154"},"PeriodicalIF":4.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.","authors":"Wai Yan Yau, Roisin Sullivan, Emer O'Connor, David Pellerin, Michael H Parkinson, Paola Giunti, Marie-Josée Dicaire, Matt C Danzi, Stephan Züchner, Bernard Brais, Nicholas W Wood, Henry Houlden, Jana Vandrovcova","doi":"10.1093/braincomms/fcaf188","DOIUrl":"10.1093/braincomms/fcaf188","url":null,"abstract":"<p><p>Less than half of the individuals with hereditary cerebellar ataxia receives a genetic diagnosis. Repeat expansions account for disproportionate number of hereditary cerebellar ataxia and have genetically heterogeneous causes. These genetic loci include <i>ATXN1</i>, <i>ATXN2</i>, <i>ATXN3</i>, <i>CACNA1A</i>, <i>ATXN7</i>, <i>ATXN8OS</i>, <i>ATXN10</i>, <i>PPP2R2B, TBP</i>, <i>ATN1</i>, <i>FMR1, BEAN1, NOP56, GLS, THAP11, GAA-FGF14, ZFHX3, FXN</i> and <i>RFC1.</i> This study aims to assess the yield of short-read whole genome sequencing in the molecular diagnosis of hereditary cerebellar ataxia. We recruited 380 patients (351 probands) from a national ataxia centre in United Kingdom. They underwent short-read whole genome sequencing as a part of the 100 000 Genomes Project. Bioinformatic pipeline of whole genome sequencing include variant prioritization in selected virtual gene panels, customized analysis with a focus on repeat expansions, structural variants and recently reported hereditary cerebellar ataxia genes. All potential genetic variants were reviewed in a multidisciplinary team, and further confirmation tests were performed as appropriate. Whole genome sequencing identified causative variants in 115 (33%) out of 351 probands. We established 46 distinct presumptive molecular diagnoses with the most frequent being <i>SPG7</i> (<i>n</i> = 22)<i>, RFC1</i> (<i>n</i> = 20) and <i>CACNA1A</i> (<i>n</i> = 10). However, it failed to detect any probands with novel ataxia gene <i>GAA-FGF14</i>, which was subsequently identified on polymerase chain reaction screening in 10 unsolved probands. In conclusion, whole genome sequencing is a useful diagnostic test in hereditary cerebellar ataxia patients and can be used to detect repeat expansions, structural and mitochondrial variants. However, identification of complex structural variants and sizing of large repeat expansions remains a challenge and require alternative molecular testing techniques.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 3","pages":"fcaf188"},"PeriodicalIF":4.1,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}