Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage.

BACKGROUND: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage, and a more hemorrhagic disease course compared to women. In this cohort study we investigated sex differences in histopathological markers associated with amyloid-ß burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. METHODS: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-ß (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo MRI-markers and local cortical iron burden, and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodelling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. RESULTS: In 6120 individuals from the NACC database (45% women, mean age 80y), the presence of parenchymal amyloid-ß (OR [95%CI]=0.68 [0.53-0.88]) but not vascular amyloid-ß was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75y), a lower microbleed count (p<0.001), but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p<0.001) compared to women. CAA percentage area was comparable in men and women (p=0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p=0.03). CONCLUSION: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodelling, may contribute, but future studies are necessary to replicate our findings in larger datasets and to further investigate the underlying mechanisms behind these complex sex differences.

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline.

Introduction: Long-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults. Methods: Using a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline. Results: Systolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022). Discussion: Long-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Minocycline in Severe Cerebral Amyloid Angiopathy: A Single-Center Cohort Study.

BACKGROUND: Evidence from animal studies suggests that minocycline may reduce lobar intracerebral hemorrhage (ICH) recurrence in cerebral amyloid angiopathy, possibly by inhibiting perivascular extracellular matrix degradation in cerebral small vessels. There is currently no evidence of its safety or efficacy in humans with cerebral amyloid angiopathy. METHODS AND RESULTS: To provide preliminary data to support future studies of minocycline's efficacy, the authors performed a retrospective single-center cohort study to assess the incidence of recurrent ICH in patients with an aggressive clinical course of probable cerebral amyloid angiopathy who had been prescribed minocycline off-label via shared decision-making. Crude incidence rate ratios were calculated to compare incidence rates before versus after treatment. Sixteen patients (mean age at minocycline initiation, 66.3±3.5 years; women 62.5%; median of 3 lobar ICHs [range, 1-6]) were initiated on minocycline and followed for a median of 12.4 months (range, 1.8-61.4 months). Adverse events were reported in 4 of 16 patients (gastroenteric, n=3; dizziness, n=1) and were considered mild. ICH incidence sharply increased the year before minocycline initiation compared with the preceding years (2.18 [95% CI, 1.50-3.07] versus 0.40 [95% CI, 0.25-0.60] events per patient-year) and fell to 0.46 (95% CI, 0.23-0.83) events per patient-year afterwards. Incidence rate ratios of recurrent ICH after minocycline was lower (0.21 [95% CI, 0.11-0.42], P<0.0001) compared with the year before initiation. CONCLUSIONS: Minocycline appeared safe and generally tolerated in a small group of patients with clinically aggressive cerebral amyloid angiopathy and was associated with reduced ICH recurrence. Determining whether this reduction represents a biological response to minocycline rather than a regression to the mean, however, will require a future controlled treatment trial.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Sensitivity and Specificity of the Boston Criteria Version 2.0 for the Diagnosis of Cerebral Amyloid Angiopathy in a Community-Based Sample.

BACKGROUND AND OBJECTIVES: The Boston criteria are a set of clinical and neuroimaging features that enable accurate diagnosis of cerebral amyloid angiopathy (CAA) without invasive methods such as brain biopsies or autopsy. The last updates to the Boston criteria, named version 2.0, were recently released and incorporated new nonhemorrhagic MRI features. These criteria have been validated in symptomatic samples, with improved diagnostic yield. We set out to investigate the accuracy of the Boston criteria v2.0 for the diagnosis of CAA in a community-based sample. METHODS: Participants were recruited from longitudinal clinical-pathologic studies of aging conducted at the Rush Alzheimer's Disease Center in Chicago: the Religious Orders Study and the Rush Memory and Aging Project. Deceased participants with in vivo 3T MRI and detailed pathologic data available were included in the analysis. We compared the diagnostic yield of the current and earlier versions of the Boston criteria in our sample. Among those classified as probable CAA according to the Boston criteria v2.0, we investigated the ability of each neuroimaging marker to distinguish between false-positive and true-positive cases. RESULTS: In total, 134 individuals were included in the study (mean age = 82.4 ± 6.0 years; 69.4% F), and 49 of them were considered pathology-proven definite cases with CAA (mean age = 82.9 ± 6.0 years; 63.3% F). The Boston criteria versions 1.0 and 1.5 yielded similar sensitivity (26.5%, both), specificity (90.6% and 89.4%, respectively), and predictive values (negative: 68.1% and 67.9%; positive: 61.9% and 59.1%, respectively). The recently released Boston criteria v2.0 offered higher sensitivity (38.8%) and slightly lower specificity (83.5%). Among those classified as probable CAA (v2.0), pathology-proven true-positive cases had higher numbers of strictly cortical lobar microbleeds compared with false-positive cases (p = 0.004). DISCUSSION: Similar to findings from symptomatic samples, the inclusion of nonhemorrhagic neuroimaging markers in the updated Boston criteria offered a 12.3% gain in sensitivity among community-dwelling individuals, at the expense of a 5.9% drop in specificity. In cases with probable CAA, the cortical location of microbleeds may represent a promising distinguishing feature between true-positive and false-positive cases. Despite its improved performance, the diagnostic sensitivity of the updated criteria in a community-based sample remains limited. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Boston criteria v2.0 accurately distinguishes people with CAA from those without CAA.

Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA. METHODS: Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers. RESULTS: One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]). DISCUSSION: These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.

Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage.

This focused update about antiplatelet agents to reduce the high risk of major adverse cardiovascular events after stroke due to spontaneous (nontraumatic) intracerebral hemorrhage (ICH) complements earlier updates about blood pressure-lowering, lipid-lowering, and oral anticoagulation or left atrial appendage occlusion for atrial fibrillation after ICH. When used for secondary prevention in people without ICH, antiplatelet agents reduce the risk of major adverse cardiovascular event (rate ratio, 0.81 [95% CI, 0.75-0.87]) and might increase the risk of ICH (rate ratio, 1.67 [95% CI, 0.97-2.90]). Before 2019, guidance for clinical decisions about antiplatelet agent use after ICH has focused on estimating patients' predicted absolute risks and severities of ischemic and hemorrhagic major adverse cardiovascular event and applying the known effects of these drugs in people without ICH to estimate whether individual ICH survivors in clinical practice might be helped or harmed by antiplatelet agents. In 2019, the main results of the RESTART (Restart or Stop Antithrombotics Randomized Trial) randomized controlled trial including 537 survivors of ICH associated with antithrombotic drug use showed, counterintuitively, that antiplatelet agents might not increase the risk of recurrent ICH compared to antiplatelet agent avoidance over 2 years of follow-up (12/268 [4%] versus 23/268 [9%]; adjusted hazard ratio, 0.51 [95% CI, 0.25-1.03]; P=0.060). Guidelines in the United States, Canada, China, and the United Kingdom and Ireland have classified the level of evidence as B and indicated that antiplatelet agents may be considered/reasonable after ICH associated with antithrombotic agent use. Three subsequent clinical trials have recruited another 174 participants with ICH, but they will not be sufficient to determine the effects of antiplatelet therapy on all major adverse cardiovascular events reliably when pooled with RESTART. Therefore, ASPIRING (Antiplatelet Secondary Prevention International Randomized Study After Intracerebral Hemorrhage) aims to recruit 4148 ICH survivors to determine the effects of antiplatelet agents after ICH definitively overall and in subgroups.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures: The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results: Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance: The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Association Between Hematoma Expansion Severity and Outcome and Its Interaction With Baseline Intracerebral Hemorrhage Volume.

BACKGROUND AND OBJECTIVES: Hematoma expansion (HE) is a major determinant of neurologic deterioration and poor outcome in intracerebral hemorrhage (ICH) and represents an appealing therapeutic target. We analyzed the prognostic effect of different degrees of HE. METHODS: This was a retrospective analysis of patients with ICH admitted at 8 academic institutions in Italy, Germany, Canada, China, and the United States. All patients underwent baseline and follow-up imaging for HE assessment. Relative HE (rHE) was classified as follows: none (<0%), mild (0%-33%), moderate (33.1%-66%), and severe (>66%). Absolute HE (aHE) was classified as none (<0 mL), mild (0-6.0 mL), moderate (6.1-12.5 mL), and severe (>12.5 mL). Predictors of poor functional outcome (90 days modified Rankin Scale 4-6) were explored with logistic regression. RESULTS: We included 2,163 patients, of whom 1,211 (56.0%) had poor outcome. The occurrence of severe aHE or rHE was more common in patients with unfavorable outcome (13.9% vs 6.5%, p < 0.001 and 18.3% vs 7.2%, p < 0.001 respectively). This association was confirmed in logistic regression (rHE odds ratio [OR] 1.98, 95% CI 1.38-2.82, p < 0.001; aHE OR 1.73, 95% CI 1.23-2.45, p = 0.002) while there was no association between mild or moderate HE and poor outcome. The association between severe HE and poor outcome was significant only in patients with baseline ICH volume below 30 mL. DISCUSSION: The strongest association between HE and outcome was observed in patients with smaller initial volume experiencing severe HE. These findings may inform clinical trial design and guide clinicians in selecting patients for antiexpansion therapies.

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

OBJECTIVE: A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid ß 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy.

BACKGROUND: Cortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury. METHODS: Accordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls' Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells. RESULTS: We observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits. CONCLUSION: Iron deposition resulting from cSS is associated with local reactive astrogliosis.

Left ventricular hypertrophy and left atrial size are associated with ischemic strokes among non-vitamin K antagonist oral anticoagulant users.

BACKGROUND: Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation. METHODS: From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up. RESULTS: 112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02-94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39-3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11-6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01-1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16-0.92]). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI [1.35-18.42]) after adjustment for age and chronic renal failure. CONCLUSIONS: Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.

Mechanistic Implications of Cortical Superficial Siderosis in Patients With Mixed Location Intracerebral Hemorrhage and Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA. METHODS: Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces [CSO-EPVS], and multispot white matter hyperintensity [WMH] pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS[+]) and without cSS (mixed ICH/cSS[-]) in univariate and multivariable models. RESULTS: Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%, p = 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%, p < 0.01) and severe CSO-EPVS (33% vs 11%, p < 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio [aOR] 1.04 per year, 95% CI 1.00-1.07, p = 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89, p = 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94, p = 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13, p < 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38, p < 0.01) compared with that in patients with mixed ICH/cSS(-). DISCUSSION: The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology.