Search

Background and aim: The revised Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) add two radiological markers to the existing criteria: severe visible perivascular spaces in the centrum semiovale and white matter hyperintensities (WMHs) in a multispot pattern. This study aims to determine the sensitivity of the updated criteria in mutation carriers with Dutch-type hereditary CAA (D-CAA) in an early and later disease stage. Methods: In this cross-sectional study, we included presymptomatic and symptomatic D-CAA mutation carriers from our prospective natural history study (AURORA) at the Leiden University Medical Center between 2018 and 2021. 3-Tesla scans were assessed for CAA-related magnetic resonance imaging (MRI) markers. We compared the sensitivity of the Boston criteria v2.0 to the previously used modified Boston criteria v1.5. Results: We included 64 D-CAA mutation carriers (mean age 49 years, 55% women, 55% presymptomatic). At least one white matter (WM) feature was seen in 55/64 mutation carriers (86%: 74% presymptomatic, 100% symptomatic). Fifteen (23%) mutation carriers, all presymptomatic, showed only WM features and no hemorrhagic markers. The sensitivity for probable CAA was similar between the new and the previous criteria: 11/35 (31%) in presymptomatic mutation carriers and 29/29 (100%) in symptomatic mutation carriers. The sensitivity for possible CAA in presymptomatic mutation carriers increased from 0/35 (0%) to 15/35 (43%) with the new criteria. Conclusion: The Boston criteria v2.0 increase the sensitivity for detecting possible CAA in presymptomatic D-CAA mutation carriers and, therefore, improve the detection of the early phase of CAA. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). Aims: We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. Methods: Symptomatic patients with D-CAA (defined as ≥1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). Results: We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1–7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4–25%) symptomatic patients and none of the 21 (0%, 95%CI 0–0%) presymptomatic carriers had ≥ 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52–76) participants (median 1.0, range 0–159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. Conclusions: Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA. [ABSTRACT FROM AUTHOR]

Background and aim: To investigate sex differences with respect to presence and location of atherosclerosis in acute ischemic stroke patients. Methods: Participants with acute ischemic stroke were included from the Dutch acute stroke trial, a large prospective multicenter cohort study performed between May 2009 and August 2013. All patients received computed tomography/computed tomography-angiography within 9 h of stroke onset. We assessed presence of atherosclerosis in the intra- and extracranial internal carotid and vertebrobasilar arteries. In addition, we determined the burden of intracranial atherosclerosis by quantifying internal carotid and vertebrobasilar artery calcifications, resulting in calcium volumes. Prevalence ratios between women and men were calculated with Poisson regression analysis and adjusted prevalence ratio for potential confounders (age, hypertension, hyperlipidemia, diabetes, smoking, and alcohol use). Results: We included 1397 patients with a mean age of 67 years, of whom 600 (43%) were women. Presence of atherosclerosis in intracranial vessel segments was found as frequently in women as in men (71% versus 72%, adjusted prevalence ratio 0.95; 95% CI 0.89–1.01). In addition, intracranial calcification volume did not differ between women and men in both intracranial internal carotid (large burden 35% versus 33%, adjusted prevalence ratio 0.93; 95% CI 0.73–1.19) and vertebrobasilar arteries (large burden 26% versus 40%, adjusted prevalence ratio 0.69; 95% CI 0.41–1.12). Extracranial atherosclerosis was less common in women than in men (74% versus 81%, adjusted prevalence ratio 0.86; 95% CI 0.81–0.92). Conclusions: In patients with acute ischemic stroke the prevalence of intracranial atherosclerosis does not differ between women and men, while extracranial atherosclerosis is less often present in women compared with men. [ABSTRACT FROM AUTHOR]

Background: Cerebral amyloid angiopathy (CAA) has a remarkably variable disease course, even in monogenetic hereditary forms. Our aim was to investigate the prevalence of vascular risk factors and their effect on disease onset and course in Dutch-type hereditary (D-)CAA and sporadic CAA., Methods: We performed a cohort study in D-CAA to investigate the association between vascular risk factors (hypertension, hypercholesterolemia, smoking and alcohol use) and age of intracerebral hemorrhage (ICH) onset and time of ICH recurrence with survival analyses. In addition, we performed a systematic review to assess the prevalence of vascular risk factors and their effect on clinical outcome in sporadic CAA. We searched PubMed, Embase, Web of Science and COCHRANE Library, from 1987-2022 and included cohorts with ≥10 patients. We created forest plots, calculated pooled estimates and reported variability (heterogeneity plus sampling variability) and risk of bias., Results: We included 70 participants with D-CAA (47% women, mean age 53y). Sixteen (23%) had hypertension, 15 (21%) hypercholesterolemia, 45 (64%) were smokers and 61 (87%) used alcohol. We found no clear effect of vascular risk factors on age of first ICH (log-rank test hypertension: p=0.35, hypercholesterolemia: p=0.41, smoking: p=0.61 and alcohol use: p=0.55) or time until ICH recurrence (log-rank test hypertension: p=0.71, hypercholesterolemia: p=0.20 and smoking: p=0.71). We identified 25 out of 1234 screened papers that assessed the prevalence of risk factors in CAA and 6 that reported clinical outcomes. The pooled prevalence estimates of hypertension was 62% (95%CI:55%-69%), diabetes 17% (95%CI:14%-20%), dyslipidemia 32% (95%CI:23%-41%), and tobacco use 27% (95%CI:18%-36%). One study reported study diabetes and hypertension to be associated with a lower risk of recurrent ICH, whereas another study reported hypertension to be associated with an increased risk. All other studies showed no association between vascular risk factors and clinical outcome. High quality studies focusing on vascular risk factors were lacking., Conclusions: In patients with D-CAA and sporadic CAA the prevalence of vascular risk factors is high. Although this suggests an opportunity for prevention, there is no clear association between these risk factors and CAA-related ICH onset and recurrence., (The Author(s). Published by S. Karger AG, Basel.)

Introduction: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited., Methods: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls. Cognition was measured with a standardized test battery. Linear regression was performed to assess the association between MRI-cSVD burden and cognition., Results: D-CAA ICH- mutation carriers exhibited poorer global cognition and executive function compared to age-matched controls. Patients with sCAA performed worse across all cognitive domains compared to D-CAA ICH+ mutation carriers and age-matched controls. MRI-cSVD burden is associated with decreased processing speed., Discussion: CAA is associated with dysfunction in multiple cognitive domains, even before ICH, with increased MRI-cSVD burden being associated with slower processing speed., Highlights: Cognitive dysfunction is present in early disease stages of cerebral amyloid angiopathy (CAA) before the occurrence of symptomatic intracerebral hemorrhage (sICH). Presymptomatic Dutch-type CAA (D-CAA) mutation carriers show worse cognition than age-matched controls. More early awareness of cognitive dysfunction in CAA before first sICH is needed. Increased cerebral small vessel disease CAA-burden on magnetic resonance imaging is linked to a decrease in processing speed., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months., Methods: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders., Results: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07-8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%)., Conclusion: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization., (© 2024. The Author(s).)

Background and Purpose: Data on health-related quality of life (HRQoL) and mood in cerebral amyloid angiopathy (CAA), a disease characterized by stroke and cognitive decline, are limited. We aimed to investigate the impacted domains of life, value-based HRQoL and the prevalence of depression and anxiety in patients with CAA., Methods: We conducted a cross-sectional study of patients with sporadic (s)CAA, lobar dominant mixed CAA and hypertensive arteriopathy (mixed CAA-HTA), or Dutch-type hereditary (D-)CAA, from prospective outpatient clinic cohorts. Participants completed four questionnaires: the EuroQoL 5 dimensions 5-level questionnaire (EQ-5D-5L; EQ-VAS for visual analogue scale; EQ-Index for index rating), the Short-Form 36 questionnaire (SF-36), the Center for Epidemiologic Studies-Depression scale (CES-D), and the Hospital Anxiety and Depression Scale (HADS; -D for depression and -A for anxiety subscales). The EQ-5D-5L assesses the domains mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The SF-36 domains are physical functioning, social functioning, physical role limitations, emotional role limitations, mental health, vitality, bodily pain, and general health perceptions. We compared age- and sex- adjusted HRQoL (SF-36 domain scores; EQ-VAS; EQ-Index) to the Dutch normative population, and estimated the prevalences of current depression (either: history of depression or current use of antidepressants, with high score on CES-D [≥16] and/or HADS-D [≥8]; or high score on both depression questionnaires) and anxiety (HADS-A ≥ 8)., Results: We included 179 patients: 77 with sCAA (mean age: 72 years, women: 36%), 31 with mixed CAA-HTA (68 years, women: 29%), and 71 with D-CAA (56 years, women: 52%, symptomatic: 35 [49%]). The SF-36 profiles of all patient groups were similar, negatively differing from the norm in emotional role functioning, social functioning and vitality. The EQ-VAS score of patients (mean [SD] sCAA: 76 [16], D-CAA: 77 [15]) was similar to the norm, as was the EQ-Index score. Fifteen patients with sCAA (23%; 95% confidence interval [CI] 13%-33%), seven with mixed CAA-HTA (27%; 95% CI 10%-44%) and eight with D-CAA (14%; 95% CI 5%-22%) were noted as having depression. The prevalences of anxiety and depression were equivalent., Conclusions: We found that CAA influenced emotional role functioning and aspects linked to social engagement consistently across its subtypes. One quarter of patients exhibited depressive or anxiety symptoms. Recognizing these impacted domains could enhance overall well-being., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (<10 mm) hemorrhages with a cystic cavity and/or irregular shape. Such hemorrhages, however, are often present in patients with cerebral amyloid angiopathy (CAA). In this study, we aimed to investigate the frequency, diameter, and volume distribution of these hemorrhages (which we called mesobleeds) in patients with CAA., Methods: We selected participants with Dutch-type hereditary CAA (D-CAA) and sporadic CAA (sCAA) and scored microbleeds, mesobleeds, and macrobleeds on 3T susceptibility-weighted images MRI. Hemorrhage diameter and volume were calculated in a subset of participants using a semi-automatic tool; their distribution was evaluated on a logarithmic scale., Results: We included 25 participants with D-CAA (mean age 56 years) and 25 with sCAA (mean age 73 years). In total, 11,007 microbleeds, 602 mesobleeds, and 195 macrobleeds were observed. Eighty-two percent of participants had ≥1 mesobleed. Hemorrhage diameter and volume were calculated in four participants with 272 microbleeds (median diameter 1.52 mm, volume 0.004 mL), 84 mesobleeds (median diameter 5.61 mm, volume 0.06 mL), and 37 macrobleeds (median diameter 19.58 mm, volume 1.33 mL). Mesobleed diameter and volume were larger than microbleeds (optimal cut-off 0.02 mL) but showed overlap with macrobleeds., Conclusion: Hemorrhages <10 mm with an irregular shape and/or cystic cavity are frequently found in participants with CAA and have a distinct diameter and volume distribution. We propose to name these hemorrhage mesobleeds and to rate them separately from micro- and macrobleeds. Future research is necessary to investigate their pathophysiology and prognostic value., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: SARS-CoV-2 infection is associated with a decline in functional outcomes; many patients experience persistent symptoms, while the underlying pathophysiology remains unclear. This study investigated white matter (WM) integrity on brain MRI in hospitalized COVID-19 patients and its associations with clinical outcomes, including long COVID., Materials and Methods: We included hospitalized COVID-19 patients and controls from CORONavirus and Ischemic Stroke (CORONIS), an observational cohort study, who underwent MRI-DWI imaging at baseline shortly after discharge (<3 months after positive PCR) and 3 months after baseline scanning. We assessed WM integrity using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) and performed comparisons between groups and within patients. Clinical assessment was conducted at 3 and 12 months with functional outcomes such as modified Rankin Scale (mRS), Post-COVID-19 Functional Status scale (PCFS), Visual Analogue Scale (VAS), and long COVID, cognitive assessment was conducted by the Modified Telephone Interview for Cognitive Status (TICS-M), and the Hospital Anxiety and Depression Scale (HADS) was used to assess mood disorder. Associations between WM integrity and clinical outcomes were evaluated using logistic regression and linear regression., Results: A total of 49 patients (mean age 59.5 years) showed higher overall peak width of skeletonized mean diffusivity (PSMD) ( p  = 0.030) and lower neurite density index (NDI) in several WM regions compared with 25 controls at the baseline ( p  < 0.05; FWE-corrected) but did not remain statistically significant after adjusting for WM hyperintensities. Orientation dispersion index (ODI) increased after 3-month follow-up in several WM regions within patients ( p  < 0.05), which remained significant after correction for changes in WMH volume. Patients exhibited worse clinical outcomes compared with controls. Low NDI at baseline was associated with worse performance on the Post-COVID-19 Functional Status scale after 12 months ( p  = 0.018)., Conclusion: After adjusting for WMH, hospitalized COVID-19 patients no longer exhibited lower WM integrity compared with controls. WM integrity was generally not associated with clinical assessments as measured shortly after discharge, suggesting that factors other than underlying WM integrity play a role in worse clinical outcomes or long COVID., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 van Lith, Li, van der Wijk, Wijers, Sluis, Wermer, de Leeuw, Meijer and Tuladhar.)

Objective: We investigated whether quantitative electroencephalography (qEEG) correlates with cognition and cortical superficial siderosis (cSS) in cerebral amyloid angiopathy., Methods: We included patients with sporadic (sCAA) and hereditary Dutch-type CAA (D-CAA). Spectral measures and the phase lag index (PLI) were analyzed on qEEG. Cognition was assessed with the MoCA and cSS presence was scored on 3T-MRI. Linear regression analyses were performed to investigate these qEEG measures and cognition. Independent samples T-tests were used to analyze the qEEG measure differences between participants with and without cSS., Results: We included 92 participants (44 D-CAA; 48 sCAA). A lower average peak frequency (β[95 %CI] = 0.986[0.252-1.721]; P = 0.009) and a higher spectral ratio (β[95 %CI] = -0.918[-1.761--0.075]; P = 0.033) on qEEG correlated with a lower MoCA score, irrespective of a history of symptomatic intracerebral hemorrhage (sICH). The PLI showed no correlation to the MoCA. qEEG slowing was not different in those with or without cSS., Conclusions: Spectral qEEG (but not PLI) reflects cognitive performance in patients with CAA with and without a history of sICH. We found no association between qEEG slowing and cSS., Significance: qEEG could be a valuable biomarker, especially in challenging cognitive testing situations in CAA, and a potential predictive tool in future studies., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies., Methods: Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated., Findings: Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62])., Interpretation: Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy., Funding: Fonds NutsOhra., Competing Interests: Declaration of interests DWJD reports unrestricted research grants from Stryker Medtronic, Cerenovus, Penumbra, and Thrombolytic Science, all paid to his institution; and is chair of the data safety monitoring boards of the Act Global and LATE MT trials and a work package of the CONTRAST consortium. HBvdW reports research grants from the Dutch Heart Foundation (via the CONTRAST consortium), the European Commission, Stryker (via the CONTRAST consortium), Bayer, and Boehringer Ingelheim; consulting fees from TargED Biopharmaceuticals, Bayer, and Boehringer Ingelheim; and honoraria for presentations from the Netherlands Vascular Forum, all paid to his institution; is chair of the data safety monitoring board of the Ghrelin in Coma (GRECO) trial and a member of the advisory board of the TENSION trial; and is on the executive committee of—and is a past president of—the European Stroke Organisation. MJHW reports participation on the data safety monitoring board of the TRIDENT trial. YBWEMR is a minor shareholder of Nicolab. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Women appear to have a higher risk for long term restrictions in participation than men. This gender difference is poorly understood, as solely biomedical factors have been examined to date., Objectives: The aims of this study are (1) to map gender differences in participation outcome one year after stroke, and (2) to identify demographic, stroke-related, or psychological predictors of participation for women and men separately., Methods: A total of 326 patients (mean age 66.5 ± 12.4y, 35.0% women) completed the restriction and satisfaction subscales of the Utrecht Scale of Evaluation of Rehabilitation-Participation (USER-P) at one year after stroke. Bivariate and multiple linear regression analyses were performed., Results: Women reported worse scores for restrictions in participation compared to men (median 75.4 versus 87.9 respectively, p  = 0.001), especially in physical activities such as daytrips and going out. Satisfaction with participation was similar between women and men. Worse cognitive functioning (β = 0.17) was associated with more restrictions in participation in men only, other predictors of restrictions in participation were similar between women and men. The presence of depressive symptoms (β = -0.49) was associated with worse satisfaction with participation in men, whereas an increased stroke severity (β = -0.29) and the presence of maladaptive psychological factors (β = -0.36) were associated with worse satisfaction with participation in women., Conclusions: Women experience more restrictions in participation compared to men one year after stroke. Taking into account gender-specific predictors of participation in stroke aftercare is important, as different biopsychosocial factors contribute to problems in participation across women and men.

Introduction: Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Second, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing., Methods: We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at 3 months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institutes of Health Stroke Scale (NIHSS) and OTDT., Results: Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were older (mean age 74.6 vs. 71.0, p &lt; 0.001) and presented with slightly higher NIHSS scores (median 3 [IQR 2-7] vs. 3 [IQR 1-6], p &lt; 0.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64; 29; 10 vs. 63; 30; 9%, p = 0.16). Women had a slightly longer OTDT (median 145 vs. 139 min, p &lt; 0.01). Women had increased odds of poor outcomes (OR 1.49 [95% CI: 1.43-1.56]). This was still statistically significant after adjusting for age and NIHSS score (OR 1.22 [95% CI: 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association., Conclusion: In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from late thirties up to 70 years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring., Methods: We included (potential) D-CAA mutation carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s), their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as the covariate and the sex of the offspring as the factor. Next, we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter, and father/son. We used a random effect per household., Results: A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p = 0.87) for D-CAA parents (n = 60) and their offspring (n = 100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, standard deviation [SD] ± 7) than offspring with a paternal inheritance (54 years, SD ± 6, p = 0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio 0.99, 95% CI: 0.94-1.03, p = 0.51. The interaction between parent's sex and child's sex was not significant (p = 0.70). The results with and without random effect were essentially identical., Conclusion: We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Haemorrhagic stroke is a severe condition with poor prognosis. Biological sex influences the risk factors, presentations, treatment, and patient outcomes of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and vascular malformations. Women are usually older at onset of intracerebral haemorrhage compared with men but have an increased risk of aneurysmal subarachnoid haemorrhage as they age. Female-specific factors such as pregnancy, eclampsia or pre-eclampsia, postmenopausal status, and hormone therapy influence a woman's long-term risk of haemorrhagic stroke. The presence of intracranial aneurysms, arteriovenous malformations, or cavernous malformations poses unique clinical dilemmas during pregnancy and delivery. In the absence of evidence-based guidelines for managing the low yet uncertain risk of haemorrhagic stroke during pregnancy and delivery in women with vascular malformations, multidisciplinary teams should carefully assess the risks and benefits of delivery methods for these patients. Health-care providers should recognise and address the challenges that women might have to confront when recovering from haemorrhagic stroke., Competing Interests: Declaration of interests ECS is national coordinator of the ANNEXAi trial (honoraria paid to the institution), is a steering committee member for the AXIOMATIC trial (BristolMyersSquibb) and OCEANIC trial (Bayer; also honoraria paid to the institution), and is on the European Stroke Organisation intracerebral haemorrhage committee. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Purpose: Patients who underwent red blood cell (RBC) transfusion from donors who later developed multiple spontaneous intracerebral hemorrhages (ICHs) have recently been identified to have increased risk of ICH themselves. This increased risk of ICH was hypothesized to be related to iatrogenic cerebral amyloid angiopathy (iCAA) transmission. Two cases are presented who had RBC transfusion as an infant and presented with CAA at a relatively young age decades later., Method: Cases were identified by prospectively asking all patients at our CAA outpatient clinic (November 2023 to January 2024) about a medical history with RBC transfusion or history with a high likelihood for RBC transfusion (e.g., hemolytic disease, trauma with massive hemorrhage). Eligible patients were all diagnosed with CAA, CAA with concomitant hypertensive arteriopathy or iCAA, and without hereditary CAA., Results: Between November 2023 and January 2024, 2/35 (6%, 95% confidence interval 2%-19%) outpatient clinic patients had a history of RBC transfusion and none had a high likelihood medical history. The cases presented at age 47 and 57 and had already developed severe CAA., Conclusions: Red blood cell transfusion might be a possible mechanism for iCAA; however, further prospective data collection and experimental evidence concerning blood transmission of amyloid-β are needed., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid-β transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had 'early-onset' disease (compared to sporadic, age-related, CAA), as a consequence of childhood procedures., Results: We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30-39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder., Conclusion: The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Angiographically negative subarachnoid hemorrhage (anSAH) has traditionally been considered a benign condition, mainly because of favorable outcomes in the acute stage in comparison to the often negative acute outcomes of aneurysmal subarachnoid hemorrhage. However, a growing body of research in recent years shows that anSAH often leads to cognitive impairments, emotional distress, and difficulties in resuming work or other daily life activities. Therefore, in this position paper, we call for a change in neurological care and a shift in patient communication, emphasizing the importance of addressing patient needs and fostering realistic expectations rather than solely focusing on the benign nature of the condition., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by early detection and treatment of intracranial aneurysms in high-risk individuals. We investigated