Symptomatic Cerebral Amyloid Angiopathy Research Articles

Diagnostic Value of the Boston criteria v2.0 for Cerebral Amyloid Angiopathy in Individuals Without Hemorrhage: An MRI-neuropathological Validation Study (S15.009)

Diagnostic Value of the Boston criteria v2.0 for Cerebral Amyloid Angiopathy in Individuals Without Hemorrhage: An MRI-neuropathological Validation Study (S15.009)

A comprehensive framework for cerebral amyloid angiopathy diagnosis: Diagnostic accuracy meta-analyses of different biomarkers (S36.008)

<h3>Objective:</h3> We synthesized evidence on the accuracy of different diagnostic approaches for cerebral amyloid angiopathy (CAA), including the clinical-MRI based Boston criteria, amyloid-PET and core CSF biomarkers. <h3>Background:</h3> An accurate non-invasive diagnosis of CAA, an age-related small vessel disease, characterised by progressive deposition of amyloid β in the cerebrovascular wall, is important for clinical decision-making, as well as research in the field. Yet, the diagnostic accuracy and validity of key MRI markers and molecular markers of the disease remain (paradoxically) poorly studied. <h3>Design/Methods:</h3> In a systematic literature search, we identified case-control studies with data relevant for sensitivity/specificity of the Boston criteria, amyloid PET positivity and core CSF biomarkers in symptomatic CAA patients vs. different comparison groups, as applicable. Using a hierarchical (multilevel) logistic regression model we calculated pooled diagnostic test accuracy. <h3>Results:</h3> Five studies had data on the Boston criteria v.1.5 (n=123): the pooled sensitivity and specificity for probable CAA diagnosis was 73.1% (95% CI, 45%–90.1%) and 86% (95% CI, 41.4%–98.1%), respectively. Thirteen amyloid-PET studies (211 CAA, 181 controls) were included in the meta-analysis. The overall pooled sensitivity of amyloid-PET for CAA diagnosis was 80% (95%CI: 67%–84%) and specificity was 82% (95%CI: 71%–86%). Seven studies (153 CAA, 185 Alzheimer’s disease patients), provided data on core CSF biomarkers (Aβ40, Aβ42, t-tau, and p-tau). Aβ40 demonstrated the best overall performance for CAA diagnosis vs Alzheimer’s disease with 80% (95%CI: 68%–83%) pooled sensitivity and 68% (95%CI: 59%–74%) specificity. The core CSF pattern characteristic of CAA was low Aβ40, with intermediate t-tau/p-tau levels (higher than healthy controls, but lower than Alzheimer’s disease) (p &lt; 0.0001 for all comparisons). <h3>Conclusions:</h3> Amyloid-PET and specific CSF patterns of Aβ40, t-tau, and p-tau have moderate-to-good diagnostic accuracy for CAA diagnosis and might supplement the Boston criteria in certain clinical settings (such an approach will be presented at the meeting). <b>Disclosure:</b> Dr. Charidimou has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Imperative Care. Dr. Charidimou has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier, Journal of Neurological Sciences. Gregoire Boulouis has nothing to disclose.

Abstract 40: Gut Dysbiosis Exacerbates Neuroinflammation By Activation Of B Cells In A Mouse Model Of Cerebral Amyloid Angiopathy

Introduction: Cerebral amyloid angiopathy (CAA) is a debilitating disease that leads to intracerebral hemorrhage, white matter disease, and progressive cognitive decline in patients &gt;50 years of age. Studies investigating the neuroimmune landscape in CAA are sparse. Here, we investigate the role of B cells in CAA. Methods: Pre-symptomatic (2 months) and symptomatic (10-13 months) male Tg-SwDI mice (CAA mice) harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein (APP) were used as a mouse model of CAA. Single cells isolated from the brain were analyzed using flow cytometry to characterize neuroinflammation and cognitive impairment was assessed using fear conditioning. Fecal microbiota transplantation (FMT) of the microbiome from pre-symptomatic and symptomatic CAA mice into young wild-type (WT) recipient male mice (2 months) was performed to determine if CAA-induced gut dysbiosis contributes to brain B cell activation. Results: Cognitive assessment using fear conditioning indicated a significantly lower delta inactive state in symptomatic CAA mice (n=4/grp, * P &lt;0.05) compared to pre-symptomatic CAA mice. Symptomatic CAA mice had a significantly lower relative frequency of microglia (CD45 int CD11b + , n=11-13/grp, ** P &lt;0.01) and significant infiltration of lymphoid (CD45 high CD11b - , n=11-13/grp, *** P &lt;0.001) cells in the brain, as compared to pre-symptomatic CAA mice. Symptomatic CAA mice had significantly higher B cells in the brain (n=10-13/grp, * P &lt;0.05. Further, activated B cells as assessed by the expression level of CD11b showed that CD11b + B cells were significantly higher in the symptomatic CAA brain (n=10-13/grp, * P &lt;0.05). Interestingly, this phenotype was recapitulated in young WT recipients reconstituted with pre-symptomatic CAA and CAA microbiome through FMT. Young WT recipients with CAA biome had significantly higher relative frequency of CD11b + B cells in the brain compared to young recipients with pre-CAA biome (n=7-9/grp, *** P &lt;0.001). Conclusions: These results suggest that the aberrant activation of B cells in the brain may be influenced by CAA-induced gut dysbiosis. Further investigations upon the functional role of CD11b + B cells in the vascular deposition of Aβ are warranted.

