Cerebral Amyloid Angiopathy Group Research Articles

Quantitative comparison of CSVD imaging markers between patients with possible amyloid small vessel disease and with non-amyloid small vessel disease

The spatial distribution patterns of cerebral microbleeds are associated with different types of cerebral small vessel disease (CSVD). This study aims to examine the disparities in brain imaging markers of CSVD among patients diagnosed with possible amyloid and non-amyloid small vessel disease. The head MR scans including susceptibility-weighted imaging (SWI) sequences from 351 patients at our institute were collected for analysis. CSVD imaging markers were quantified or graded across various CSVD dimensions in the patient images. Patients were categorized into the cerebral amyloid angiopathy group (CAA), hypertensive arteriopathy group (HA), or mixed small vessel disease group (Mixed), based on the spatial distribution of microbleeds. White matter lesions (WML) were segmented using an artificial neural network and assessed via a voxel-wise approach. Significant differences were observed among the three groups in several indices: microbleed count, lacune count at the centrum semiovale and basal ganglia levels, grade of enlarged perivascular space (EPVS) at the basal ganglia, and white matter lesion volume. These indices were substantially higher in the Mixed group compared to the other groups. Additionally, the incidences of cerebral hemorrhages (χ2 = 7.659, P = 0.006) and recent small subcortical infarcts (χ2 = 4.660, P = 0.031) were significantly more frequent in the HA group than in the CAA group. These results indicate that mixed spatial distribution patterns of microbleeds demonstrated the highest burden of cerebral small vessel disease. Microbleeds located in the deep brain regions were associated with a higher incidence of recent small subcortical infarcts and cerebral hemorrhages compared to those in the cortical areas.

Subcortical hemorrhage caused by cerebral amyloid angiopathy compared with hypertensive hemorrhage

ObjectivesMost published reports on lobular hemorrhage in cerebral amyloid angiopathy (CAA) include patients diagnosed only by imaging studies. This study analyzed patients with subcortical hemorrhage histologically diagnosed as CAA or non-CAA (hypertensive). MethodsThis is a retrospective study analyzing data from 100 craniotomy cases. Tissue of hematoma cavity wall was collected for histological investigation in hematoma removal by surgery in patients with subcortical hemorrhage. Statistical analyses of blood pressure, hematoma location and volume, outcome, and mortality was performed in CAA and non-CAA groups. ResultsThere were 47 CAA and 53 non-CAA cases, and average age was significantly older in the CAA group (p < 0.01). Blood pressure was significantly lower (p < 0.01) but hematoma volume was significantly greater (p < 0.05) in the CAA group. Rebleeding occurred in two CAA cases and one non-CAA case, but no re-operations were required. Average score of modified Rankin Scale, which is used to measure the degree of disability in patients who have had a stroke, at three months after surgery was not significantly different between the two groups (CAA: 3.94 ± 1.28, non-CAA: 3.58 ± 1.50). There were seven deaths in the CAA and six in the non-CAA group, and intraventricular hemorrhage highly complicated in the death cases in both groups. In the CAA group, average age of the fatal cases was significantly older than that of the surviving cases (p < 0.05) and six cases demonstrated dementia before onset of hemorrhage. ConclusionsSurgical removal of a subcortical hemorrhage caused by CAA is not contraindicated. However, age > 80 years, complication with intraventricular hemorrhage, hematoma volume ≥ 50 ml, and dementia before onset of hemorrhage contribute to high mortality, and craniotomy should be carefully considered for such patients. A limitation of this study is that comparison between CAA and non-CAA groups was performed in the patients with only surgically indicated ICH, and does not evaluate entire ICH cases with CAA. However, this study appropriately compared pathologically diagnosed CAA and non-CAA in patients with moderate to severe lobular ICH with surgical indications.

Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

Association of antithrombotic therapy with postoperative rebleeding in patients with cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy is a common cause of subcortical hemorrhage in older adults. Although open hematoma removal may be performed for severe subcortical hemorrhage, its safety in patients with cerebral amyloid angiopathy has not been established, and postoperative rebleeding may occur. Therefore, this study aimed to investigate factors associated with postoperative rebleeding.MethodsOut of 145 consecutive patients who had undergone craniotomy for surgical removal of subcortical intracerebral hemorrhage between April 2010 and August 2019 at a single institution in Japan, we examined 109 patients with subcortical hemorrhage who met the inclusion criteria. After excluding 30 patients whose tissue samples were unsuitable for the study, the final study cohort comprised 79 patients.ResultsOf the 79 patients, 50 (63%) were diagnosed with cerebral amyloid angiopathy (cerebral amyloid angiopathy group) and 29 (37%) were not diagnosed with noncerebral amyloid angiopathy (noncerebral amyloid angiopathy group). Postoperative rebleeding occurred in 12 patients (24%) in the cerebral amyloid angiopathy group and in 2 patients (7%) in the noncerebral amyloid angiopathy group. Preoperative prothrombin time–international normalized ratio and intraoperative bleeding volume were significantly associated with postoperative rebleeding in the cerebral amyloid angiopathy group (odds ratio = 42.4, 95% confidence interval = 1.14–1578; p = 0.042 and odds ratio = 1.005, 95% confidence interval = 1.001–1.008; p = 0.007, respectively).ConclusionsPatients with cerebral amyloid angiopathy-related cerebral hemorrhage who are receiving antithrombotic therapy, particularly warfarin therapy, are at a high risk of postoperative rebleeding.Trial registrationRegistry and Registration Number of the study: 19–220, 2019/12/23, retrospectively registered.

Applicability of the Edinburgh CT Criteria for Lobar Intracerebral Hemorrhage Associated with Cerebral Amyloid Angiopathy.

Based on histopathology, Edinburgh diagnostic criteria were proposed to consider anontraumatic intracerebral lobar hemorrhage (ICH) as related to cerebral amyloid angiopathy (CAA) using the initial computed tomography (CT) scan and the APOE genetic status. We aimed to externally validate the Edinburgh prediction model, excluding the APOE genotyping and based on the modified Boston criteria on the MRI for CAA diagnosis METHODS: We included patients admitted for spontaneous lobar ICH in the emergency department between 2016 and 2019 who underwent noncontrast CT scan and MRI. According to the MRI, patients were classified into the CAA group or into the non-CAA group in the case of other causes of ICH. Two neuroradiologists, blinded to the final retained diagnosis, rated each radiological feature on initial CT scan described in the Edinburgh study on initial CT scan RESULTS: A total of 102 patients were included, of whom 36were classified in the CAA group, 46in the non-CAA causes group and 20of undetermined cause (excluded from the primary analysis). The Edinburgh prediction model, including finger-like projections and subarachnoid extension showed an area under receiver operating characteristic curves (AUC) of 0.760 (95% confidence interval, CI: 0.660-0.859) for the diagnosis of CAA. The AUC reached 0.808 (95%CI: 0.714-0.901) in anew prediction model integrating athird radiologic variable: the ICH cortical involvement. Using the Boston MRI criteria as afinal assessment, we provided anew external confirmation of the radiological Edinburgh CT criteria, which are directly applicable in acute settings of spontaneous lobar ICH and further proposed an original 3‑set model considering finger-like projections, subarachnoid extension, and cortical involvement that may achieve ahigh discrimination performance.

Imaging features of small vessel disease in cerebral amyloid angiopathy among patients with Alzheimer’s disease

Background and purposeCerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer’s disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. MethodsThe study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer’s Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. ResultsThe study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (β = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2–4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. ConclusionAmong patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.

Subcortical volumes in cerebral amyloid angiopathy compared with Alzheimer's disease and controls.

