Causes and consequences of cerebral small vessel disease. The RUN DMC study: a prospective cohort study. Study rationale and protocol

Contains fulltext : 96704.pdf (publisher's version ) (Open Access)BACKGROUND: Cerebral small vessel disease (SVD) is a frequent finding on CT and MRI scans of elderly people and is related to vascular risk factors and cognitive and motor impairment, ultimately leading to dementia or parkinsonism in some. In general, the relations are weak, and not all subjects with SVD become demented or get parkinsonism. This might be explained by the diversity of underlying pathology of both white matter lesions (WML) and the normal appearing white matter (NAWM). Both cannot be properly appreciated with conventional MRI. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity. The association between SVD, its microstructural integrity, and incident dementia and parkinsonism has never been investigated. METHODS/DESIGN: The RUN DMC study is a prospective cohort study on the risk factors and cognitive and motor consequences of brain changes among 503 non-demented elderly, aged between 50-85 years, with cerebral SVD. First follow up is being prepared for July 2011. Participants alive will be included and invited to the research centre to undergo a structured questionnaire on demographics and vascular risk factors, and a cognitive, and motor, assessment, followed by a MRI protocol including conventional MRI, DTI and resting state fMRI. DISCUSSION: The follow up of the RUN DMC study has the potential to further unravel the causes and possibly better predict the consequences of changes in white matter integrity in elderly with SVD by using relatively new imaging techniques. When proven, these changes might function as a surrogate endpoint for cognitive and motor function in future therapeutic trials. Our data could furthermore provide a better understanding of the pathophysiology of cognitive and motor disturbances in elderly with SVD. The execution and completion of the follow up of our study might ultimately unravel the role of SVD on the microstructural integrity of the white matter in the transition from "normal" aging to cognitive and motor decline and impairment and eventually to incident dementia and parkinsonism

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Cognitive performance is associated with return to work after ischemic stroke in young adults:The ODYSSEY study

INTRODUCTION: Limited data exist on cognitive performance and return to work after ischemic stroke, especially in patients under 50 years. We investigated whether cognitive performance in the subacute phase after ischemic stroke in young adults was associated with unemployment and the inability to retain their jobs among those who returned to work. PATIENTS AND METHODS: We conducted a multicenter prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischemic stroke. Cognitive assessments were performed within 6 months following the index event, covering seven cognitive domains. We categorized patients with cognitive impairment ( -score &lt; -1.5 on a domain) and as no/mild or major vascular cognitive disorder (VCD; -score &lt; -2.0 in one or more domains). Cognitive performance and other predefined characteristics were chosen to identify factors associated with unemployment and, among patients who returned to work, the inability to maintain employment. RESULTS: Of 525 patients (median age 44.3 [IQR 38.0-47.4] years; 243 women [46.3%]); median follow-up of 6.6 [IQR 4.5-8.2] years), 426 patients (81.1%) returned to work. Sixty-five patients (15.3%) were unable to maintain employment. In multivariable logistic regression analysis, major VCD (OR = 2.0; 95% CI 1.3-3.0; = 0.002) and cognitive impairment in processing speed (OR = 2.0; 95% CI 1.3-3.3; = 0.004) were associated with unemployment, but not with the inability to maintain employment. DISCUSSION AND CONCLUSION: In young patients after a first-ever ischemic stroke, major VCD and impaired processing speed in the subacute phase after stroke were independently associated with unemployment, but not with the inability to maintain employment

Trigger factors in patients with a patent foramen ovale-associated stroke:A case-crossover study

BACKGROUND: Patent foramen ovale (PFO) is a congenital anatomical variant which is associated with strokes in young adults. Contrary to vascular risk factors and atherosclerosis, a PFO is present from birth. However, it is completely unknown how an anatomical structure that is already present at birth in a large proportion of the population can convert into a PFO that causes stroke in a few. Recent studies reported a significant association between certain trigger factors and ischemic stroke in young adults. This study aims to investigate these triggers in PFO-associated stroke. METHODS: The ODYSSEY study, a multicenter prospective cohort study between 2013 and 2021, included patients aged 18-49 years experiencing their first-ever ischemic event. Participants completed a questionnaire about exposure to potential trigger factors. A case-crossover design was used to assess the relative risks (RR) with 95% confidence intervals (95% CI). The primary outcome was the RR of potential trigger factors for PFO-associated stroke. RESULTS: Overall, 1043 patients completed the questionnaire and had an ischemic stroke, of which 124 patients had a PFO-associated stroke (median age 42.1 years, 45.2% men). For patients with PFO-associated stroke, the RR was 26.0 (95% CI 8.0-128.2) for fever, 24.2 (95% CI 8.5-68.7) for flu-like disease, and 3.31 (95% CI 2.2-5.1) for vigorous exercise. CONCLUSION: In conclusion, flu-like disease, fever, and vigorous exercise may convert an asymptomatic PFO into a stroke-causing PFO in young adults. DATA ACCESS STATEMENT: The raw and anonymized data used in this study can be made available to other researchers on request. Written proposals can be addressed to the corresponding author and will be assessed by the ODYSSEY investigators for appropriateness of use, and a data sharing agreement in accordance with Dutch regulations will be put in place before data are shared

sj-docx-1-eso-10.1177_23969873221132032 – Supplemental material for Subacute cognitive impairment after first-ever transient ischemic attack or ischemic stroke in young adults: The ODYSSEY study

Supplemental material, sj-docx-1-eso-10.1177_23969873221132032 for Subacute cognitive impairment after first-ever transient ischemic attack or ischemic stroke in young adults: The ODYSSEY study by Mijntje MI Schellekens, Esther M Boot, Jamie I Verhoeven, Merel S Ekker, Mayte E van Alebeek, Paul JAM Brouwers, Renate M Arntz, Gert W van Dijk, Rob AR Gons, Inge WM van Uden, Tom den Heijer, Paul LM de Kort, Karlijn F de Laat, Anouk van Norden, Sarah E Vermeer, Marian SG van Zagten, Robert J van Oostenbrugge, Marieke JH Wermer, Paul J Nederkoorn, Frank G van Rooij, Ido R van den Wijngaard, Frank-Erik de Leeuw, Roy PC Kessels and Anil M Tuladhar in European Stroke Journal</p

sj-docx-1-wso-10.1177_17474930241242625 – Supplemental material for Trigger factors in patients with a patent foramen ovale—associated stroke: A case-crossover study

Supplemental material, sj-docx-1-wso-10.1177_17474930241242625 for Trigger factors in patients with a patent foramen ovale—associated stroke: A case-crossover study by Maikel HM Immens, Merel S Ekker, Esmee Verburgt, Jamie I Verhoeven, Mijntje MI Schellekens, Nina A Hilkens, Esther M Boot, Mayte E Van Alebeek, Paul JAM Brouwers, Renate M Arntz, Gert W Van Dijk, Rob AR Gons, Inge WM Van Uden, Tom den Heijer, Paul LM de Kort, KF de Laat, Anouk GW Van Norden, Sarah E Vermeer, Marian SG Van Zagten, Robert J Van Oostenbrugge, Marieke JH Wermer, Paul J Nederkoorn, Henk Kerkhoff, FA Rooyer, Frank G Van Rooij, Ido R Van den Wijngaard, Catharina JM Klijn, Anil M Tuladhar, Tim JF ten Cate and Frank-Erik de Leeuw in International Journal of Stroke</p

Stroke genetics informs drug discovery and risk prediction across ancestries

: Previous genome-wide association studies (GWASs) of stroke&nbsp;-&nbsp;the second leading cause of death worldwide&nbsp;-&nbsp;were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P &lt; 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries