Adriana Cortés, Toan K Phung, Lorena de Mena, Alicia Garrido, Jon Infante, Javier Ruíz-Martínez, Miquel À Galmés-Ordinas, Sophie Glendinning, Jesica Pérez, Ana Roig, Marta Soto, Marina Cosgaya, Valeria Ravasi, Manel Fernández, Alejandro Rubiano-Castro, Ramón Díaz, Haizea Hernández-Eguiazu, Coro Sánchez-Quintana, Ana Vinagre-Aragón, Elisabet Mondragón, Ioana Croitoru, María Rivera-Sánchez, Andrea Corrales-Pardo, María Sierra, Eduardo Tolosa, Cristina Malagelada, Raja S Nirujogi, Joaquín Fernández-Irigoyen, Enrique Santamaría, Dario R Alessi, María J Martí, Mario Ezquerra, Rubén Fernández-Santiago
Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson’s disease (L2PD) and idiopathic PD (iPD). However, pharmaco-dynamic readouts and progression biomarkers for clinical trials aiming for disease modification are insufficient since no endogenous marker reflecting enhanced kinase activity of the most common LRRK2 G2019S mutation has been reported yet in L2PD patients. Employing phospho-/proteomic analyses we assessed the impact that LRRK2 activating mutations had in peripheral blood mononuclear cells (PBMCs) from a LRRK2 clinical cohort from Spain (n=174). The groups of study encompassed G2019S L2PD patients (n=37), non-manifesting LRRK2 mutation carriers of G2019S, here, G2019S L2NMCs (n=27), R1441G L2PD patients (n=14), R1441G L2NMCs (n=11), iPD patients (n=40), and healthy controls (n=45). We identified 207 differential proteins in G2019S L2PD compared to controls (39 up/168 down) and 67 in G2019S L2NMCs (10 up/57 down). G2019S down-regulated proteins affected the endolysosomal pathway, proteostasis, and mitochondria, e.g., ATIC, RAB9A, or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n=48). Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature discriminating G2019S L2PD, L2NMCs, and controls with 96% accuracy that correlated with disease severity, i.e., UPDRS-III motor scoring. Using easily accessible PBMCs from a LRRK2 clinical cohort, we identified elevated levels of pSer106 RAB12 as an endogenous biomarker of G2019S carriers. Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials.
{"title":"In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s disease","authors":"Adriana Cortés, Toan K Phung, Lorena de Mena, Alicia Garrido, Jon Infante, Javier Ruíz-Martínez, Miquel À Galmés-Ordinas, Sophie Glendinning, Jesica Pérez, Ana Roig, Marta Soto, Marina Cosgaya, Valeria Ravasi, Manel Fernández, Alejandro Rubiano-Castro, Ramón Díaz, Haizea Hernández-Eguiazu, Coro Sánchez-Quintana, Ana Vinagre-Aragón, Elisabet Mondragón, Ioana Croitoru, María Rivera-Sánchez, Andrea Corrales-Pardo, María Sierra, Eduardo Tolosa, Cristina Malagelada, Raja S Nirujogi, Joaquín Fernández-Irigoyen, Enrique Santamaría, Dario R Alessi, María J Martí, Mario Ezquerra, Rubén Fernández-Santiago","doi":"10.1093/brain/awae404","DOIUrl":"https://doi.org/10.1093/brain/awae404","url":null,"abstract":"Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson’s disease (L2PD) and idiopathic PD (iPD). However, pharmaco-dynamic readouts and progression biomarkers for clinical trials aiming for disease modification are insufficient since no endogenous marker reflecting enhanced kinase activity of the most common LRRK2 G2019S mutation has been reported yet in L2PD patients. Employing phospho-/proteomic analyses we assessed the impact that LRRK2 activating mutations had in peripheral blood mononuclear cells (PBMCs) from a LRRK2 clinical cohort from Spain (n=174). The groups of study encompassed G2019S L2PD patients (n=37), non-manifesting LRRK2 mutation carriers of G2019S, here, G2019S L2NMCs (n=27), R1441G L2PD patients (n=14), R1441G L2NMCs (n=11), iPD patients (n=40), and healthy controls (n=45). We identified 207 differential proteins in G2019S L2PD compared to controls (39 up/168 down) and 67 in G2019S L2NMCs (10 up/57 down). G2019S down-regulated proteins affected the endolysosomal pathway, proteostasis, and mitochondria, e.g., ATIC, RAB9A, or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n=48). Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature discriminating G2019S L2PD, L2NMCs, and controls with 96% accuracy that correlated with disease severity, i.e., UPDRS-III motor scoring. Using easily accessible PBMCs from a LRRK2 clinical cohort, we identified elevated levels of pSer106 RAB12 as an endogenous biomarker of G2019S carriers. Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"32 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mathias De Decker, Pavol Zelina, Thomas G Moens, Jimmy Beckers, Matilde Contardo, Katarina Stoklund Dittlau, Evelien Van Schoor, Alicja Ronisz, Kristel Eggermont, Matthieu Moisse, Siddharthan Chandran, Jan H Veldink, Dietmar Rudolf Thal, Ludo Van Den Bosch, R Jeroen Pasterkamp, Philip Van Damme
Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.
