Lobar Cerebral Microbleeds Research Articles

Causal effect of cerebral small vessel disease on unexplained dizziness: A Mendelian randomization study

BackgroundPrevious cohort studies have suggested an association between cerebral small vessel disease (cSVD) and “unexplained dizziness”. The causality of this link remains uncertain, but it would be of significant clinical importance, considering the substantial number of patients presenting with unexplained dizziness is large. We aimed to investigate the causal effect of cSVD-related phenotypes on unexplained dizziness using a Mendelian randomization approach. MethodsGenetic instruments for each cSVD-related phenotype - white matter hyperintensity (WMH) volume, lacunar stroke (LS), perivascular spaces (PVS), and cerebral microbleeds (CMBs) - as well as unexplained dizziness were identified through large-scale genome-wide association studies. We conducted 2-sample Mendelian randomization analyses. The random-effects inverse-variance weighted (IVW) method was chosen for the primary analysis. For sensitivity analyses, we employed the weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. ResultsWe successfully identified a significant causal effect of WMH volume on unexplained dizziness (odds ratio [95% CI], 1.12 [1.01–1.23]). However, we were unable to detect any significant causal effects of the other cSVD-related phenotypes on unexplained dizziness, with odds ratios [95% CI] of 1.03 [0.98–1.09] for LS, 0.75 [0.55–1.02] for white matter PVS, 1.02 [0.68–1.52] for basal ganglia PVS, 0.80 [0.43–1.51] for hippocampal PVS, 0.95 [0.90–1.00] for lobar CMBs, and 0.97 [0.92–1.01] for mixed CMBs respectively. The results from the sensitivity analyses were generally consistent with those of the primary analyses. ConclusionsThis MR study supports a causal relationship between WMH, a phenotype associated with cSVD, and the risk of unexplained dizziness, but does not support such a relationship between other cSVD-related phenotypes and unexplained dizziness. These findings require further validation through randomized controlled trials, larger cohort studies, and MR studies based on more extensive GWASs.

The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA.MethodsTwenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings.ResultsrhApoJ-treated APP23 presented fewer cortical CMBs (50–300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036).ConclusionsChronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Intracranial Drain-Related Intracerebral Hemorrhage in Two Sporadic Cerebral Amyloid Angiopathy Patients.

Alzheimer's disease and cerebral amyloid angiopathy (CAA) are often associated. Amyloid accumulation within leptomeningeal and small/median-sized cerebral blood vessels in CAA results in vessel fragility, leading to spontaneous leptomeningeal bleeding, lobar intracerebral hemorrhage (ICH) and cerebral microbleeds. CAA is also associated with non-traumatic subdural hematoma. The role of CAA-related vessel fragility in hemorrhagic complications after trauma, brain surgery, and intracranial drain insertion in CAA is unknown. We present two sporadic CAA patients with intracranial drain-related ICH, probably due to different underlying mechanisms, related to indirect and direct CAA-associated vessel fragility.

Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage.

There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

A Bidirectional Mendelian Randomization Study of Gut Microbiota and Cerebral Small Vessel Disease

BackgroundThe causal nature of gut microbiota and cerebral small vessel disease (CSVD) is still obscure regardless of evidence supporting their observational correlations. ObjectivesThe primary objective of this research is to investigate the potentially pathogenic or protective causal impacts of specific gut microbiota on various neuroimaging subtypes of CSVD. MethodsWe obtained the latest summary-level genome-wide databases for gut microbiota and 9 CSVD traits. The univariable and multivariable Mendelian randomization (MR) studies were conducted to examine the possible causal link between exposure and outcome. Meanwhile, we conducted sensitivity analyses sequentially, containing the heterogeneity, pleiotropy, and leave-one-out analysis. Additionally, to clarify the potential bidirectional causality, the causality from CSVD traits to the identified gut microbiota was implemented through reverse MR analysis. ResultsThe univariable MR analysis identified 22 genetically predicted bacterial abundances that were correlated with CSVD traits. Although conditioning on macronutrient dietary compositions, 2 suggestive relationships were retained using the multivariable MR analysis. Specifically, the class Negativicutes and order Selenomonadales exhibited a negative causal association with strictly lobar cerebral microbleeds, one neuroimaging trait of CSVD. There is insufficient evidence indicating the presence of heterogeneity and horizontal pleiotropy. Furthermore, the identified causal relationship was not driven by any single nucleotide polymorphism. The results of the reverse MR analysis did not reveal any statistically significant causality from CSVD traits to the identified gut microbiota. ConclusionsOur study indicated several suggestive causal effects from gut microbiota to different neuroimaging subtypes of CSVD. These findings provided a latent understanding of the pathogenesis of CSVD from the perspective of the gut-brain axis.

Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study

BackgroundStrictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. MethodsEighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. ResultsNine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). ConclusionsOur results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Prevalence of small vessel disease and incidental DWI-positive lesions in patients with aneurysmal subarachnoid hemorrhage versus intracerebral hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) and intracerebral hemorrhage (ICH) are main forms of hemorrhagic stroke. Data regarding cerebral small vessel disease (SVD) burden and incidental small lesions on diffusion-weighted imaging (DWI) following aSAH are sparse. We retrospectively analyzed a prospective cohort of aSAH and ICH patients with brain MRI within 30 days after onset from March 2015 to January 2023. White matter hyperintensity (WMH), lacune, perivascular space, cerebral microbleed (CMB), total SVD score, and incidental DWI lesions were assessed and compared between aSAH and ICH. Clinical and radiological characteristics associated with small DWI lesions in aSAH were investigated. We included 180 patients with aSAH (median age [IQR] 53 [47-61] years) and 299 with ICH (63 [53-73] years). DWI lesions were more common in aSAH than ICH (47.8% vs 14.4%, p < 0.001). Higher total SVD score was associated with ICH versus aSAH irrespective of hematoma location, whereas DWI lesions and strictly lobar CMBs were correlated with aSAH. Multivariable analysis showed that shorter time from onset to MRI, anterior circulation aneurysm rupture, CMB ⩾ 5, and total SVD score were associated with DWI lesions in aSAH. Incidental DWI lesions and strictly lobar CMBs were more frequent in aSAH versus ICH whereas ICH had higher SVD burden. Incidental DWI lesions in aSAH were associated with multiple clinical and imaging factors. Longitudinal studies to investigate the dynamic change and prognostic value of the covert hemorrhagic and ischemic lesions in aSAH seem justified.

Differences in lobar microbleed topography in cerebral amyloid angiopathy and hypertensive arteriopathy

Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9–191.4], P = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8–68.1], P = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05–1.52] vs. 1.08 [1.02–1.19], P = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds (P < 0.001) and negatively correlated with the number of subcortical lobar microbleeds (P = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease.

Abstract WP170: Patients With Cerebral Microbleeds Are More Likely to Have Poor Collaterals at the Time of Mechanical Thrombectomy

Introduction: Collateral cerebrovasculature is important for the survival of penumbral tissue in patients with large vessel occlusive (LVO) stroke, and adequate collateralization is associated with favorable outcomes. The presence of cerebral microbleeds (CMB) have been implicated in vessel wall remodeling and impaired vasoreactivity. We investigated whether the presence of deep and/or lobar CMB predicts poor collateral recruitment in patients with LVO stroke who underwent thrombectomy (MT). Methods: We performed a retrospective, single-center study of adults who presented with LVO stroke and had MT between January 2012-June 2020. CT angiography of head prior to MT was used to assess collateral status with poor status defined as ≤50% filling and good status as &gt;50% filling. CMBs were assessed using T2*-weighted gradient echo or susceptibility weighted magnetic resonance images. Location of CMB was further characterized as deep vs. lobar using consensus definitions. Poor stroke outcome was defined as modified Rankin Scale (mRS) ≥3 at 90 days. Multivariable logistic regressions were performed to evaluate the associations between CMB, CMB types (lobar, deep, lobar+deep) and poor collaterals after adjusting for vascular risk factors. Results: Consecutive 151 subjects were included (mean age 68±15 years, 47% women), with a median NIHSS of 18. CMB were identified in 57 subjects (37.4%). Of these, 20.5% had lobar CMB, 5.3% had deep CMB and 11.9% had combined lobar &amp; deep CMB. Patients with CMB had higher odds of having poor collaterals compared to those without CMB (OR 1.56, 95% CI 1.09-2.23, P=0.015). The association of CMB with poor collaterals was strongest in patients with combined lobar &amp; deep CMB (OR 4.78, 95% CI 1.43-15.93, P=0.011), compared with those with exclusively deep CMB (OR 2.78, 95% CI 0.44-17.62, P=0.278) or lobar CMB (OR 0.52, 95% CI 0.19-1.38, P=0.188). Patients with poor collaterals were more likely to have poor outcome compared with those with good collaterals (48.4% vs. 31.0%, P=0.03). Conclusion: Cerebral microbleeds are independently associated with poor collateral recruitment when adjusted for traditional vascular risk factors. Further study is warranted to elucidate the differential effects of CMB types on collateral recruitment.

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Diagnostic Performance Using a Combination of MRI Findings for Evaluating Cognitive Decline.

We investigated potentially promising imaging findings and their combinations in the evaluation of cognitive decline. This retrospective study included 138 patients with subjective cognitive impairments, who underwent brain MRI. We classified the same group of patients into Alzheimer's disease (AD) and non-AD groups, based on the neuropsychiatric evaluation. We analyzed imaging findings, including white matter hyperintensity (WMH) and cerebral microbleeds (CMBs), using the Kruskal-Wallis test for group comparison, and receiver operating characteristic (ROC) curve analysis for assessing the diagnostic performance of imaging findings. CMBs in the lobar or deep locations demonstrated higher prevalence in the patients with AD compared to those in the non-AD group. The presence of lobar CMBs combined with periventricular WMH (area under the ROC curve [AUC] = 0.702 [95% confidence interval: 0.599-0.806], p < 0.001) showed the highest performance in differentiation of AD from non-AD group. Combinations of imaging findings can serve as useful additive diagnostic tools in the assessment of cognitive decline.

Review Of Cerebral Microbleeds using FAZEKA Classification

Introduction: Cerebral microbleeds (CMBs), also known as cerebral microhemorrhages, are tiny hypointense foci discovered by susceptibility-weighted (SW) magnetic resonance imaging (MR). CMBs have been interpreted as asymptomatic lesions that may be identified by chance during a brain MRI. This study was done to understand the etiology and various imaging patterns of the cerebral microbleeds on MRI Materials &amp; Methods: This study was done with a sample size of 325 patients who underwent MRI Brain and diagnosed with CMB at our hospital. Detailed supportive history was taken and data was analysed. Results: Present study shows strong correlation between CMB’s and white matter changes. CMBs in parietal lobe found to have correlation with cognitive dysfunction. Lacunar infract is the most common subtype associated with the CMB’s Conclusion: The markers of microangiopathy on MRI brain are CMBs and white matter changes. Correlation of lobar CMBs with periventricular white matter hyperintensities and deep, infratentorial CMBs with deep white matter hyperintensities were found.

Cerebral amyloid angiopathy frequency at baseline and after 4 years of follow‐up in the INSIGHT‐preAD study

AbstractBackgroundCerebral amyloid angiopathy (CAA) diagnostic is of special interest due to its association with cognitive impairment, Alzheimer disease (AD) and Amyloid‐Related Imaging Abnormalities (ARIA) in trials with anti‐amyloid immunotherapies. We aimed to assess the frequency of CAA diagnosis and associated lesions in subjects with cognitive complaint and normal cognition enrolled in the INSIGHT‐preAD study.MethodCognitively normal elderly with memory complaint included in the INSIGHT‐preAD study were assessed with multimodal explorations for 5 years follow‐up. 3T MRI‐scans were performed at baseline and during follow‐up at 2 and 4 years. Lobar cerebral microbleeds (CMB), cortical superficial siderosis (CSS), enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated according to validated scales and guidelines. Boston criteria V2.0 were applied to diagnose possible and probable CAA.ResultAmong the 318 subjects (median [Q1, Q3] age: 76.4 [74.1, 78.5] years, 201 (63.2%) women) enrolled at baseline, 41 (12.9%) had at least one lobar CMB, 4 (1.3%) CSS, 68 (21.7%) severe EPVS in the centrum semi‐ovale and 245 (77%) WMH with a spot pattern ≥10. The median FAZEKAS score was 2.0 [1.0, 2.0]. At baseline, 251 (78.9%) subjects had CAA: 218 (68.5%) possible CAA and 33 (10.4%) probable CAA with a median number of CMB of 1.0 [1.0, 1.0]. Compared to non‐CAA subjects (n = 67), those with probable CAA at baseline were not different on demographics and vascular risk factor, had more executive dysfunction, and tended to be associated with Apoe4 status and lower hippocampal volume. After 2‐ and 4‐ years of follow‐up, 81.2% and 81.3% of the subjects still in the study had CAA, with 13.3% and 14.1% of probable CAA respectively, and the number of subjects with CMB increased to 15.9% and 18.3%.ConclusionIn the INSIGHT‐preAD study, the high frequence of CAA, with minimal change after 4 years follow‐up, was essentially due to the non‐hemorrhagic lesions. The hemorrhagic lesions (CMB and CSS) were uncommon, probably underestimated by the MRI T2* sequence. These results have implications in clinical setting and could be useful in pre‐symptomatic AD anti‐amyloid immunotherapy trial.

Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort

AbstractBackgroundThe role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.MethodWe included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.ResultHigher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p&lt;0.001) and higher P‐tau181 (ß = 0.21; p&lt;0.001). Aß1‐42 was negatively associated with all CSVD markers (all p&lt;0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction&lt;0.005) scores, and higher regional WMH (all p‐interactions&lt;0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p&lt;0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p&lt;0.001) and HCV (ß = 0.06; p&lt;0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p&lt;0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p &lt; 0.05) and HCV (indirect effect: ß = ‐0.24; p &lt; 0.05) through Aß1‐42 was observed.ConclusionExpression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.

Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort

AbstractBackgroundThe role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.MethodWe included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aβ1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aβ1‐42 and p‐Tau181, including an interaction between CSVD indices and Aβ1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.ResultHigher FRS scores were associated with lower CSF Aβ1‐42 (β = ‐0.18; p&lt;0.001) and higher P‐tau181 (β = 0.21; p&lt;0.001). Aβ1‐42 was negatively associated with all CSVD markers (all p&lt;0.001; Figure‐2).We found stronger association between Aβ1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction&lt;0.005) scores, and higher regional WMH (all p‐interactions&lt;0.005) volumes.Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aβ1‐42 (indirect effect: β = ‐0.03; p&lt;0.001). Aβ1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aβ1‐42 on P‐tau181 levels (β = ‐0.14; p&lt;0.001) and HCV (β = 0.06; p&lt;0.05), and of P‐tau181 levels onto HCV (β = ‐0.05; p&lt;0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: β = 0.36; p &lt; 0.05) and HCV (indirect effect: β = ‐0.24; p &lt; 0.05) through Aβ1‐42 was observed.ConclusionExpression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.

Etiology of Primary Cerebellar Intracerebral Hemorrhage Based on Topographic Localization.

Cerebellar intracerebral hemorrhage (cICH) is often attributed to hypertension or cerebral amyloid angiopathy (CAA). However, deciphering the exact etiology can be challenging. A recent study reported a topographical etiologic relationship with superficial cICH secondary to CAA. We aimed to reexamine this relationship between topography and etiology in a separate cohort of patients and using the most recent Boston criteria version 2.0. We performed a retrospective analysis of consecutive patients with primary cICH admitted to a tertiary academic center between 2000 and 2022. cICH location on brain computed tomography/magnetic resonance imaging scan(s) was divided into strictly superficial (cortex, surrounding white matter, vermis) versus deep (cerebellar nuclei, deep white matter, peduncular region) or mixed (both regions). Magnetic resonance imaging was rated for markers of cerebral small vessel disease. We assigned possible/probable versus absent CAA using Boston criteria 2.0. We included 197 patients; 106 (53.8%) were females, median age was 74 (63-82) years. Fifty-six (28%) patients had superficial cICH and 141 (72%) deep/mixed cICH. Magnetic resonance imaging was available for 112 (57%) patients (30 [26.8%] with superficial and 82 [73.2%] with deep/mixed cICH). Patients with superficial cICH were more likely to have possible/probable CAA (48.3% versus 8.6%; odds ratio [OR], 11.43 [95% CI, 3.26-40.05]; P<0.001), strictly lobar cerebral microbleeds (51.7% versus 6.2%; OR, 14.18 [95% CI, 3.98-50.50]; P<0.001), and cortical superficial siderosis (13.8% versus 1.2%; OR, 7.70 [95% CI, 0.73-80.49]; P=0.08). Patients with deep/mixed cICH were more likely to have deep/mixed cerebral microbleeds (59.2% versus 3.4%; OR, 41.39 [95% CI, 5.01-341.68]; P=0.001), lacunes (54.9% versus 17.2%; OR, 6.14 [95% CI, 1.89-19.91]; P=0.002), severe basal ganglia enlarged perivascular spaces (36.6% versus 7.1%; OR, 7.63 [95% CI, 1.58-36.73]; P=0.01), hypertension (84.4% versus 62.5%; OR, 3.43 [95% CI, 1.61 to -7.30]; P=0.001), and higher admission systolic blood pressure (172 [146-200] versus 146 [124-158] mm Hg, P<0.001). Our results suggest that superficial cICH is strongly associated with CAA whereas deep/mixed cICH is strongly associated with hypertensive arteriopathy.

The association between hypertensive angiopathy and cerebral amyloid angiopathy in primary intracerebral hemorrhage

ObjectiveTo determine the association between the burden of cerebral small vessel disease (CSVD) due to hypertensive angiopathy (HA) and cerebral amyloid angiopathy (CAA) on MRI in patients with primary intracerebral hemorrhage (ICH).MethodsPatients with primary ICH admitted to our center from March 2012 to November 2021 were consecutively enrolled. We used multivariate binary and ordinal regression analyses to assess the association between HA-CSVD burden and CAA-CSVD burden. Lobar cerebral microbleeds (CMBs) were categorized into three level of severity: 0–1, 2–4, and ≥ 5 lobar CMBs. A high CAA-CSVD score was defined as a CAA-CSVD score of ≥3.ResultsOverall, 222 participants (mean age 59.88 ± 13.56) were included into analysis. Age and ICH etiology differed among different lobar CMB severity and between the presence and absence of high CAA-CSVD score (all p &amp;lt; 0.05). Positive associations between HA-related markers and both lobar CMB severity and high CAA-CSVD score (p &amp;lt; 0.05 for the presence of lacune, deep CMBs ≥5, the presence of WMH, and HA-CSVD score) were observed in univariate analysis. These associations remained significant after adjusting for age, sex, ICH etiology, and potential vascular risk factors. The distribution of CAA-CSVD score was significantly different between patients with and without CMBs ≥5 (adjusted OR 2.351, 95% CI 1.242–4.455, p = 0.009) after correcting for age, sex, ICH etiology, and vascular risk factors.ConclusionOur study provides evidence of an association between HA-CSVD and CAA-CSVD in patients with primary ICH, which needs to be verified in future studies.

Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds.

The angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been studied as a genetic candidate for cerebral small vessel disease (CSVD). However, no previous study has evaluated the relationship between the ACE I/D polymorphism and cerebral microbleed (CMB), an important CSVD marker. We evaluated the association between ACE I/D polymorphisms and 2-year changes in CMBs. The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Of 256 subjects, 186 participants who underwent a 2-year follow-up brain scan and ACE genotyping were included. Our analysis was conducted by dividing the ACE genotype into two groups (DD vs. ID/II) under the assumption of the recessive effects of the D allele. A linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between the DD and combined ID/II genotypes. Among 186 patients included in this study, 24 (12.9%) had the DD genotype, 91 (48.9%) had the ID genotype, and 71 (38.2%) had the II genotype. Baseline clinical characteristics and cerebral small vessel disease markers were not different between the two groups (DD vs. ID/II) except for the prevalence of hypertension (DD 66.7% vs. ID/II 84.6%; p = 0.04). A multivariate linear mixed-effects model showed that the DD carriers had a greater increase in total CMB counts than the ID/II carriers after adjusting for the baseline number of CMBs, age, sex, and hypertension (estimated mean of difference [standard error (SE)] = 1.33 [0.61]; p = 0.03). When we performed an analysis of cases divided into deep and lobar CMBs, only lobar CMBs were significantly different between the two groups (estimated mean of difference [SE] = 0.94 [0.42]; p = 0.02). The progression of CMBs over 2 years was greater in the ACE DD carriers compared with the combined II/ID carriers. The results of our study indicate a possible association between the ACE I/D polymorphism and CMB. A study with a larger sample size is needed to confirm this association.

Correlation between lipid-lowering therapy and cerebral microbleeds.

To investigate if there is a correlation between lipid-lowering treatment with statins and the occurrence, number, and location of cerebral microbleeds (CMBs) among patients with ischemic cerebrovascular disease (ICVD), and also to compare treatment with atorvastatin and rosuvastatin in terms of the occurrence of CMBs and their differences. In this retrospective study, we included patients who were diagnosed with ICVD and underwent susceptibility weighted imaging (SWI) in a grade A tertiary hospital from October 1, 2014 to October 1, 2022. We collected information on previous statin use, past medical history, clinical test indicators, and imaging data. We found that out of 522 patients, 310 patients (59.4%) had no CMB and 212 patients (40.6%) had CMBs. There was no statistically significant correlation between prior statin use, the occurrence, and number of CMBs in patients diagnosed with ICVD (P < 0.05). As for the location of CMB, there was a statistically significant correlation between prior statin use and lobar CMBs (P < 0.048). However, there was no statistically significant correlation between the use of atorvastatin and rosuvastatin and the occurrence of CMBs (P > 0.05). There was no independent correlation between previous statin use, and the occurrence, and number of CMBs in patients with ICVD. As for CMBs in different locations, there was a correlation between previous use of statin and lobar CMBs. There was no significant difference between atorvastatin and rosuvastatin in the occurrence of CMBs in patients with ICVD.

Histopathological Correlates of Lobar Microbleeds in False-Positive Cerebral Amyloid Angiopathy Cases.

A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false-positive CAA cases. In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified. Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false-positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon. These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856-870.