whether individuals at high risk of aSAH in the general population can be identified by developing an aSAH prediction model with electronic health records (EHR) data. To assess the aSAH model's relative performance, we additionally developed prediction models for acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) and compared the discriminative performance of the models. We included individuals aged ≥35 years without history of stroke from a Dutch routine care database (years 2007-2020) and defined outcomes aSAH, AIS and ICH using International Classification of Diseases (ICD) codes. Potential predictors included sociodemographic data, diagnoses, medications, and blood measurements. We cross-validated a Cox proportional hazards model with an elastic net penalty on derivation cohorts and reported the c-statistic and 10-year calibration on validation cohorts. We examined 1,040,855 individuals (mean age 54.6 years, 50.9% women) for a total of 10,173,170 person-years (median 11 years). 17,465 stroke events occurred during follow-up: 723 aSAH, 14,659 AIS, and 2,083 ICH. The aSAH model's c-statistic was 0.61 (95%CI 0.57-0.65), which was lower than the c-statistic of the AIS (0.77, 95%CI 0.77-0.78) and ICH models (0.77, 95%CI 0.75-0.78). All models were well-calibrated. The aSAH model identified 19 predictors, of which the 10 strongest included age, female sex, population density, socioeconomic status, oral contraceptive use, gastroenterological complaints, obstructive airway medication, epilepsy, childbirth complications, and smoking. Discriminative performance of the aSAH prediction model was moderate, while it was good for the AIS and ICH models. We conclude that it is currently not feasible to accurately identify individuals at increased risk for aSAH using EHR data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kanning et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Limited data exists on cognitive recovery in young stroke patients. We aimed to investigate the longitudinal course of cognitive performance during the first year after stroke at young age and identify predictors for cognitive recovery., Methods: We conducted a multicentre prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischaemic stroke. Cognitive assessments were performed within 6 months and after 1 year following the index event, covering seven cognitive domains. Composite Z-scores using normative data determined cognitive impairment (Z-score<-1.5). A Reliable Change Index (RCI) assessed cognitive recovery (RCI>1.96) or decline (RCI<-1.96)., Results: 393 patients (median age 44.3 years, IQR 38.4-47.2) completed cognitive assessments with a median time interval of 403 days (IQR 364-474) between assessments. Based on RCI, a similar proportion of patients showed improvement and decline in each cognitive domain, while the majority exhibited no cognitive change. Among cognitively impaired patients at baseline, improvements were observed in processing speed (23.1%), visuoconstruction (40.1%) and executive functioning (20.0%). Younger age was associated with better cognitive recovery in visuoconstruction, and larger lesion volume was related to cognitive recovery in processing speed. No other predictors for cognitive recovery were identified., Conclusions: Cognitive impairment remains prevalent in young stroke even 1 year after the event. Most patients showed no cognitive change, however, recovery may have occurred in the early weeks after stroke, which was not assessed in our study. Among initially cognitively impaired patients, cognitive recovery is observed in processing speed, visuoconstruction and executive functioning. It is still not possible to predict cognitive recovery in individual patients., Competing Interests: Competing interests: AMT is a junior staff member of the Dutch Heart Foundation (grant number 2016T044). F-EDL is a clinical established investigator of the Dutch Heart Foundation (2014 T060). MJHW has received a VIDI grant (9171337) of the ZonMw/NWO and the clinical established investigator Dutch Heart Foundation grant (2016T86)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer's disease (AD)., Methods: In this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aβ42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups., Results: sCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH., Conclusions: In participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms., (© 2024. The Author(s).)

Background: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH., Methods: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation., Results: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years., Conclusions: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted., Competing Interests: Disclosures Dr Anderson has received sponsored research support from Bayer AG and has consulted for ApoPharma unrelated to this work. Dr Rosand reports compensation from National Football League and Takeda Development Center Americas for consultant services, unrelated to this work. The other authors report no conflicts.

Background: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA., Methods: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aβ40 and Aβ42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups., Results: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*10 3 pg/mL vs. 4.4*10 3 pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*10 2 pg/mL vs. 7.8*10 2 pg/mL; P=0.01 and GFAP:11.4*10 3 pg/mL vs. 7.5*10 3 pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*10 2 pg/mL vs 7.8*10 2 pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aβ42 levels (P=0.01/0.02)., Conclusions: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA., (© 2024. The Author(s).)

Background: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA., Methods: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences., Results: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.β = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.β=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.β=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women., Discussion: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately., (© 2024. The Author(s).)