{"title":"C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis","authors":"Mathias De Decker, Pavol Zelina, Thomas G Moens, Jimmy Beckers, Matilde Contardo, Katarina Stoklund Dittlau, Evelien Van Schoor, Alicja Ronisz, Kristel Eggermont, Matthieu Moisse, Siddharthan Chandran, Jan H Veldink, Dietmar Rudolf Thal, Ludo Van Den Bosch, R Jeroen Pasterkamp, Philip Van Damme","doi":"10.1093/brain/awae331","DOIUrl":"https://doi.org/10.1093/brain/awae331","url":null,"abstract":"Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"74 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriel N Aughey, Elisa Cali, Reza Maroofian, Maha S Zaki, Alistair T Pagnamenta, Zafar Ali, Uzma Abdulllah, Fatima Rahman, Lara Menzies, Anum Shafique, Mohnish Suri, Emmanuel Roze, Mohammed Aguennouz, Zouiri Ghizlane, Saadia Maryam Saadi, Ambrin Fatima, Huma Arshad Cheema, Muhammad Nadeem Anjum, Godelieve Morel, Stephanie Robin, Robert McFarland, Umut Altunoglu, Verena Kraus, Moneef Shoukier, David Murphy, Kristina Flemming, Hilde Yttervik, Hajar Rhouda, Gaetan Lesca, Nicolas Chatron, Massimiliano Rossi, Bibi Nazia Murtaza, Mujaddad Ur Rehman, Jenny Lord, Edoardo Giacopuzzi, Azam Hayat, Muhammad Siraj, Reza Shervin Badv, Go Hun Seo, Christian Beetz, Hülya Kayserili, Yamna Krioulie, Wendy K Chung, Sadaf Naz, Shazia Maqbool, Kate Chandler, Christopher Kershaw, Thomas Wright, Siddharth Banka, Joseph G Gleeson, Jenny C Taylor, Stephanie Efthymiou, Shahid Mahmood Baig, Mariasavina Severino, James E C Jepson, Henry Houlden
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF.
