Pub Date : 2024-05-21DOI: 10.1093/braincomms/fcae178
Martin Furlepa, Yu P Zhang, Evgeniia Lobanova, Lakmini Kahanawita, Giorgio Vivacqua, C. Williams-Gray, David Klenerman
Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson’s disease. Candidate diagnostic tests for Parkinson’s disease to date have predominantly focused on measurements of alpha-synuclein in cerebrospinal fluid, but there is a need for accurate tests utilising more easily accessible sample types. Prior studies utilising saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single molecule approaches can characterise the structure of individual aggregates present in the biofluid and may therefore provide greater insight than bulk measurements. We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate number and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features. We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost two-fold in Parkinson’s disease patients (n = 20) compared to controls (n = 20, p <0.05). Morphological information also provides insight with saliva from Parkinson’s disease patients containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva (p <0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone distinguishing between the people with Parkinson’s disease (n = 17) and controls (n = 18) with a high degree of accuracy (AUC = 0.87, p <0.001) and a larger dynamic range. We therefore demonstrate for the first time the application of highly sensitive single molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information further expanding the potential utility of saliva-based diagnostic methods.
{"title":"Single molecule characterisation of salivary protein aggregates from Parkinson's disease patients – a pilot study","authors":"Martin Furlepa, Yu P Zhang, Evgeniia Lobanova, Lakmini Kahanawita, Giorgio Vivacqua, C. Williams-Gray, David Klenerman","doi":"10.1093/braincomms/fcae178","DOIUrl":"https://doi.org/10.1093/braincomms/fcae178","url":null,"abstract":"\u0000 Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson’s disease. Candidate diagnostic tests for Parkinson’s disease to date have predominantly focused on measurements of alpha-synuclein in cerebrospinal fluid, but there is a need for accurate tests utilising more easily accessible sample types. Prior studies utilising saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single molecule approaches can characterise the structure of individual aggregates present in the biofluid and may therefore provide greater insight than bulk measurements.\u0000 We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate number and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features.\u0000 We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost two-fold in Parkinson’s disease patients (n = 20) compared to controls (n = 20, p <0.05). Morphological information also provides insight with saliva from Parkinson’s disease patients containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva (p <0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone distinguishing between the people with Parkinson’s disease (n = 17) and controls (n = 18) with a high degree of accuracy (AUC = 0.87, p <0.001) and a larger dynamic range.\u0000 We therefore demonstrate for the first time the application of highly sensitive single molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information further expanding the potential utility of saliva-based diagnostic methods.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"85 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141116296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-21DOI: 10.1093/braincomms/fcae177
K. H. Kenyon, M. Strik, Gustavo Noffs, Angela T Morgan, S. Kolbe, Ian H Harding, Adam P Vogel, F. M. Boonstra, Anneke van der Walt
Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction, and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract, and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca’s area, Wernicke’s area, the corpus callosum, thalamus, and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness - a perceptual measure of dysarthria – and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared to controls, though no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.
{"title":"Volumetric and diffusion MRI abnormalities associated with dysarthria in multiple sclerosis","authors":"K. H. Kenyon, M. Strik, Gustavo Noffs, Angela T Morgan, S. Kolbe, Ian H Harding, Adam P Vogel, F. M. Boonstra, Anneke van der Walt","doi":"10.1093/braincomms/fcae177","DOIUrl":"https://doi.org/10.1093/braincomms/fcae177","url":null,"abstract":"\u0000 Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear.\u0000 In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction, and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract, and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca’s area, Wernicke’s area, the corpus callosum, thalamus, and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness - a perceptual measure of dysarthria – and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared to controls, though no brain volumetrics correlated with measures of dysarthria.\u0000 These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"126 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141115252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13DOI: 10.1093/braincomms/fcae165
Haoer Shi, A. R. Pattnaik, Carlos Aguila, Alfredo Lucas, N. Sinha, Brian Prager, Marissa Mojena, Ryan Gallagher, Alexandra Parashos, Leonardo Bonilha, E. Gleichgerrcht, Kathryn A Davis, Brian Litt, E. Conrad
Abstract Studies of intracranial EEG networks have been used to reveal seizure generators in patients with drug-resistant epilepsy. Intracranial EEG is implanted to capture the epileptic network, the collection of brain tissue that forms a substrate for seizures to start and spread. Interictal intracranial EEG measures brain activity at baseline, and networks computed during this state can reveal aberrant brain tissue without requiring seizure recordings. Intracranial EEG network analyses require choosing a reference and applying statistical measures of functional connectivity. Approaches to these technical choices vary widely across studies, and the impact of these technical choices on downstream analyses is poorly understood. Our objective was to examine the effects of different re-referencing and connectivity approaches on connectivity results and on the ability to lateralize the seizure onset zone in patients with drug-resistant epilepsy. We applied 48 pre-processing pipelines to a cohort of 125 patients with drug-resistant epilepsy recorded with interictal intracranial EEG across two epilepsy centres to generate intracranial EEG functional connectivity networks. Twenty-four functional connectivity measures across time and frequency domains were applied in combination with common average re-referencing or bipolar re-referencing. We applied an unsupervised clustering algorithm to identify groups of pre-processing pipelines. We subjected each pre-processing approach to three quality tests: (i) the introduction of spurious correlations; (ii) robustness to incomplete spatial sampling; and (iii) the ability to lateralize the clinician-defined seizure onset zone. Three groups of similar pre-processing pipelines emerged: common average re-referencing pipelines, bipolar re-referencing pipelines and relative entropy-based connectivity pipelines. Relative entropy and common average re-referencing networks were more robust to incomplete electrode sampling than bipolar re-referencing and other connectivity methods (Friedman test, Dunn–Šidák test P < 0.0001). Bipolar re-referencing reduced spurious correlations at non-adjacent channels better than common average re-referencing (Δ mean from machine ref = −0.36 versus −0.22) and worse in adjacent channels (Δ mean from machine ref = −0.14 versus −0.40). Relative entropy-based network measures lateralized the seizure onset hemisphere better than other measures in patients with temporal lobe epilepsy (Benjamini–Hochberg-corrected P < 0.05, Cohen’s d: 0.60–0.76). Finally, we present an interface where users can rapidly evaluate intracranial EEG pre-processing choices to select the optimal pre-processing methods tailored to specific research questions. The choice of pre-processing methods affects downstream network analyses. Choosing a single method among highly correlated approaches can reduce redundancy in processing. Relative entropy outperforms other connectivity methods in multiple quality tests. We present
{"title":"Utility of intracranial EEG networks depends on re-referencing and connectivity choice","authors":"Haoer Shi, A. R. Pattnaik, Carlos Aguila, Alfredo Lucas, N. Sinha, Brian Prager, Marissa Mojena, Ryan Gallagher, Alexandra Parashos, Leonardo Bonilha, E. Gleichgerrcht, Kathryn A Davis, Brian Litt, E. Conrad","doi":"10.1093/braincomms/fcae165","DOIUrl":"https://doi.org/10.1093/braincomms/fcae165","url":null,"abstract":"Abstract Studies of intracranial EEG networks have been used to reveal seizure generators in patients with drug-resistant epilepsy. Intracranial EEG is implanted to capture the epileptic network, the collection of brain tissue that forms a substrate for seizures to start and spread. Interictal intracranial EEG measures brain activity at baseline, and networks computed during this state can reveal aberrant brain tissue without requiring seizure recordings. Intracranial EEG network analyses require choosing a reference and applying statistical measures of functional connectivity. Approaches to these technical choices vary widely across studies, and the impact of these technical choices on downstream analyses is poorly understood. Our objective was to examine the effects of different re-referencing and connectivity approaches on connectivity results and on the ability to lateralize the seizure onset zone in patients with drug-resistant epilepsy. We applied 48 pre-processing pipelines to a cohort of 125 patients with drug-resistant epilepsy recorded with interictal intracranial EEG across two epilepsy centres to generate intracranial EEG functional connectivity networks. Twenty-four functional connectivity measures across time and frequency domains were applied in combination with common average re-referencing or bipolar re-referencing. We applied an unsupervised clustering algorithm to identify groups of pre-processing pipelines. We subjected each pre-processing approach to three quality tests: (i) the introduction of spurious correlations; (ii) robustness to incomplete spatial sampling; and (iii) the ability to lateralize the clinician-defined seizure onset zone. Three groups of similar pre-processing pipelines emerged: common average re-referencing pipelines, bipolar re-referencing pipelines and relative entropy-based connectivity pipelines. Relative entropy and common average re-referencing networks were more robust to incomplete electrode sampling than bipolar re-referencing and other connectivity methods (Friedman test, Dunn–Šidák test P < 0.0001). Bipolar re-referencing reduced spurious correlations at non-adjacent channels better than common average re-referencing (Δ mean from machine ref = −0.36 versus −0.22) and worse in adjacent channels (Δ mean from machine ref = −0.14 versus −0.40). Relative entropy-based network measures lateralized the seizure onset hemisphere better than other measures in patients with temporal lobe epilepsy (Benjamini–Hochberg-corrected P < 0.05, Cohen’s d: 0.60–0.76). Finally, we present an interface where users can rapidly evaluate intracranial EEG pre-processing choices to select the optimal pre-processing methods tailored to specific research questions. The choice of pre-processing methods affects downstream network analyses. Choosing a single method among highly correlated approaches can reduce redundancy in processing. Relative entropy outperforms other connectivity methods in multiple quality tests. We present","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":" 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141128549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-21DOI: 10.1093/braincomms/fcae091
Chao Chen, Shengqi Li, Fangyue Sun, Yiqun Chen, H. Qiu, Jiaqi Huang, Yining Jin, Jiexi Huang, Jiahan Xu, Zerui Jiang, Kun Li, Yanchu Wang, Hai Lin
The neutrophil-to-apolipoprotein A1 ratio (NAR) has emerged as a possible prognostic biomarker in different medical conditions. Nonetheless, the predictive potential of NAR in determining the 3-month prognosis of acute ischemic stroke (AIS) patients who undergo intravenous thrombolysis has yet to be fully acknowledged. In this study, 196 AIS patients with recombinant tissue plasminogen activator (r-tPA) and 133 healthy controls were included. Meanwhile, we incorporated a total of 386 non-thrombolytic AIS patients. The AIS patients with r-tPA were divided into four groups based on quartiles of NAR. The association between NAR and the 3-month prognosis was evaluated through univariate and multivariate regression analyses. Additionally, subgroup analyses were conducted to investigate the predictive value of NAR in different patient populations. Adverse outcomes were defined as a modified Rankin Scale (mRS) score of 3-6. The study findings revealed a significant association between elevated NAR levels and poor prognosis in AIS patients. In the highest quartile of NAR levels (Q4), after controlling for age, gender, admission The National Institutes of Health Stroke Scale score, blood urea nitrogen, and stroke subtypes, the odds ratio (OR) for adverse outcomes at 3-months was 13.314 (95% CI: 2.878-61.596, p = 0.001). An elevated NAR value was found to be associated with a poor prognosis in AIS patients, regardless of whether they received r-tPA treatment or not. The new model, which incorporating NAR into the conventional model, demonstrated a statistically significant improvement in discriminatory power and risk reclassification for 3-month poor outcomes in AIS patients treated with r-tPA. The new model exhibited a categorical Net Reclassification Index (NRI) (p = 0.035) of 12.9% and an Integrated Discrimination Improvement (IDI) (p = 0.013) of 5.2%. Subgroup analyses indicated that the predictive value of NAR differed across stroke subtypes. NAR is a potential biomarker for predicting the prognosis of AIS patients. The clinical implications of our findings are significant, as early identification and intervention in high-risk patients can improve their outcomes. However, further studies are required to validate our results and elucidate the underlying mechanisms of the association between NAR and poor prognosis in AIS patients.
{"title":"Predictive value of neutrophil to apolipoprotein A1 ratio in patients with acute ischemic stroke","authors":"Chao Chen, Shengqi Li, Fangyue Sun, Yiqun Chen, H. Qiu, Jiaqi Huang, Yining Jin, Jiexi Huang, Jiahan Xu, Zerui Jiang, Kun Li, Yanchu Wang, Hai Lin","doi":"10.1093/braincomms/fcae091","DOIUrl":"https://doi.org/10.1093/braincomms/fcae091","url":null,"abstract":"\u0000 The neutrophil-to-apolipoprotein A1 ratio (NAR) has emerged as a possible prognostic biomarker in different medical conditions. Nonetheless, the predictive potential of NAR in determining the 3-month prognosis of acute ischemic stroke (AIS) patients who undergo intravenous thrombolysis has yet to be fully acknowledged. In this study, 196 AIS patients with recombinant tissue plasminogen activator (r-tPA) and 133 healthy controls were included. Meanwhile, we incorporated a total of 386 non-thrombolytic AIS patients. The AIS patients with r-tPA were divided into four groups based on quartiles of NAR. The association between NAR and the 3-month prognosis was evaluated through univariate and multivariate regression analyses. Additionally, subgroup analyses were conducted to investigate the predictive value of NAR in different patient populations. Adverse outcomes were defined as a modified Rankin Scale (mRS) score of 3-6. The study findings revealed a significant association between elevated NAR levels and poor prognosis in AIS patients. In the highest quartile of NAR levels (Q4), after controlling for age, gender, admission The National Institutes of Health Stroke Scale score, blood urea nitrogen, and stroke subtypes, the odds ratio (OR) for adverse outcomes at 3-months was 13.314 (95% CI: 2.878-61.596, p = 0.001). An elevated NAR value was found to be associated with a poor prognosis in AIS patients, regardless of whether they received r-tPA treatment or not. The new model, which incorporating NAR into the conventional model, demonstrated a statistically significant improvement in discriminatory power and risk reclassification for 3-month poor outcomes in AIS patients treated with r-tPA. The new model exhibited a categorical Net Reclassification Index (NRI) (p = 0.035) of 12.9% and an Integrated Discrimination Improvement (IDI) (p = 0.013) of 5.2%. Subgroup analyses indicated that the predictive value of NAR differed across stroke subtypes. NAR is a potential biomarker for predicting the prognosis of AIS patients. The clinical implications of our findings are significant, as early identification and intervention in high-risk patients can improve their outcomes. However, further studies are required to validate our results and elucidate the underlying mechanisms of the association between NAR and poor prognosis in AIS patients.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":" 40","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140221823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-20DOI: 10.1093/braincomms/fcae096
Chelsea A. Crossley, Tamunotonye Omoluabi, Sarah E. Torraville, Sarah Duraid, Aida Maziar, Zia Hasan, Vishaal Rajani, K. Ando, Johannes W Hell, Qi Yuan
Aging and Alzheimer’s disease are associated with chronic elevations in neuronal calcium influx via L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer’s disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood.
衰老和阿尔茨海默病与神经元通过 L 型钙通道流入的钙长期升高有关。海马是大脑中主要的记忆编码结构，在阿尔茨海默病中更容易受到钙失调的影响。最近的研究表明，L 型钙通道与 tau 过度磷酸化之间存在联系。然而，L 型钙通道介导的 tau 毒性的确切机制尚不清楚。
{"title":"Hippocampal hyperphosphorylated tau-induced deficiency is rescued by L-type calcium channel blockade","authors":"Chelsea A. Crossley, Tamunotonye Omoluabi, Sarah E. Torraville, Sarah Duraid, Aida Maziar, Zia Hasan, Vishaal Rajani, K. Ando, Johannes W Hell, Qi Yuan","doi":"10.1093/braincomms/fcae096","DOIUrl":"https://doi.org/10.1093/braincomms/fcae096","url":null,"abstract":"\u0000 Aging and Alzheimer’s disease are associated with chronic elevations in neuronal calcium influx via L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer’s disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"28 28","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140226723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1093/braincomms/fcae092
Ádám Takács, E. Tóth-Fáber, Lina Schubert, Z. Tarnok, Foroogh Ghorbani, Madita Trelenberg, D. Németh, Alexander Münchau, Christian Beste
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. GTS is associated with enhanced processing of stimulus-response (S-R) associations, including a higher propensity to learn probabilistic S-R contingencies (i.e., statistical learning), the nature of which is still elusive. In this study, we investigated the hypothesis that resting-state theta network organization is key for the understanding of superior statistical learning in these patients. We investigated the graph-theoretical network architecture of theta oscillations in adult patients with GTS and healthy controls (HC) during a statistical learning task, and in resting states both before and after learning. We found that patients with GTS showed a higher statistical learning score than healthy controls, as well as a more optimal (small-world-like) theta network before the task. Thus, patients with GTS had a superior facility to integrate and evaluate novel information as a trait-like characteristic. Additionally, the theta network architecture in GTS adapted more to the statistical information during the task than in HC. We suggest that hyper-learning in patients with GTS is likely a consequence of increased sensitivity to perceive and integrate sensorimotor information leveraged through theta-oscillation-based resting state dynamics. The study delineates the neural basis of a higher propensity in patients with GTS to pick up statistical contingencies in their environment. Moreover, the study emphasizes pathophysiologically endowed abilities in patients with GTS, which are often not taken into account in the perception of this common disorder but could play an important role in destigmatization.
{"title":"Resting network architecture of theta oscillations reflects hyper-learning of sensorimotor information in Gilles de la Tourette syndrome","authors":"Ádám Takács, E. Tóth-Fáber, Lina Schubert, Z. Tarnok, Foroogh Ghorbani, Madita Trelenberg, D. Németh, Alexander Münchau, Christian Beste","doi":"10.1093/braincomms/fcae092","DOIUrl":"https://doi.org/10.1093/braincomms/fcae092","url":null,"abstract":"\u0000 Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. GTS is associated with enhanced processing of stimulus-response (S-R) associations, including a higher propensity to learn probabilistic S-R contingencies (i.e., statistical learning), the nature of which is still elusive. In this study, we investigated the hypothesis that resting-state theta network organization is key for the understanding of superior statistical learning in these patients. We investigated the graph-theoretical network architecture of theta oscillations in adult patients with GTS and healthy controls (HC) during a statistical learning task, and in resting states both before and after learning. We found that patients with GTS showed a higher statistical learning score than healthy controls, as well as a more optimal (small-world-like) theta network before the task. Thus, patients with GTS had a superior facility to integrate and evaluate novel information as a trait-like characteristic. Additionally, the theta network architecture in GTS adapted more to the statistical information during the task than in HC. We suggest that hyper-learning in patients with GTS is likely a consequence of increased sensitivity to perceive and integrate sensorimotor information leveraged through theta-oscillation-based resting state dynamics. The study delineates the neural basis of a higher propensity in patients with GTS to pick up statistical contingencies in their environment. Moreover, the study emphasizes pathophysiologically endowed abilities in patients with GTS, which are often not taken into account in the perception of this common disorder but could play an important role in destigmatization.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"74 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140242235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1093/braincomms/fcae087
A version of this article was published in error and has been temporarily removed. The article will be re-published at this location shortly. The Publisher apologizes for any inconvenience.