Abstract 161: Aberrant B Cell Responses Promote Neuroinflammation In Mice With Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a small vessel disease, characterized by amyloid beta deposition in the cerebral vasculature. CAA increases the incidence of hemorrhagic stroke and dementia in the elderly. Evidence has revealed that aging alone induces disruption in B cell differentiation and immunosenescence by promoting the presence of age-associated B cells (ABCs) characterized by an upregulation of CD11b high . However, little is known on how these ABCs influence the neuroimmune landscape of vascular dementia, an immune-mediated age-associated disease. Hypothesis: CAA induces the differentiation of B cells in the brain resulting in neuroinflammation characterized by an exacerbated presence of microglia and lymphocytic infiltration. Pre-symptomatic (2mo) and symptomatic (18mo) Tg-SwDI (harboring Swedish, Dutch, and Iowa) mutations of human amyloid precursor protein male mice were used as a model of CAA. Through flow cytometry, we investigated the role of CD11b high B cells in promoting neuroinflammation in CAA. Age-matched C57BL/6 wild-type (WT) male mice were included to determine CAA-specific effects. Results: A remarkably heterogeneous CD19 + B cell population was identified in symptomatic CAA mice. Interestingly, CD19 + CD11b high B cells were significantly increased in the symptomatic CAA brain (n=4-6/gp, P =&lt;0.0001) as compared to pre-symptomatic and age-matched WT mice. Protein expression of CD73, CD80, and CD138 was assessed to determine memory formation, antibody production, and inflammatory properties of these CD19 + CD11b high B cells. Notably, CD19 + CD11b high B cells from CAA symptomatic mice had significantly lower expression of CD73 (n=4-6/gp, P =0.0004), CD80 (n=4-6/gp, P =0.0007), and CD138 (n=4-6/gp, P =0.0154) compared with those CD19 + CD11b high B cells from age-matched WT brain. Finally, CAA mice had significantly higher microglial counts (n=4-6/gp, P =0.0013) and lymphocytic infiltration (n=4-6/gp, P =0.0071) in the brain as compared to pre-symptomatic and WT aged mice. Here, we highlight the diversity of B cells in age-associated vascular dementia. Our data give us further perception into the influence of humoral immunity mediated by ABCs and their immune crosstalk in CAA.

Cerebral amyloid angiopathy is associated with decreased functional brain connectivity

Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhage and neurological decline in the elderly. CAA results in focal brain lesions, but the influence on global brain functioning needs further investigation. Here we study functional brain connectivity in patients with Dutch type hereditary CAA using resting state functional MRI. Twenty-four DNA-proven Dutch CAA mutation carriers (11 presymptomatic, 13 symptomatic) and 29 age-matched control subjects were included. Using a set of standardized networks covering the entire cortex, we assessed both within- and between-network functional connectivity. We investigated group differences using general linear models corrected for age, sex and gray matter volume. First, all mutation carriers were contrasted against control subjects and subsequently presymptomatic- and symptomatic mutation carriers against control subjects separately, to assess in which stage of the disease differences could be found. All mutation carriers grouped together showed decreased connectivity in the medial and lateral visual networks, default mode network, executive control and bilateral frontoparietal networks. Symptomatic carriers showed diminished connectivity in all but one network, and between the left and right frontoparietal networks. Presymptomatic carriers also showed diminished connectivity, but only in the frontoparietal left network. In conclusion, global brain functioning is diminished in patients with CAA, predominantly in symptomatic CAA and can therefore be considered to be a late consequence of the disease.

Cortical superficial siderosis progression in cerebral amyloid angiopathy: Prospective MRI study.

To investigate the prevalence, predictors, and clinical relevance of cortical superficial siderosis (cSS) progression in cerebral amyloid angiopathy (CAA). Consecutive patients with symptomatic CAA meeting Boston criteria in a prospective cohort underwent baseline and follow-up MRI within 1 year. cSS progression was evaluated on an ordinal scale and categorized into mild (score 1-2 = cSS extension within an already present cSS focus or appearance of 1 new cSS focus) and severe progression (score 3-4 = appearance of ≥2 new cSS foci). Binominal and ordinal multivariable logistic regression were used to determine cSS progression predictors. We investigated future lobar intracerebral hemorrhage (ICH) risk in survival analysis models. We included 79 patients with CAA (mean age, 69.2 years), 56 (71%) with lobar ICH at baseline. cSS progression was detected in 23 (29%) patients: 15 (19%) patients had mild and 8 (10%) severe progression. In binominal multivariable logistic regression, ICH presence (odds ratio [OR], 7.54; 95% confidence interval [CI], 1.75-53.52; p = 0.016) and baseline cSS (OR, 10.41; 95% CI, 2.84-52.83; p = 0.001) were independent predictors of cSS progression. In similar models, presence of disseminated (but not focal) cSS at baseline (OR, 5.58; 95% CI, 1.81-19.41; p = 0.004) was an independent predictor of cSS progression. Results were similar in ordinal multivariable logistic regression models. In multivariable Cox regression analysis, severe cSS progression was independently associated with increased future ICH risk (HR, 5.90; 95% CI, 1.30-26.68; p = 0.021). cSS evolution on MRI is common in patients with symptomatic CAA and might be a potential biomarker for assessing disease severity and future ICH risk. External validation of these findings is warranted.

Abstract WP144: Cerebral Amyloid Angiopathy Pathology Worsens Stroke Outcome and Has a Detrimental Effect on the Gut Microbiome in Mice

Background: Cerebral amyloid angiopathy (CAA) is associated with both ischemic and hemorrhagic stroke, is a known cause of vascular cognitive impairment (VCI), and predicts worsened outcome after stroke. A growing body of literature has highlighted the importance of the gut microbiome in stroke outcome and neurodegenerative diseases such as Alzheimerz’s. However, little is known about how changes in the microbiome can affect CAA progression. The gut-brain axis is highly involved in the systemic inflammatory response following stroke. Furthermore, the gut is a primary source of bacterial translocation resulting in cerebral inflammation which further may contribute to vascular pathology. Therefore, the cross talk between CAA, stroke, and gut function could be key in our understanding and treatment of stroke in patients with CAA. Methods: Symptomatic male Tg-SwDI (4 mths old) and C57BL/6 wild type (WT) mice underwent a 60 minute transient MCAO. Stroke was confirmed with cresyl violet staining and presence of amyloid β (Aβ) plaques were demonstrated with thioflavin. Post-stroke motor function was assessed at day 4 with open field-testing and results were compared to pre-stroke baseline and WT values and cognitive assessment was performed with the Y-maze test. Furthermore, PCR was used to identify the presence of Firmicutes and Bacteroidetes ratio (F:B) in both brain tissue and gut content. Results: We demonstrate a significant decrease in the total distance traveled in both open field and cognitive Y-maze (p&lt;0.05 and p&lt;0.01 respectively) at baseline of Tg-SwDI mice. This was associated with the presence of Aβ plaque in the brain. PCR did not reveal any conclusive evidence for bacterial translocation in the brain at day 4. However, there was a pathogenic shift in the gut F:B ratio following stroke in Tg-SwDI mice compared to sham Tg-SwDI or sham WT controls and this will be confirmed by 16S rRNA gene sequencing. Conclusion: Symptomatic CAA mice exhibit decreased motor and cognitive function compared to WT controls. Furthermore, 16S sequencing was performed to look at the bacterial translocation in detail from the gut to the brain. This is the first study to link CAA, stroke, and the gut brain axis, that may be crucial in understanding the complexity of stroke pathology.

Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy: A meta-analysis.