{"title":"Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.","authors":"Gabriel N Aughey, Elisa Cali, Reza Maroofian, Maha S Zaki, Alistair T Pagnamenta, Zafar Ali, Uzma Abdulllah, Fatima Rahman, Lara Menzies, Anum Shafique, Mohnish Suri, Emmanuel Roze, Mohammed Aguennouz, Zouiri Ghizlane, Saadia Maryam Saadi, Ambrin Fatima, Huma Arshad Cheema, Muhammad Nadeem Anjum, Godelieve Morel, Stephanie Robin, Robert McFarland, Umut Altunoglu, Verena Kraus, Moneef Shoukier, David Murphy, Kristina Flemming, Hilde Yttervik, Hajar Rhouda, Gaetan Lesca, Nicolas Chatron, Massimiliano Rossi, Bibi Nazia Murtaza, Mujaddad Ur Rehman, Jenny Lord, Edoardo Giacopuzzi, Azam Hayat, Muhammad Siraj, Reza Shervin Badv, Go Hun Seo, Christian Beetz, Hülya Kayserili, Yamna Krioulie, Wendy K Chung, Sadaf Naz, Shazia Maqbool, Kate Chandler, Christopher Kershaw, Thomas Wright, Siddharth Banka, Joseph G Gleeson, Jenny C Taylor, Stephanie Efthymiou, Shahid Mahmood Baig, Mariasavina Severino, James E C Jepson, Henry Houlden","doi":"10.1093/brain/awae363","DOIUrl":"https://doi.org/10.1093/brain/awae363","url":null,"abstract":"<p><p>Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea Mastrangelo, Angela Mammana, Sara Hall, Erik Stomrud, Corrado Zenesini, Marcello Rossi, Shorena Janelidze, Alice Ticca, Sebastian Palmqvist, Franco Magliocchetti, Simone Baiardi, Niklas Mattsson-Carlgren, Oskar Hansson, Piero Parchi
Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a cohort of longitudinally repeatedly sampled Lewy Body disease patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n=718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal (Imax). were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn positive CSF samples available. One hundred ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (p=0.001) and a longer Lag (p=0.001) than subjects displaying α-syn seeding activity from the first available sample. Nrep increased longitudinally in the whole cohort (β=0.09, 95% confidence interval (95%CI) 0.06-0.12, p<0.001), in asymptomatic LBD (β=0.15, 95%CI 0.09-0.21, p<0.001) and Parkinson’s disease individuals without dementia (β=0.07, 95%CI 0.02-0.12, p=0.01). The Lag decreased longitudinally in asymptomatic LBD (β=-0.24, 95%CI -0.42 - -0.06, p=0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort (Hazard ratio (HR) 1.57, 95%CI 1.19-2.07, p=0.001) and the Parkinson’s disease subgroup (HR 1.83, 95%CI 1.17-2.85, p=0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95%CI 0.59–0.99, p=0.04) and Parkinson’s disease subgroup (HR 0.69, 95%CI 0.50-0.95, p=0.02). α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with pathology progression over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.
{"title":"Alpha-synuclein seed amplification assay longitudinal outcomes in Lewy body disease spectrum","authors":"Andrea Mastrangelo, Angela Mammana, Sara Hall, Erik Stomrud, Corrado Zenesini, Marcello Rossi, Shorena Janelidze, Alice Ticca, Sebastian Palmqvist, Franco Magliocchetti, Simone Baiardi, Niklas Mattsson-Carlgren, Oskar Hansson, Piero Parchi","doi":"10.1093/brain/awae405","DOIUrl":"https://doi.org/10.1093/brain/awae405","url":null,"abstract":"Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a cohort of longitudinally repeatedly sampled Lewy Body disease patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n=718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal (Imax). were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn positive CSF samples available. One hundred ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (p=0.001) and a longer Lag (p=0.001) than subjects displaying α-syn seeding activity from the first available sample. Nrep increased longitudinally in the whole cohort (β=0.09, 95% confidence interval (95%CI) 0.06-0.12, p&lt;0.001), in asymptomatic LBD (β=0.15, 95%CI 0.09-0.21, p&lt;0.001) and Parkinson’s disease individuals without dementia (β=0.07, 95%CI 0.02-0.12, p=0.01). The Lag decreased longitudinally in asymptomatic LBD (β=-0.24, 95%CI -0.42 - -0.06, p=0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort (Hazard ratio (HR) 1.57, 95%CI 1.19-2.07, p=0.001) and the Parkinson’s disease subgroup (HR 1.83, 95%CI 1.17-2.85, p=0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95%CI 0.59–0.99, p=0.04) and Parkinson’s disease subgroup (HR 0.69, 95%CI 0.50-0.95, p=0.02). α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with pathology progression over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"145 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marios Kritsilis, Lotte Vanherle, Marko Rosenholm, René In 't Zandt, Yuan Yao, Kelley M Swanberg, Pia Weikop, Michael Gottschalk, Nagesh C Shanbhag, Jiebo Luo, Kimberly Boster, Maiken Nedergaard, Anja Meissner, Iben Lundgaard
Heart failure (HF) is associated with progressive reduction in cerebral blood flow (CBF) and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of HF, induced by myocardial infarction (MI), to investigate the effects of HF with reduced ejection fraction on the brain’s glymphatic function. Using dynamic contrast-enhanced MRI and high-resolution fluorescence microscopy, we found increased solute influx from the CSF spaces to the brain, i.e. glymphatic influx, at 12 weeks post MI. Two-photon microscopy revealed that cerebral arterial pulsatility, a major driver of the glymphatic system, was potentiated at this timepoint, and could explain this increase in glymphatic influx. However, clearance of proteins from the brain parenchyma did not increase proportionately with influx, while a relative increase in brain parenchyma volume was found at 12 weeks post MI, suggesting dysregulation of brain fluid dynamics. Additionally, our results showed a correlation between brain clearance and CBF. These findings highlight the role of CBF as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced CBF. This study paves the way for future investigations into the effects of cardiovascular diseases on the brain's clearance mechanisms, which may provide novel insights into the prevention and treatment of cognitive decline.
{"title":"Loss of glymphatic homeostasis in heart failure","authors":"Marios Kritsilis, Lotte Vanherle, Marko Rosenholm, René In 't Zandt, Yuan Yao, Kelley M Swanberg, Pia Weikop, Michael Gottschalk, Nagesh C Shanbhag, Jiebo Luo, Kimberly Boster, Maiken Nedergaard, Anja Meissner, Iben Lundgaard","doi":"10.1093/brain/awae411","DOIUrl":"https://doi.org/10.1093/brain/awae411","url":null,"abstract":"Heart failure (HF) is associated with progressive reduction in cerebral blood flow (CBF) and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of HF, induced by myocardial infarction (MI), to investigate the effects of HF with reduced ejection fraction on the brain’s glymphatic function. Using dynamic contrast-enhanced MRI and high-resolution fluorescence microscopy, we found increased solute influx from the CSF spaces to the brain, i.e. glymphatic influx, at 12 weeks post MI. Two-photon microscopy revealed that cerebral arterial pulsatility, a major driver of the glymphatic system, was potentiated at this timepoint, and could explain this increase in glymphatic influx. However, clearance of proteins from the brain parenchyma did not increase proportionately with influx, while a relative increase in brain parenchyma volume was found at 12 weeks post MI, suggesting dysregulation of brain fluid dynamics. Additionally, our results showed a correlation between brain clearance and CBF. These findings highlight the role of CBF as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced CBF. This study paves the way for future investigations into the effects of cardiovascular diseases on the brain's clearance mechanisms, which may provide novel insights into the prevention and treatment of cognitive decline.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"88 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Garrett Allington, Neel H Mehta, Evan Dennis, Kedous Y Mekbib, Benjamin Reeves, Emre Kiziltug, Shuang Chen, Shujuan Zhao, Phan Q Duy, Maha Saleh, Lee C Ang, Baojian Fan, Carol Nelson-Williams, Andrés Moreno-de-Luca, Shozeb Haider, Richard P Lifton, Seth L Alper, Stephen McGee, Sheng Chih Jin, Kristopher T Kahle
Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay, and dysmorphic features harbored loss-of-function DNVs that truncate LDB1’s carboxy-terminal LIM interaction domain, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through it’s binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging DNVs in our cohort, with SMARCC1 (p = 5.83 x 10-9) and ARID1B (p = 1.80 x 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest an LDB1-regulated transcriptional program is essential for human brain morphogenesis.
{"title":"De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly","authors":"Garrett Allington, Neel H Mehta, Evan Dennis, Kedous Y Mekbib, Benjamin Reeves, Emre Kiziltug, Shuang Chen, Shujuan Zhao, Phan Q Duy, Maha Saleh, Lee C Ang, Baojian Fan, Carol Nelson-Williams, Andrés Moreno-de-Luca, Shozeb Haider, Richard P Lifton, Seth L Alper, Stephen McGee, Sheng Chih Jin, Kristopher T Kahle","doi":"10.1093/brain/awae395","DOIUrl":"https://doi.org/10.1093/brain/awae395","url":null,"abstract":"Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (&gt;2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay, and dysmorphic features harbored loss-of-function DNVs that truncate LDB1’s carboxy-terminal LIM interaction domain, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through it’s binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging DNVs in our cohort, with SMARCC1 (p = 5.83 x 10-9) and ARID1B (p = 1.80 x 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest an LDB1-regulated transcriptional program is essential for human brain morphogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"30 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea Pilotto, Virginia Quaresima, Chiara Trasciatti, Chiara Tolassi, Diego Bertoli, Cristina Mordenti, Alice Galli, Andrea Rizzardi, Salvatore Caratozzolo, Andrea Zancanaro, José Contador, Oskar Hansson, Sebastian Palmqvist, Giovanni De Santis, Henrik Zetterberg, Kaj Blennow, Duilio Brugnoni, Marc Suárez-Calvet, Nicholas J Ashton, Alessandro Padovani
Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate Alzheimer's disease from other neurodegenerative diseases and controls was investigated using receiver operating characteristic analyses. The p-tau217 levels measured by the two techniques demonstrated a strong correlation, showing a consistent relationship with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating Alzheimer's disease from other neurodegenerative diseases [area under the curve (AUC) 0.952, 95% confidence interval (CI) 0.927-0.978 versus 0.955, 95% CI 0.928-0.982, respectively] and healthy controls (AUC 0.938, 95% CI 0.910-0.966 and 0.937, 95% CI 0.907-0.967 for both assays). This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using fully automated or semi-automated techniques.
{"title":"Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison.","authors":"Andrea Pilotto, Virginia Quaresima, Chiara Trasciatti, Chiara Tolassi, Diego Bertoli, Cristina Mordenti, Alice Galli, Andrea Rizzardi, Salvatore Caratozzolo, Andrea Zancanaro, José Contador, Oskar Hansson, Sebastian Palmqvist, Giovanni De Santis, Henrik Zetterberg, Kaj Blennow, Duilio Brugnoni, Marc Suárez-Calvet, Nicholas J Ashton, Alessandro Padovani","doi":"10.1093/brain/awae368","DOIUrl":"10.1093/brain/awae368","url":null,"abstract":"<p><p>Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate Alzheimer's disease from other neurodegenerative diseases and controls was investigated using receiver operating characteristic analyses. The p-tau217 levels measured by the two techniques demonstrated a strong correlation, showing a consistent relationship with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating Alzheimer's disease from other neurodegenerative diseases [area under the curve (AUC) 0.952, 95% confidence interval (CI) 0.927-0.978 versus 0.955, 95% CI 0.928-0.982, respectively] and healthy controls (AUC 0.938, 95% CI 0.910-0.966 and 0.937, 95% CI 0.907-0.967 for both assays). This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using fully automated or semi-automated techniques.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ann-Sophie Kiesel, Lucia Laugwitz, Rebecca Buchert, Mona Grimmel, Sarah Baumann, Marc Sturm, Selina Reich, Martje G Pauly, Norbert Brüggemann, Alexander Münchau, Olga Oleksiuk, Matthis Synofzik, Tobias B Haack, Susana Peralta
{"title":"Elevated cholesterol is a common phenotype for dominant and recessive ATAD3-associated disorders.","authors":"Ann-Sophie Kiesel, Lucia Laugwitz, Rebecca Buchert, Mona Grimmel, Sarah Baumann, Marc Sturm, Selina Reich, Martje G Pauly, Norbert Brüggemann, Alexander Münchau, Olga Oleksiuk, Matthis Synofzik, Tobias B Haack, Susana Peralta","doi":"10.1093/brain/awae402","DOIUrl":"https://doi.org/10.1093/brain/awae402","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Di Wang, Nicolas Honnorat, Jon B Toledo, Karl Li, Sokratis Charisis, Tanweer Rashid, Anoop Benet Nirmala, Sachintha Ransara Brandigampala, Mariam Mojtabai, Sudha Seshadri, Mohamad Habes
Concurrent neurodegenerative and vascular pathologies pose a diagnostic challenge in the clinical setting, with histopathology remaining the definitive modality for dementia-type diagnosis. To address this clinical challenge, we introduce a neuropathology-based, data-driven, multi-label deep learning framework to identify and quantify in-vivo biomarkers for Alzheimer's disease (AD), vascular dementia (VD), and Lewy body dementia (LBD) using antemortem T1-weighted MRI scans of 423 demented and 361 control participants from NACC and ADNI datasets. Based on the best-performing deep learning model, explainable heatmaps are extracted to visualize disease patterns, and the novel Deep Signature of Pathology Atrophy REcognition (DeepSPARE) indices are developed, where a higher DeepSPARE score indicates more brain alterations associated with that specific pathology. A substantial discrepancy in clinical and neuropathology diagnosis was observed in the demented patients: 71% of them had more than one pathology, but 67% of them were clinically diagnosed as AD only. Based on these neuropathology diagnoses and leveraging cross-validation principles, the deep learning model achieved the best performance with a balanced accuracy of 0.844, 0.839, and 0.623 for AD, VD, and LBD, respectively, and was used to generate the explainable deep-learning heatmaps and DeepSPARE indices. The explainable deep-learning heatmaps revealed distinct neuroimaging brain alteration patterns for each pathology: the AD heatmap highlighted bilateral hippocampal regions, the VD heatmap emphasized white matter regions, and the LBD heatmap exposed occipital alterations. The DeepSPARE indices were validated by examining their associations with cognitive testing, neuropathological, and neuroimaging measures using linear mixed-effects models. The DeepSPARE-AD index was associated with MMSE, Trail B, memory, PFDR-adjustedhippocampal volume, Braak stages, CERAD scores, and Thal phases (PFDR-adjusted < 0.05). The DeepSPARE-VD index was associated with white matter hyperintensity volume and cerebral amyloid angiopathy (PFDR-adjusted < 0.001). The DeepSPARE-LBD index was associated with Lewy body stages (PFDR-adjusted < 0.05). The findings were replicated in an out-of-sample ADNI dataset by testing associations with cognitive, imaging, plasma, and CSF measures. CSF and plasma pTau181 were significantly associated with DeepSPARE-AD in the AD/MCIΑβ+ group (PFDR-adjusted < 0.001), and CSF α-synuclein was associated solely with DeepSPARE-LBD (PFDR-adjusted = 0.036). Overall, these findings demonstrate the advantages of our innovative deep-learning framework in detecting antemortem neuroimaging signatures linked to different pathologies. The newly deep learning-derived DeepSPARE indices are precise, pathology-sensitive, and single-valued noninvasive neuroimaging metrics, bridging the traditional widely available in-vivo T1 imaging with histopathology.
{"title":"Deep learning reveals pathology-confirmed neuroimaging signatures in Alzheimer’s, vascular and Lewy body dementias","authors":"Di Wang, Nicolas Honnorat, Jon B Toledo, Karl Li, Sokratis Charisis, Tanweer Rashid, Anoop Benet Nirmala, Sachintha Ransara Brandigampala, Mariam Mojtabai, Sudha Seshadri, Mohamad Habes","doi":"10.1093/brain/awae388","DOIUrl":"https://doi.org/10.1093/brain/awae388","url":null,"abstract":"Concurrent neurodegenerative and vascular pathologies pose a diagnostic challenge in the clinical setting, with histopathology remaining the definitive modality for dementia-type diagnosis. To address this clinical challenge, we introduce a neuropathology-based, data-driven, multi-label deep learning framework to identify and quantify in-vivo biomarkers for Alzheimer's disease (AD), vascular dementia (VD), and Lewy body dementia (LBD) using antemortem T1-weighted MRI scans of 423 demented and 361 control participants from NACC and ADNI datasets. Based on the best-performing deep learning model, explainable heatmaps are extracted to visualize disease patterns, and the novel Deep Signature of Pathology Atrophy REcognition (DeepSPARE) indices are developed, where a higher DeepSPARE score indicates more brain alterations associated with that specific pathology. A substantial discrepancy in clinical and neuropathology diagnosis was observed in the demented patients: 71% of them had more than one pathology, but 67% of them were clinically diagnosed as AD only. Based on these neuropathology diagnoses and leveraging cross-validation principles, the deep learning model achieved the best performance with a balanced accuracy of 0.844, 