Search

Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Objective: Elevated levels of anti-amyloid-β (anti-Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy-related inflammation (CAA-RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA-RI., Methods: We replicated the immunoassay to detect CSF anti-Aβ autoantibodies using CSF from CAA-RI patients and non-CAA controls with unrelated disorders and further characterized its performance. Moreover, we conducted a literature review of CAA-RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA-RI., Results: The assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (r sp  = 0.51, p = 0.02). Assay levels were not elevated in CAA-RI patients (n = 6) compared to non-CAA controls (n = 20; p = 0.64). Literature review indicated only occasional presence of B-lymphocytes and plasma cells (i.e., antibody-producing cells), alongside the abundant presence of activated microglial cells, T-cells, and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production., Interpretation: We were unable to reproduce the reported elevation of anti-Aβ autoantibody concentration in CSF of CAA-RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA-RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti-Aβ autoantibodies as a diagnostic biomarker for CAA-RI., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Brain amyloid-β (Aβ) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aβ 40 peptide, whereas Aβ 42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aβ isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aβ isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aβ 1-34 , Aβ 1-37 , Aβ 1-38 , Aβ 1-39 , Aβ 1-40 , and Aβ 1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aβ peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aβ 1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aβ 1-42 , none of the Aβ peptides were decreased in AD-like subjects compared with controls. All Aβ peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aβ 1-42 in the model (since decreased Aβ 1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aβ profiles. Peptides shorter than Aβ 1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aβ accumulation. This study supports the potential use of this panel of CSF Aβ peptides to indicate presence of CAA pathology with high accuracy., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τ b  = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75-5.29] vs 3.60 ng/ml [IQR 3.11-4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aβ40 (spearman r (r s ) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH., (© 2024. The Author(s).)

Background: Sporadic cerebral amyloid angiopathy (sCAA) is a disease characterised by the progressive deposition of the amyloid beta (Aβ) in the cerebral vasculature, capable of causing a variety of symptoms, from (mild) cognitive impairment, to micro- and major haemorrhagic lesions. Modern diagnosis of sCAA relies on radiological detection of late-stage hallmarks of disease, complicating early diagnosis and potential interventions in disease progression. Our goal in this study was to identify and validate novel biomarkers for sCAA., Methods: We performed a proximity extension assay (PEA) on cerebrospinal fluid (CSF) samples of sCAA/control participants (n = 34/51). Additionally, we attempted to validate the top candidate biomarker in CSF and serum samples (n = 38/26) in a largely overlapping validation cohort, through analysis with a targeted immunoassay., Results: Thirteen proteins were differentially expressed through PEA, with top candidate NFL significantly increased in CSF of sCAA patients (p < 0.0001). Validation analyses using immunoassays revealed increased CSF and serum NFL levels in sCAA patients (both p < 0.0001) with good discrimination between sCAA and controls (AUC: 0.85; AUC: 0.79 respectively). Additionally, the CSF: serum NFL ratio was significantly elevated in sCAA (p = 0.002)., Discussion: Large-scale targeted proteomics screening of CSF of sCAA patients and controls identified thirteen biomarker candidates for sCAA. Orthogonal validation of NFL identified NFL in CSF and serum as biomarker, capable of differentiating between sCAA patients and controls., (© 2024. The Author(s).)

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: Shear wave elastography (SWE) is mainly used for stiffness estimation of large, homogeneous tissues, such as the liver and breasts. However, little is known about its accuracy and applicability in thin (∼0.5-2 mm) vessel walls. To identify possible performance differences among vendors, we quantified differences in measured wave velocities obtained by commercial SWE implementations of various vendors over different imaging depths in a vessel-mimicking phantom. For reference, we measured SWE values in the cylindrical inclusions and homogeneous background of a commercial SWE phantom. Additionally, we compared the accuracy between a research implementation and the commercially available clinical SWE on an Aixplorer ultrasound system in phantoms and in vivo in patients., Methods: SWE measurements were performed over varying depths (0-35 mm) using three ultrasound machines with four ultrasound probes in the homogeneous 20 kPa background and cylindrical targets of 10, 40, and 60 kPa of a multi-purpose phantom (CIRS-040GSE) and in the anterior and posterior wall of a homogeneous polyvinyl alcohol vessel-mimicking phantom. These phantom data, along with in vivo SWE data of carotid arteries in 23 patients with a (prior) head and neck neoplasm, were also acquired in the research and clinical mode of the Aixplorer ultrasound machine. Machine-specific estimated phantom stiffness values (CIRS phantom) or wave velocities (vessel phantom) over all depths were visualized, and the relative error to the reference values and inter-frame variability (interquartile range/median) were calculated. Correlations between SWE values and target/vessel wall depth were explored in phantoms and in vivo using Spearman's correlations. Differences in wave velocities between the anterior and posterior arterial wall were assessed with Wilcoxon signed-rank tests. Intra-class correlation coefficients were calculated for a sample of ten patients as a measure of intra- and interobserver reproducibility of SWE analyses in research and clinical mode., Results: There was a high variability in obtained SWE values among ultrasound machines, probes, and, in some cases, with depth. Compared to the homogeneous CIRS-background, this variation was more pronounced for the inclusions and the vessel-mimicking phantom. Furthermore, higher stiffnesses were generally underestimated. In the vessel-mimicking phantom, anterior wave velocities were (incorrectly) higher than posterior wave velocities (3.4-5.6 m/s versus 2.9-5.9 m/s, p ≤ 0.005 for 3/4 probes) and remarkably correlated with measurement depth for most machines (Spearman's ρ = -0.873-0.969, p < 0.001 for 3/4 probes). In the Aixplorer's research mode, this difference was smaller (3.3-3.9 m/s versus 3.2-3.6 m/s, p = 0.005) and values did not correlate with measurement depth (Spearman's ρ = 0.039-0.659, p ≥ 0.002). In vivo, wave velocities were higher in the posterior than the anterior vessel wall in research (left p = 0.001, right p < 0.001) but not in clinical mode (left: p = 0.114, right: p = 0.483). Yet, wave velocities correlated with vessel wall depth in clinical (Spearman's ρ = 0.574-0.698, p < 0.001) but not in research mode (Spearman's ρ = -0.080-0.466, p ≥ 0.003)., Conclusions: We observed more variation in SWE values among ultrasound machines and probes in tissue with high stiffness and thin-walled geometry than in low stiffness, homogeneous tissue. Together with a depth-correlation in some machines, where carotid arteries have a fixed location, this calls for caution in interpreting SWE results in clinical practice for vascular applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: Possible differences in the prevalence of cerebral amyloid angiopathy (CAA) in East-Asian compared to Western populations have received little attention, and results so far have been ambiguous. Our aim is to compare the prevalence of CAA neuropathology and magnetic resonance imaging markers of CAA in East-Asian and Western cohorts reflecting the general population, cognitively normal elderly, patients with Alzheimer's disease (AD), and patients with (lobar) intracerebral hemorrhage (ICH)., Methods: We performed a systematic literature search in PubMed and Embase for original research papers on the prevalence of CAA and imaging markers of CAA published up until February 17th 2022. Records were screened by two independent reviewers. Pooled estimates were determined using random-effects models. We compared studies from Japan, China, Taiwan, South Korea (East-Asian cohorts) to studies from Europe or North America (Western cohorts) by meta-regression models., Results: We identified 12,257 unique records, and we included 143 studies on Western study populations and 53 studies on East-Asian study populations. Prevalence of CAA neuropathology did not differ between East-Asian and Western cohorts in any of the investigated patient domains. The prevalence of strictly lobar microbleeds was lower in East-Asian cohorts of population-based individuals (5.6% vs. 11.4%, P=0.020), cognitively normal elderly (2.6% vs. 11.4%, P=0.001), and patients with ICH (10.2% vs. 24.6%, P<0.0001). However, age was in general lower in the East-Asian cohorts., Conclusion: The prevalence of CAA neuropathology in the general population, cognitively normal elderly, patients with AD, and patients with (lobar) ICH is similar in East-Asian and Western countries. In East-Asian cohorts reflecting the general population, cognitively normal elderly, and patients with ICH, strictly lobar microbleeds were less prevalent, likely due to their younger age. Consideration of potential presence of CAA is warranted in decisions regarding antithrombotic treatment and potential new anti-amyloid-β immunotherapy as treatment for AD in East-Asian and Western countries alike.

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).)

Cerebral amyloid angiopathy (CAA) is a form of small vessel disease characterised by the progressive deposition of amyloid β protein in the cerebral vasculature, inducing symptoms including cognitive impairment and cerebral haemorrhages. Due to their accessibility and homogeneous disease phenotypes, animal models are advantageous platforms to study diseases like CAA. Untargeted proteomics studies of CAA rat models (e.g. rTg-DI) and CAA patients provide opportunities for the identification of novel biomarkers of CAA. We performed untargeted, data-independent acquisition proteomic shotgun analyses on the cerebrospinal fluid of rTg-DI rats and wild-type (WT) littermates. Rodents were analysed at 3 months (n = 6/10), 6 months (n = 8/8), and 12 months (n = 10/10) for rTg-DI and WT respectively. For humans, proteomic analyses were performed on CSF of sporadic CAA patients (sCAA) and control participants (n = 39/28). We show recurring patterns of differentially expressed (mostly increased) proteins in the rTg-DI rats compared to wild type rats, especially of proteases of the cathepsin protein family (CTSB, CTSD, CTSS), and their main inhibitor (CST3). In sCAA patients, decreased levels of synaptic proteins (e.g. including VGF, NPTX1, NRXN2) and several members of the granin family (SCG1, SCG2, SCG3, SCG5) compared to controls were discovered. Additionally, several serine protease inhibitors of the SERPIN protein family (including SERPINA3, SERPINC1 and SERPING1) were differentially expressed compared to controls. Fifteen proteins were significantly altered in both rTg-DI rats and sCAA patients, including (amongst others) SCG5 and SERPING1. These results identify specific groups of proteins likely involved in, or affected by, pathophysiological processes involved in CAA pathology such as protease and synapse function of rTg-DI rat models and sCAA patients, and may serve as candidate biomarkers for sCAA., (© 2023. The Author(s).)

Introduction: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated the changes in IPH over 2 years in patients who recently started versus those with continued antiplatelet use., Methods: In the Plaque at Risk (PARISK) study, symptomatic patients with &lt;70% ipsilateral carotid stenosis underwent carotid plaque magnetic resonance imaging (MRI) at the baseline and after 2 years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. The IPH volume change over a period of 2 years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and (1) newly developed ipsilateral or contralateral IPH and (2) IPH volume progression., Results: A total of 108 patients underwent carotid MRI at the baseline and follow-up. At the baseline, previous antiplatelet therapy was associated with any IPH (OR = 5.6, 95% CI: 1.3-23.1; p = 0.02). Ipsilateral IPH volume did not change significantly during the 2 years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2-235.9] vs. 59.3 mm3 [11.4-260.3]; p = 0.6) nor in the new antiplatelet users (n = 31) (61.5 mm3 [0.0-166.9] vs. 27.7 mm3 [9.5-106.4]; p = 0.4). Similar results of a nonsignificant change in contralateral IPH volume during those 2 years were observed in both groups (p &gt; 0.05). No significant associations were found between new antiplatelet use and newly developed IPH at 2 years (odds ratio [OR] = 1.0, 95% CI: 0.1-7.4) or the progression of IPH (ipsilateral: OR = 2.4, 95% CI: 0.3-19.1; contralateral: OR = 0.3, 95% CI: 0.01-8.5)., Conclusion: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after transient ischemic attack/stroke was not associated with the newly developed IPH or progression of IPH volume over the subsequent 2 years., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation., Methods: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133., Findings: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA 2 DS 2 -VASc score ≤4, and 163 [40%] with CHA 2 DS 2 -VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I 2 =0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I 2 =0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I 2 =0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I 2 =50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I 2 =0%)., Interpretation: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials., Funding: British Heart Foundation., Competing Interests: Declaration of interests SJC reports institutional funding from Daiichi Sankyo. CC reports funding from the French Ministry of Health, Novartis (advisory board), and Biogen, Bayer and Bristol Myers Squibb (BMS; steering committees). HK reports funding from the US National Institutes of Health (NIH) and National Institute of Neurological Disorders and Stroke (NINDS; U01NS095869, R01HL144541, R01NS123576, and U01NS106513); funding from BMS-Pfizer Alliance; funding from Roche Diagnostics; being Deputy Editor for JAMA Neurology; participation on clinical trial steering or executive committees for Medtronic, Janssen, and Javelin Medical; participation on endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. CJMK and FHBMS report institutional funding from the Dutch Heart Foundation Clinical Established Investigator grant (2012T077) for APACHE-AF. DEN reports institutional funding from BMS and provision of a PET tracer from Life Molecular Imaging. APJ reports personal consulting fees and speaker fees from AstraZeneca. RA-SS reports institutional funding from the British Heart Foundation (CS/18/2/33719) for this work, institutional funding from the UK National Institute for Health and Care Research and The Stroke Association outside the submitted work, being Data Monitoring Committee chair for ELAN (NCT03148457), and consulting fees paid to the University of Edinburgh from Recursion Pharmaceuticals, Bioxodes, and Population Health Research Institute at McMaster University (Hamilton, ON, Canada). KS reports institutional funding from NIH NINDS (U01NS106513, U24NS129500, R01MD016178, R01EB31114, U24NS107215, R01NR018335, R01NS110721), American Heart Association, Hyperfine, Biogen, and Bard, and consulting fees from Astrocyte, Zoll and Sense (Data Safety and Monitoring Board), and CSL Behring. AS reports institutional funding from Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, NIH, Bayer, Daiichi Sankyo, and Servier Canada; consulting fees from Bayer, Daiichi Sankyo, Servier Canada, AstraZeneca, and Bioxodes; speaker fees from Bayer, Daiichi Sankyo, Servier Canada, and AstraZeneca; payment for expert testimony from Canadian Medical Protective Agency, support for meetings from Bayer, and Data Monitoring Committee membership for Bayer. HBvdW reports institutional funding from Stryker, Dutch Heart Foundation, and the EU, consulting fees from Bayer and TargED, and membership of the Executive Committee of the European Stroke Organisation. RV reports institutional funding from Bayer, BMS, Pfizer, Daiichi Sankyo, Boehringer, and Medtronic; consulting fees from AstraZeneca; speaker fees from BMS-Pfizer, Data Monitoring Committee participation for Bayer and Portola; stock options in Bayer and Novartis; materials from Medtronic; and chair of the World Stroke Organisation research committee. CV reports personal support from NIH NINDS (UO1NS106513). PMW reports institutional funding from Stryker, Medtronic, and Penumbra, and Data Monitoring Committee membership for PROTECT-U, TENSION, and MR CLEAN NO IV. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The diagnosis of probable cerebral amyloid angiopathy (CAA) is currently mostly based on characteristics of brain MRI. Blood biomarkers would be a cost-effective, easily accessible diagnostic method that may complement diagnosis by MRI and aid in monitoring disease progression. We studied the diagnostic potential of plasma Aβ38, Aβ40, and Aβ42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA)., Methods: All Aβ peptides were quantified in the plasma by immunoassays in a discovery cohort (11 patients with presymptomatic D-CAA and 24 patients with symptomatic D-CAA, and 16 and 24 matched controls, respectively) and an independent validation cohort (54 patients with D-CAA, 26 presymptomatic and 28 symptomatic, and 39 and 46 matched controls, respectively). In addition, peptides were quantified in the plasma in a group of 61 patients with sCAA and 42 matched controls. We compared Aβ peptide levels between patients and controls using linear regression adjusting for age and sex., Results: In the discovery cohort, we found significantly decreased levels of all Aβ peptides in patients with presymptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.009; Aβ42: p < 0.001) and patients with symptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.01; Aβ42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aβ38, Aβ40, and Aβ42 were similar in patients with presymptomatic D-CAA and controls (Aβ38: p = 0.18; Aβ40: p = 0.28; Aβ42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aβ38 and Aβ40 were similar (Aβ38: p = 0.14; Aβ40: p = 0.38), whereas plasma Aβ42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aβ38, Aβ40, and Aβ42 levels were similar in patients with sCAA and controls (Aβ38: p = 0.092; Aβ40: p = 0.64. Aβ42: p = 0.68)., Conclusions: Plasma Aβ42 levels, but not plasma Aβ38 and Aβ40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aβ38, Aβ40, and Aβ42 levels do not appear to be applicable as a biomarker in patients with sCAA., (© 2023. The Author(s).)

Background: Previous randomised controlled trials could not demonstrate that surgical evacuation of intracerebral haemorrhage (ICH) improves functional outcome. Increasing evidence suggests that minimally invasive surgery may be beneficial, in particular when performed early after symptom onset. The aim of this study was to investigate safety and technical efficacy of early minimally invasive endoscopy-guided surgery in patients with spontaneous supratentorial ICH., Methods: The Dutch Intracerebral Haemorrhage Surgery Trial pilot study was a prospective intervention study with blinded outcome assessment in three neurosurgical centres in the Netherlands. We included adult patients with spontaneous supratentorial ICH ≥10mL and National Institute of Health Stroke Scale (NIHSS) score ≥2 for minimally invasive endoscopy-guided surgery within 8 h after symptom onset in addition to medical management. Primary safety outcome was death or increase in NIHSS ≥4 points at 24 h. Secondary safety outcomes were procedure-related serious adverse events (SAEs) within 7 days and death within 30 days. Primary technical efficacy outcome was ICH volume reduction (%) at 24 h., Results: We included 40 patients (median age 61 years; IQR 51-67; 28 men). Median baseline NIHSS was 19.5 (IQR 13.3-22.0) and median ICH volume 47.7mL (IQR 29.4-72.0). Six patients had a primary safety outcome, of whom two already deteriorated before surgery and one died within 24 h. Sixteen other SAEs were reported within 7 days in 11 patients (of whom two patients that already had a primary safety outcome), none device related. In total, four (10%) patients died within 30 days. Median ICH volume reduction at 24 h was 78% (IQR 50-89) and median postoperative ICH volume 10.5mL (IQR 5.1-23.8)., Conclusions: Minimally invasive endoscopy-guided surgery within 8 h after symptom onset for supratentorial ICH appears to be safe and can effectively reduce ICH volume. Randomised controlled trials are needed to determine whether this intervention also improves functional outcome., Trial Registration: Clinicaltrials.gov : NCT03608423, August 1st, 2018., (© 2023. The Author(s).)

Objective: Vascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD)., Methods: Aβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI)., Results: We found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aβ43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aβ peptides except Aβ43 were also decreased in sCAA compared to AD (CSF Aβ38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aβ40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aβ42: AUC = 0.79, 95% CI = 0.66-0.92)., Interpretation: A combined biomarker panel of CSF Aβ38, Aβ40, Aβ42, and Aβ43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA)., Methods: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers., Results: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined., Conclusions: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Background: Perihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood., Aims: We aimed to investigate the association between systemic blood pressure (BP) variability (BPV) and formation of PHE., Methods: From a multicenter prospective observational study, we selected patients with sICH who underwent 3T brain MRI within 21 days after sICH, and had at least 5 BP measurements available in the first week after sICH. Primary outcome was the association between coefficient of variation (CV) of systolic BP (SBP) and edema extension distance (EED) using multivariable linear regression, adjusting for age, sex, ICH volume and timing of the MRI. In addition, we investigated the associations of mean SBP, mean arterial pressure (MAP), their CVs with EED and absolute and relative PHE volume., Results: We included 92 patients (mean age 64 years; 74% men; median ICH volume 16.8 mL (IQR 6.6-36.0), median PHE volume 22.5 mL (IQR 10.2-41.4). Median time between symptom onset and MRI was 6 days (IQR 4-11), median number of BP measurements was 25 (IQR 18-30). Log-transformed CV of SBP was not associated with EED (B = 0.050, 95%-CI -0.186 to 0.286, p = 0.673). Furthermore, we found no association between mean SBP, mean and CV of MAP and EED, nor between mean SBP, mean MAP or their CVs and absolute or relative PHE., Discussion: Our results do not support a contributing role for BPV on PHE, suggesting mechanisms other than hydrostatic pressure such as inflammatory processes, may play a more important role., 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., (Copyright © 2023 Sondag, Wolsink, Jolink, Voigt, van Walderveen, Wermer, Klijn and Schreuder.)

Background: To evaluate the potential of cerebrospinal fluid (CSF) levels of matrix metalloproteinases and tissue-type inhibitors (MMP; TIMP), and ratios of MMPs to TIMPs, to function as biomarkers for sporadic or hereditary cerebral amyloid angiopathy (CAA)., Methods: CSF concentrations of the matrix metalloproteinases MMP-2, MMP-9 and MMP-14, as well as the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, were determined using immunoassays. These assays were applied to two, independent study groups of sporadic CAA (sCAA) (n = 28/43) and control subjects (n = 40/40), as well as to groups of pre-symptomatic (n = 11) and symptomatic hereditary Dutch-CAA (D-CAA) patients (n = 12), and age-matched controls (n = 22/28, respectively)., Results: In the sCAA/control cohorts, inconsistent differences were found for individual MMPs and TIMPs, but MMP-2/TIMP-2 (discovery/validation: p = 0.004; p = 0.02) and MMP-14/TIMP-2 ratios (discovery/validation: p < 0.001; p = 0.04) were consistently decreased in sCAA, compared to controls. Moreover, MMP-14 was decreased in symptomatic D-CAA (p = 0.03), compared to controls. The MMP-14/TIMP-1 (p = 0.03) and MMP-14/TIMP-2 (p = 0.04) ratios were decreased in symptomatic D-CAA compared to controls and also compared to pre-symptomatic D-CAA (p = 0.004; p = 0.005, respectively)., Conclusion: CSF MMP-2/TIMP-2 and MMP-14/TIMP-2 were consistently decreased in sCAA, compared to controls. Additionally, MMP-14/TIMP-2 levels were also decreased in symptomatic D-CAA, compared to both pre-symptomatic D-CAA and controls, and can therefore be considered a biomarker for sporadic and late-stage hereditary forms of CAA., (© 2023. The Author(s).)

Background: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown., Objective: We therefore aimed to investigate synaptic dysfunction in CAA., Methods: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls., Results: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987)., Conclusion: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Background: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making., Objectives: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging., Methods: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score., Results: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78)., Conclusions: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025)., Competing Interests: Funding Support and Disclosures This work was supported by the Dutch Heart Foundation (grant number DHF2008-T094) and was performed within the framework of the Center for Translational Molecular Medicine, project PARISK (Plaque At RISK; grant number 01C-202). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRβ levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD)., Methods: CSF PDGFRβ levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRβ both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers., Results: PDGFRβ levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRβ levels compared to (A-T-[N-]) controls (P = .006)., Conclusion: Our findings indicate that PDGFRβ levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Aims: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA)., Materials and Methods: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-β (Aβ) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA)., Results: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aβ deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aβ deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objective: Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH., Methods: We selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI., Results: We included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1-19). Median ICH volume was 17.0 mL (IQR 1.4-88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = -0.003, 95% CI -0.003-0.03, p = 0.83), nor for any of the individual radiological cSVD markers., Conclusion: We found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE., 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., (Copyright © 2022 Cliteur, Sondag, Wolsink, Rasing, Meijer, Jolink, Wermer, Klijn and Schreuder.)

The current study aimed to investigate whether diffusion-weighted imaging-positive (DWI+) lesions after acute intracerebral hemorrhage (ICH) are associated with underlying small vessel disease (SVD) or linked to the acute ICH. We included patients ≥18 years with spontaneous ICH confirmed on neuroimaging and performed 3T MRIs after a median of 11 days (interquartile range [IQR] 6-43). DWI+ lesions were assessed in relation to the hematoma (perihematomal vs. distant and ipsilateral vs. contralateral). Differences in clinical characteristics, ICH characteristics, and MRI markers of SVD between participants with or without DWI+ lesions were investigated using non-parametric tests. We observed 54 DWI+ lesions in 30 (22%) of the 138 patients (median age [IQR] 65 [55-73] years; 71% men, 59 lobar ICH) with available DWI images. We found DWI+ lesions ipsilateral (54%) and contralateral (46%) to the ICH, and 5 (9%) DWI+ lesions were located in the immediate perihematomal region. DWI+ lesion presence was associated with probable CAA diagnosis (38 vs. 15%, p = 0.01) and larger ICH volumes (37 [8-47] vs. 12 [6-24] ml, p = 0.01), but not with imaging features of SVD. Our findings suggest that DWI+ lesions after ICH are a feature of both the underlying SVD and ICH-related mechanisms., 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., (Copyright © 2022 Wiegertjes, Voigt, Jolink, Koemans, Schreuder, van Walderveen, Wermer, Meijer, Duering, de Leeuw and Klijn.)

Background: In patients with spontaneous supratentorial intracerebral hemorrhage (ICH), open craniotomy has failed to improve a functional outcome. Innovative minimally invasive neurosurgery (MIS) may improve a health outcome and reduce healthcare costs., Aims: Before starting phase-III trials, we aim to assess conditions that need to be met to reach the potential cost-effectiveness of MIS compared to usual care in patients with spontaneous supratentorial ICH., Methods: We used a state-transition model to determine at what effectiveness and cost MIS would become cost-effective compared to usual care in terms of quality-adjusted life-years (QALYs) and direct healthcare costs. Threshold and two-way sensitivity analyses were used to determine the minimal effectiveness and maximal costs of MIS, and the most cost-effective strategy for each combination of cost and effectiveness. Scenario and probabilistic sensitivity analyses addressed model uncertainty., Results: Given €10,000 of surgical costs, MIS would become cost-effective when at least 0.7-1.3% of patients improve to a modified Rankin Scale (mRS) score of 0-3 compared to usual care. When 11% of patients improve to mRS 0-3, surgical costs may be up to €83,301-€164,382, depending on the population studied. The cost-effectiveness of MIS was mainly determined by its effectiveness. In lower mRS states, MIS needs to be more effective to be cost-effective compared to higher mRS states., Conclusion: MIS has the potential to be cost-effective in patients with spontaneous supratentorial ICH, even with relatively low effectiveness. These results support phase-III trials to investigate the effectiveness of MIS., 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., (Copyright © 2022 Schreuder, Scholte, Ulehake, Sondag, Rovers, Dammers, Klijn and Grutters.)

Background: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset., Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors., Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8-3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3-6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2-19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7-60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8-55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4-63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6-37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1-95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7-6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9-4.2)., Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

Background and Purpose: Although evidence accumulates that the cerebellum is involved in cerebral amyloid angiopathy (CAA), cerebellar superficial siderosis is not considered to be a disease marker. The objective of this study is to investigate cerebellar superficial siderosis frequency and its relation to hemorrhagic magnetic resonance imaging markers in patients with sporadic and Dutch-type hereditary CAA and patients with deep perforating arteriopathy-related intracerebral hemorrhage., Methods: We recruited patients from 3 prospective 3 Tesla magnetic resonance imaging studies and scored siderosis and hemorrhages. Cerebellar siderosis was identified as hypointense linear signal loss (black) on susceptibility-weighted or T2*-weighted magnetic resonance imaging which follows at least one folia of the cerebellar cortex (including the vermis)., Results: We included 50 subjects with Dutch-type hereditary CAA, (mean age 50 years), 45 with sporadic CAA (mean age 72 years), and 43 patients with deep perforating arteriopathy-related intracerebral hemorrhage (mean age 54 years). Cerebellar superficial siderosis was present in 5 out of 50 (10% [95% CI, 2-18]) patients with Dutch-type hereditary CAA, 4/45 (9% [95% CI, 1-17]) patients with sporadic CAA, and 0 out of 43 (0% [95% CI, 0-8]) patients with deep perforating arteriopathy-related intracerebral hemorrhage. Patients with cerebellar superficial siderosis had more supratentorial lobar (median number 9 versus 2, relative risk, 2.9 [95% CI, 2.5-3.4]) and superficial cerebellar macrobleeds (median number 2 versus 0, relative risk, 20.3 [95% CI, 8.6-47.6]) compared with patients without the marker. The frequency of cortical superficial siderosis and superficial cerebellar microbleeds was comparable., Conclusions: We conclude that cerebellar superficial siderosis might be a novel marker for CAA.

Background and Purpose: Intraplaque hemorrhage contributes to lipid core enlargement and plaque progression, leading to plaque destabilization and stroke. The mechanisms that contribute to the development of intraplaque hemorrhage are not completely understood. A higher incidence of intraplaque hemorrhage and thin/ruptured fibrous cap (upstream of the maximum stenosis in patients with severe [≥70%] carotid stenosis) has been reported. We aimed to noninvasively study the distribution of intraplaque hemorrhage and a thin/ruptured fibrous cap in patients with mild-to-moderate carotid stenosis., Materials and Methods: Eighty-eight symptomatic patients with stroke (<70% carotid stenosis included in the Plaque at Risk study) demonstrated intraplaque hemorrhage on MR imaging in the carotid artery plaque ipsilateral to the side of TIA/stroke. The intraplaque hemorrhage area percentage was calculated. A thin/ruptured fibrous cap was scored by comparing pre- and postcontrast black-blood TSE images. Differences in mean intraplaque hemorrhage percentages between the proximal and distal regions were compared using a paired-samples t test. The McNemar test was used to reveal differences in proportions of a thin/ruptured fibrous cap., Results: We found significantly larger areas of intraplaque hemorrhage in the proximal part of the plaque at 2, 4, and 6 mm from the maximal luminal narrowing, respectively: 14.4% versus 9.6% ( P  = .04), 14.7% versus 5.4% ( P  < .001), and 11.1% versus 2.2% ( P  = .001). Additionally, we found an increased proximal prevalence of a thin/ruptured fibrous cap on MR imaging at 2, 4, 6, and 8 mm from the MR imaging section with the maximal luminal narrowing, respectively: 33.7% versus 18.1%, P  = .007; 36.1% versus 7.2%, P  < .001; 33.7% versus 2.4%, P  = .001; and 30.1% versus 3.6%, P  = .022., Conclusions: We demonstrated that intraplaque hemorrhage and a thin/ruptured fibrous cap are more prevalent on the proximal side of the plaque compared with the distal side in patients with mild-to-moderate carotid stenosis., (© 2022 by American Journal of Neuroradiology.)

Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer's disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: In patients with spontaneous cerebellar intracerebral hemorrhage (ICH) guidelines advocate evacuation when the hematoma diameter is > 3 cm. We studied outcome in patients with cerebellar ICH > 3 cm who did not undergo immediate hematoma evacuation., Methods: We included consecutive patients with cerebellar ICH > 3 cm at two academic hospitals between 2008 and 2017. Patients who died < 24 h (h) were excluded because of probable confounding by indication. We determined patient characteristics, hematoma volumes, EVD placement, secondary hematoma evacuation, in-hospital and 3-month case-fatality, and functional outcome., Results: Of 130 patients with cerebellar ICH, 98 (77%) had a hematoma > 3 cm of whom 22 (23%) died < 24 h and 28 (29%) underwent hematoma evacuation < 24 h. Thus, 48 patients were initially treated conservatively (mean age 70 ± 13, 24 (50%) female). Of these 48 patients, 7 (15%) underwent secondary hematoma evacuation > 24 h, of whom 1 (14%) had received an EVD < 24 h. Five others also received an EVD < 24 h without subsequent hematoma evacuation. Of the 41 patients without secondary hematoma evacuation, 11 (28%) died and 20 (51%) had a favorable outcome (mRS of 0-3) at 3 months. The 7 patients who underwent secondary hematoma evacuation had a decrease in GCS score of at least two points prior to surgery; two (29%) had deceased at 3 months; and 5 (71%) had a good functional outcome (mRS 0-3)., Conclusions: While cerebellar ICH > 3 cm is often considered an indication for immediate hematoma evacuation, there may be a subgroup of patients in whom surgery can be safely deferred. Further data are needed to assess the optimal timing and indications of surgical treatment in these patients., (© 2021. The Author(s).)