To assess the association of cortical superficial siderosis (cSS) presence and extent with future bleeding risk in cerebral amyloid angiopathy (CAA). This was a meta-analysis of clinical cohorts of symptomatic patients with CAA who had T2*-MRI at baseline and clinical follow-up for future intracerebral hemorrhage (ICH). We pooled data in a 2-stage meta-analysis using random effects models. Covariate-adjusted hazard ratios (adjHR) from multivariable Cox proportional hazard models were used. We included data from 6 eligible studies (n = 1,239). cSS pooled prevalence was 34% (95% confidence interval [CI] 26%-41%; I 2 87.94%; p < 0.001): focal cSS prevalence was 14% (95% CI 12%-16%; I 2 6.75%; p = 0.37), and disseminated cSS prevalence was 20% (95% CI 13%-26%; I 2 90.39%; p < 0.001). During a mean follow-up of 3.1 years (range 1-4 years), 162/1,239 patients experienced a symptomatic ICH-pooled incidence rate 6.9% per year (95% CI 3.9%-9.8% per year; I 2 83%; p < 0.001). ICH incidence rates per year according to cSS status were 3.9% (95% CI 1.7%-6.1%; I 2 70%; p = 0.018) for patients without cSS, 11.1% (95% CI 7%-15.2%; I 2 56.8%; p = 0.074) for cSS presence, 9.1% (95% CI 5.5%-12.8%; I 2 0%; p = 0.994) for focal cSS, and 12.5% (95% CI 5.3%-19.7%; I 2 73.2%; p = 0.011) for disseminated cSS. In adjusted pooled analysis, any cSS presence was independently associated with increased future ICH risk (adjHR 2.14; 95% CI 1.19-3.85; p < 0.0001). Focal cSS was linked with ICH risk (adjHR 2.11; 95% CI 1.31-2.41; p = 0.002), while disseminated cSS conferred the strongest bleeding risk (adjHR 4.28; 95% CI 2.91-6.30; p < 0.0001). In patients with CAA, cSS presence and extent are the most important MRI prognostic risk factors for future ICH, likely useful in treatment planning. This study provides Class III evidence that in symptomatic CAA survivors with baseline T2*-MRI, cSS (particularly if disseminated, i.e., affecting >3 sulci) increases the risk of future ICH.

APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms.

To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.

Abstract TP171: Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: The Edan Study

Background: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. As recent data suggest that the latter group might have CAA, we investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds. Methods: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all ≥ 55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student’s t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds. Results: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, P=0.179 and P=0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds. Conclusions: In the general population, lobar microbleeds are not related to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.

Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: TheEDAN Study.

In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA. We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds. From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student's t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds. Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p = 0.179 and p = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds. In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.

Abstract 3208: Sensitivity and Reliability of SWI Compared to T2* GRE MRI for Detection of Microbleeds in Cerebral Amyloid Angiopathy

Introduction: Case examples and small case series suggest that MRI susceptibility weighted imaging (SWI) may be more sensitive for cerebral microbleed (CMB) detection compared to MRI T2* gradient-recalled echo (GRE). However, there are few data on CMB counts measured by SWI vs. GRE, or inter-rater reliability, in groups of patients with cerebral small vessel disease. We used data from a prospective cohort study of cerebral amyloid angiopathy (CAA), a cerebral small-vessel disease marked by high numbers of CMBs, to quantify the sensitivity and reliability of SWI vs. GRE for CMB detection. Methods: Nine patients with symptomatic CAA (mean age 71±8.3; 7 males and 2 females) and 21 healthy non-CAA controls (mean age 68±6.3; 10 M/11 F) underwent T2* GRE and SWI on a 3.0T MR scanner. Probable CAA was diagnosed according to the Boston criteria prior to study entry using information from clinical MRI with GRE sequences. Two raters (labeled 1 and 2) independently interpreted the GRE and SWI scans blinded to clinical information. The phase-filtered magnitude image was used for SWI interpretation. Agreement reliability was assessed using the kappa coefficient (where a kappa of ≥0.60 indicates good agreement) or the intraclass correlation coefficient (ICC). Results: Overall, the raters identified 1,432 CMBs in the 9 CAA cases (range 1-434 per patient) and 8 CMBs in the healthy controls (range 0-3). Rater 1 identified CMBs in 5/21 healthy controls on SWI and 5/21 on GRE, while rater 2 identified CMBs in 4/21 on SWI and 3/21 on GRE (kappa 0.70 for GRE and 0.57 for SWI). In CAA cases more CMBs were seen on SWI compared to the GRE sequence but the difference was significant only for rater 1 (rater 1: on average 85% more per patient on SWI than on GRE, p=0.008; rater 2: 19% more, p=0.25). Among CAA cases the reliability between raters was poor for GRE (ICC 0.36) but excellent for SWI (0.94, p&lt;0.05 for comparison with GRE). Review suggested that the differing reliability was because rater 1 was less likely than rater 2 to identify faint lesions on GRE as CMB, whereas these lesions were more conspicuous on SWI. If SWI rather than GRE were used to determine CAA status according to the Boston criteria, all 9 CAA cases would remain classified as probable CAA but 2/21 controls would be reclassified as either possible (n=1) or probable (n=1) asymptomatic CAA based on the detection of one or more lobar microbleeds on SWI. Conclusions: SWI confers greater reliability as well as greater sensitivity for CMB detection compared to GRE, and should be the preferred sequence for quantifying CMBs. SWI may more frequently identify lobar microbleeds that could represent asymptomatic CAA. Further research is needed to determine whether the Boston criteria require revision to take into account the greater sensitivity of SWI for CMB detection.

A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene.

Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.