0.839, and 0.623 for AD, VD, and LBD, respectively, and was used to generate the explainable deep-learning heatmaps and DeepSPARE indices. The explainable deep-learning heatmaps revealed distinct neuroimaging brain alteration patterns for each pathology: the AD heatmap highlighted bilateral hippocampal regions, the VD heatmap emphasized white matter regions, and the LBD heatmap exposed occipital alterations. The DeepSPARE indices were validated by examining their associations with cognitive testing, neuropathological, and neuroimaging measures using linear mixed-effects models. The DeepSPARE-AD index was associated with MMSE, Trail B, memory, PFDR-adjustedhippocampal volume, Braak stages, CERAD scores, and Thal phases (PFDR-adjusted &lt; 0.05). The DeepSPARE-VD index was associated with white matter hyperintensity volume and cerebral amyloid angiopathy (PFDR-adjusted &lt; 0.001). The DeepSPARE-LBD index was associated with Lewy body stages (PFDR-adjusted &lt; 0.05). The findings were replicated in an out-of-sample ADNI dataset by testing associations with cognitive, imaging, plasma, and CSF measures. CSF and plasma pTau181 were significantly associated with DeepSPARE-AD in the AD/MCIΑβ+ group (PFDR-adjusted &lt; 0.001), and CSF α-synuclein was associated solely with DeepSPARE-LBD (PFDR-adjusted = 0.036). Overall, these findings demonstrate the advantages of our innovative deep-learning framework in detecting antemortem neuroimaging signatures linked to different pathologies. The newly deep learning-derived DeepSPARE indices are precise, pathology-sensitive, and single-valued noninvasive neuroimaging metrics, bridging the traditional widely available in-vivo T1 imaging with histopathology.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fatemeh Koohi, Eric L Harshfield, Dipender Gill, Wenjing Ge, Stephen Burgess, Hugh S Markus
Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs may be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption, and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia, and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460), and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels, and the ratio of triglycerides to high density lipoprotein (HDL) also showed detrimental associations with LS risk, while genetic predisposition to higher HDL concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure-lowering through calcium channel blockers (CCBs) was associated with cSVD imaging markers, while genetically proxied HDL-raising through Cholesteryl Ester Transfer Protein (CETP) inhibitors, triglyceride-lowering through lipoprotein lipase (LPL), and weight-lowering through gastric inhibitory polypeptide receptor (GIPR) were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and BMI, in cSVD, but not other e.g. LDL. The findings further demonstrate the potential beneficial effects of CCBs on cSVD imaging markers and CETP inhibitors, LPL enhancement, and GIPR obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.
{"title":"Optimizing treatment of cardiovascular risk factors in cerebral small vessel disease using genetics","authors":"Fatemeh Koohi, Eric L Harshfield, Dipender Gill, Wenjing Ge, Stephen Burgess, Hugh S Markus","doi":"10.1093/brain/awae399","DOIUrl":"https://doi.org/10.1093/brain/awae399","url":null,"abstract":"Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs may be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption, and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia, and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460), and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels, and the ratio of triglycerides to high density lipoprotein (HDL) also showed detrimental associations with LS risk, while genetic predisposition to higher HDL concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure-lowering through calcium channel blockers (CCBs) was associated with cSVD imaging markers, while genetically proxied HDL-raising through Cholesteryl Ester Transfer Protein (CETP) inhibitors, triglyceride-lowering through lipoprotein lipase (LPL), and weight-lowering through gastric inhibitory polypeptide receptor (GIPR) were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and BMI, in cSVD, but not other e.g. LDL. The findings further demonstrate the potential beneficial effects of CCBs on cSVD imaging markers and CETP inhibitors, LPL enhancement, and GIPR obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"39 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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