本文的一个版本发布有误，已被暂时删除。文章将很快在此重新发布。给您带来的不便，出版商深表歉意。
{"title":"Repeat expansions in AR, ATXN1, ATXN2, and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis","authors":"","doi":"10.1093/braincomms/fcae087","DOIUrl":"https://doi.org/10.1093/braincomms/fcae087","url":null,"abstract":"\u0000 A version of this article was published in error and has been temporarily removed. The article will be re-published at this location shortly. The Publisher apologizes for any inconvenience.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"78 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140241727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1093/braincomms/fcae088
M. Beydoun, Hind A Beydoun, Yi-Han Hu, Ziad W. El-Hajj, Michael F. Georgescu, Nicole Noren Hooten, Zhiguang Li, Jordan Weiss, Donald M Lyall, Shari R Waldstein, D. Hedges, Shawn D Gale, L. Launer, Michele K. Evans, A. Zonderman
Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori (Hp) infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006-2021, age range: 40-70 y) were used to examine whether Hp seropositivity (Hps) (e.g. presence of antibodies), serointensities of five Hp antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural magnetic resonance imaging (MRI), (total, white, gray matter, frontal gray matter (Left/Right), white matter hyperintensity as % intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9-10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity of over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer’s Disease polygenic risk score tertile when exposures were Hp antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between Hps or persistent infection burden with various volumetric outcomes (P > 0.007, from multivariable regression models), unlike previously reported in past research. However, Hp antigen serointensities, particularly immunoglobulin G against the Vacuolating cytotoxin A (VacA), GroEL and Outer Membrane Protein (OMP) antigens, were associated with poorer tract-specific white matter integrity (P < 0.007), with OMP serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer’s Disease polygenic risk. VacA serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer’s Disease polygenic risk, while among individuals with highest Alzheimer’s Disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the VacA serointensity was linked to reduced Right putamen volume (P < 0.007). OMP and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer’s Disease polygenic risk levels (P < 0.007). Our results shed light on the relationship between Hps, Hp antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer’s Disease and can be used for development of drugs and preventive interventions that would reduce t
{"title":"Helicobacter pylori, persistent infection burden and structural brain imaging markers","authors":"M. Beydoun, Hind A Beydoun, Yi-Han Hu, Ziad W. El-Hajj, Michael F. Georgescu, Nicole Noren Hooten, Zhiguang Li, Jordan Weiss, Donald M Lyall, Shari R Waldstein, D. Hedges, Shawn D Gale, L. Launer, Michele K. Evans, A. Zonderman","doi":"10.1093/braincomms/fcae088","DOIUrl":"https://doi.org/10.1093/braincomms/fcae088","url":null,"abstract":"\u0000 Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori (Hp) infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006-2021, age range: 40-70 y) were used to examine whether Hp seropositivity (Hps) (e.g. presence of antibodies), serointensities of five Hp antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural magnetic resonance imaging (MRI), (total, white, gray matter, frontal gray matter (Left/Right), white matter hyperintensity as % intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9-10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity of over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer’s Disease polygenic risk score tertile when exposures were Hp antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between Hps or persistent infection burden with various volumetric outcomes (P > 0.007, from multivariable regression models), unlike previously reported in past research. However, Hp antigen serointensities, particularly immunoglobulin G against the Vacuolating cytotoxin A (VacA), GroEL and Outer Membrane Protein (OMP) antigens, were associated with poorer tract-specific white matter integrity (P < 0.007), with OMP serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer’s Disease polygenic risk. VacA serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer’s Disease polygenic risk, while among individuals with highest Alzheimer’s Disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the VacA serointensity was linked to reduced Right putamen volume (P < 0.007). OMP and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer’s Disease polygenic risk levels (P < 0.007). Our results shed light on the relationship between Hps, Hp antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer’s Disease and can be used for development of drugs and preventive interventions that would reduce t","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140248295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.1093/braincomms/fcae086
Hsin-Hsi Tsai, Chia-Ju Liu, Bo-Ching Lee, Ya-Fang Chen, R. Yen, J. Jeng, Li-Kai Tsai
Tau, a hallmark of Alzheimer’s disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau PET scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy (n=31) and hypertensive small vessel disease (n=27) using 11C- Pittsburgh compound B and 18F-T807 PET. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy. Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe (1.25 [1.17‒1.42] vs. 1.08 [1.05‒1.22], P<0.001) and all Braak stage regions of interest (P<0.05) than hypertensive small vessel disease, though the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis (β=0.12, 95% confidence interval 0.04‒0.21) and cerebral amyloid angiopathy score (β=0.12, 95% confidence interval 0.03‒0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman’s ρ=-0.56, P=0.001) and hippocampal volume (-0.49, P=0.007), even after adjustment. In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer’s disease.
Tau是阿尔茨海默病的特征之一，但在脑淀粉样血管病中的特征并不明显。我们旨在评估 tau PET 扫描与脑淀粉样血管病之间的临床放射学相关性。我们使用 11C- 匹兹堡化合物 B 和 18F-T807 PET 评估了可能患有脑淀粉样血管病（31 人）和高血压小血管病（27 人）的患者的脑淀粉样蛋白和高磷酸化 tau。采用多变量回归模型评估与脑淀粉样血管病中脑tau病理相关的放射临床特征。与高血压性小血管病相比，脑淀粉样血管病在颞下叶（1.25 [1.17-1.42] vs. 1.08 [1.05-1.22]，P<0.001）和所有布拉克分期相关区域（P<0.05）表现出更高的脑tau负荷，但经年龄调整后差异减小。在对年龄、载脂蛋白E4状态和整个皮层淀粉样蛋白负荷进行调整后，脑tau病理学与脑淀粉样血管病变相关的血管标记物显著相关，包括皮层浅层苷脂沉积（β=0.12，95%置信区间为0.04-0.21）和脑淀粉样血管病变评分（β=0.12，95%置信区间为0.03-0.21）。即使经过调整，Tau病理与认知评分（Spearman's ρ=-0.56，P=0.001）和海马体积（-0.49，P=0.007）也有显著相关性。总之，在散发性脑淀粉样血管病中，tau病理学比高血压小血管病更常见。与脑淀粉样血管病变相关的血管病变，尤其是皮质表层菱形细胞增多症，是脑tau病变的潜在标志物，提示可能并发阿尔茨海默病。
{"title":"Cerebral tau pathology in cerebral amyloid angiopathy","authors":"Hsin-Hsi Tsai, Chia-Ju Liu, Bo-Ching Lee, Ya-Fang Chen, R. Yen, J. Jeng, Li-Kai Tsai","doi":"10.1093/braincomms/fcae086","DOIUrl":"https://doi.org/10.1093/braincomms/fcae086","url":null,"abstract":"\u0000 Tau, a hallmark of Alzheimer’s disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau PET scans and cerebral amyloid angiopathy.\u0000 We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy (n=31) and hypertensive small vessel disease (n=27) using 11C- Pittsburgh compound B and 18F-T807 PET. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy.\u0000 Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe (1.25 [1.17‒1.42] vs. 1.08 [1.05‒1.22], P<0.001) and all Braak stage regions of interest (P<0.05) than hypertensive small vessel disease, though the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis (β=0.12, 95% confidence interval 0.04‒0.21) and cerebral amyloid angiopathy score (β=0.12, 95% confidence interval 0.03‒0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman’s ρ=-0.56, P=0.001) and hippocampal volume (-0.49, P=0.007), even after adjustment.\u0000 In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer’s disease.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140249889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-08DOI: 10.1093/braincomms/fcae071
Nikolaos Karvelas, Bradley C Oh, Earnest Wang, Y. Cobigo, T-H Tsuei, Stephen Fitzsimons, K. Younes, Alexander Ehrenberg, M. Geschwind, Daniel Schwartz, Joel H. Kramer, Adam R Ferguson, Bruce L. Miller, Lisa C. Silbert, H. Rosen, F. Elahi
Enlarged perivascular spaces (ePVS) have been previously reported in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), but their significance and pathophysiology remains unclear. We investigated associations of white matter ePVS with classical imaging measures, cognitive measures and plasma proteins to better understand what ePVS represents in CADASIL and whether radiographic measures of ePVS would be of value in future therapeutic discovery studies for CADASIL. 24 individuals with CADASIL and 24 age and sex matched controls were included. Disease status was determined based on presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity (WMH), brain parenchymal fraction (BPF), white matter ePVS volumes, clinical, and cognitive measures, as well as plasma proteomics were used in models. White matter ePVS volumes were calculated via a novel, semi-automated pipeline and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of ePVS with global burden of WMH, brain atrophy, functional status, neurocognitive measures, and plasma proteins were modelled with linear regression models. CADASIL and control groups did not exhibit differences in mean ePVS volumes. However, increased ePVS volumes in CADASIL were associated with increased WMH volume (β=0.57, p = 0.05), Clinical Dementia Rating (CDR) Sum-of-Boxes score (β=0.49, p = 0.04), and marginally with decreased BPF (β=-0.03, p = 0.10). In interaction term models, the interaction term between CADASIL disease status and ePVS volume was associated with increased WMH volume (β=0.57, p = 0.02), Clinical Dementia Rating (CDR) Sum-of-Boxes score (β=0.52, p = 0.02), Mini Mental State Examination (MMSE) score (β=-1.49, p = 0.03) and marginally with decreased BPF (β=-0.03, p = 0.07). Proteins positively associated with ePVS volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with ePVS volumes: CXC motif chemokine ligand 8/interleukin-8 (CXCL8/IL-8), and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 (CCL2/MCP-1). The levels of CXCL8/IL8 were also associated with increased WMH volume (β=42.86, p = 0.03), and levels of CCL2/MCP-1 were further associated with decreased BPF (β=-0.0007, p < 0.01), MMSE score (β=-0.02, p < 0.01), and increased Trail Making Test B (TRAILB) completion time (β=0.76, p < 0.01). No protein was associated with all 3 studied imaging measures of pathology (BPF, ePVS, WMH). Based on associations uncovered between ePVS volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter ePVS volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in CADASIL.
{"title":"Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","authors":"Nikolaos Karvelas, Bradley C Oh, Earnest Wang, Y. Cobigo, T-H Tsuei, Stephen Fitzsimons, K. Younes, Alexander Ehrenberg, M. Geschwind, Daniel Schwartz, Joel H. Kramer, Adam R Ferguson, Bruce L. Miller, Lisa C. Silbert, H. Rosen, F. Elahi","doi":"10.1093/braincomms/fcae071","DOIUrl":"https://doi.org/10.1093/braincomms/fcae071","url":null,"abstract":"\u0000 Enlarged perivascular spaces (ePVS) have been previously reported in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), but their significance and pathophysiology remains unclear. We investigated associations of white matter ePVS with classical imaging measures, cognitive measures and plasma proteins to better understand what ePVS represents in CADASIL and whether radiographic measures of ePVS would be of value in future therapeutic discovery studies for CADASIL. 24 individuals with CADASIL and 24 age and sex matched controls were included. Disease status was determined based on presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity (WMH), brain parenchymal fraction (BPF), white matter ePVS volumes, clinical, and cognitive measures, as well as plasma proteomics were used in models. White matter ePVS volumes were calculated via a novel, semi-automated pipeline and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of ePVS with global burden of WMH, brain atrophy, functional status, neurocognitive measures, and plasma proteins were modelled with linear regression models. CADASIL and control groups did not exhibit differences in mean ePVS volumes. However, increased ePVS volumes in CADASIL were associated with increased WMH volume (β=0.57, p = 0.05), Clinical Dementia Rating (CDR) Sum-of-Boxes score (β=0.49, p = 0.04), and marginally with decreased BPF (β=-0.03, p = 0.10). In interaction term models, the interaction term between CADASIL disease status and ePVS volume was associated with increased WMH volume (β=0.57, p = 0.02), Clinical Dementia Rating (CDR) Sum-of-Boxes score (β=0.52, p = 0.02), Mini Mental State Examination (MMSE) score (β=-1.49, p = 0.03) and marginally with decreased BPF (β=-0.03, p = 0.07). Proteins positively associated with ePVS volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with ePVS volumes: CXC motif chemokine ligand 8/interleukin-8 (CXCL8/IL-8), and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 (CCL2/MCP-1). The levels of CXCL8/IL8 were also associated with increased WMH volume (β=42.86, p = 0.03), and levels of CCL2/MCP-1 were further associated with decreased BPF (β=-0.0007, p < 0.01), MMSE score (β=-0.02, p < 0.01), and increased Trail Making Test B (TRAILB) completion time (β=0.76, p < 0.01). No protein was associated with all 3 studied imaging measures of pathology (BPF, ePVS, WMH). Based on associations uncovered between ePVS volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter ePVS volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in CADASIL.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140076790","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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