Previous reports have suggested that patients with cerebral amyloid angiopathy (CAA) may harbor smaller white matter, basal ganglia, and cerebellar volumes compared to age-matched healthy controls (HC) or patients with Alzheimer's disease (AD). We investigated whether CAA is associated with subcortical atrophy. The study was based on the multi-site Functional Assessment of Vascular Reactivity cohort and included 78 probable CAA (diagnosed according to the Boston criteria v2.0), 33 AD, and 70 HC. Cerebral and cerebellar volumes were extracted from brain 3D T1-weighted MRI using FreeSurfer (v6.0). Subcortical volumes, including total white matter, thalamus, basal ganglia, and cerebellum were reported as proportion (%) of estimated total intracranial volume. White matter integrity was quantified by the peak width of skeletonized mean diffusivity. Participants in the CAA group were older (74.0 ± 7.0, female 44%) than the AD (69.7 ± 7.5, female 42%) and HC (68.8 ± 7.8, female 69%) groups. CAA participants had the highest white matter hyperintensity volume and worse white matter integrity of the three groups. After adjusting for age, sex, and study site, CAA participants had smaller putamen volumes (mean differences, -0.024% of intracranial volume; 95% confidence intervals, -0.041% to -0.006%; p = 0.005) than the HCs but not AD participants (-0.003%; -0.024 to 0.018%; p = 0.94). Other subcortical volumes including subcortical white matter, thalamus, caudate, globus pallidus, cerebellar cortex or cerebellar white matter were comparable between all three groups. In contrast to prior studies, we did not find substantial atrophy of subcortical volumes in CAA compared to AD or HCs, except for the putamen. Differences between studies may reflect heterogeneity in CAA presenting syndromes or severity.

Role of White Matter Abnormalities in the Relationship Between Microbleed Burden and Cognitive Impairment in Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) often presents as cognitive impairment, but the mechanism of cognitive decline is unclear. Recent studies showed that number of microbleeds were associated with cognitive decline. We aimed to investigate how microbleeds contribute to cognitive impairment in association with white matter tract abnormalities or cortical thickness in CAA. This retrospective comparative study involved patients with probable CAA according to the Boston criteria (Aβ+ CAA) and patients with Alzheimer's disease (Aβ+ AD), all of whom showed severe amyloid deposition on amyloid PET. Using mediation analysis, we investigated how FA or cortical thickness mediates the correlation between the number of lobar microbleeds and cognition. We analyzed 30 patients with Aβ+ CAA (age 72.2±7.6, female 53.3%) and 30 patients with Aβ+ AD (age 71.5±7.6, female 53.3%). The two groups showed similar degrees of cortical amyloid deposition in AD-related regions. The Aβ+ CAA group had significantly lower FA values in the clusters of the posterior area than did the Aβ+ AD group(family-wise error-corrected p < 0.05). The correlation between the number of lobar microbleeds and visuospatial function was indirectly mediated by white matter tract abnormality of right posterior thalamic radiation (PTR) and tapetum, while lobar microbleeds and language function was indirectly mediated by the abnormality of left PTR and sagittal stratum. Cortical thickness did not mediate the association between lobar microbleeds and cognition. This result supports the hypothesis that microbleeds burden leads to white matter tract damage and subsequent cognitive decline in CAA.

Abstract WP136: Recurrent Intracerebral Hemorrhage In Patients With Cerebral Amyloid Angiopathy

Background: Studies suggest an increased risk of recurrent intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA). In this study, we sought to compare the rates of recurrent cerebrovascular events in patients admitted for ICH with and without CAA. Methods: We utilized the National Readmissions Database 2016-2018 to identify hospitalizations with the primary discharge diagnosis of ICH with and without a concomitant diagnosis of CAA. Hospitalizations with age &gt;55 years, survival to discharge, and known discharge disposition were included for further analysis. Propensity score matching was used to match for the differences in demographics, comorbidities, and disease severity between the CAA and no CAA groups. Survival analysis was performed to evaluate the rates of recurrent ICH, subarachnoid hemorrhage (SAH), and acute ischemic stroke (AIS) in the propensity-matched groups. Results: A total of 194,290 patients with ICH met the study inclusion criteria; 8,247 with CAA and 186,043 without CAA. After propensity score matching, we identified 7,857 hospitalizations with CAA and 7,874 without CAA. Patients with CAA were more likely to be readmitted due to ICH [hazards ratio (HR): 3.4, 95% confidence interval (CI): 2.6-4.6, P &lt;0.001] and SAH (HR: 2.5, 95% CI: 1.2-5.4, P 0.007) during the mean follow-up period of 6 months. However, there was no statistically significant difference in readmissions due to AIS (HR: 0.7, 95% CI: 0.5-1.0, P 0.061) [Figure 1]. Age (HR: 0.96 per year increase in age, 95% CI: 0.95-0.98, P &lt;0.001) and Medicare payer (HR: 3.23; 95% CI: 1.92-5.41, P &lt;0.001) were independently associated with readmissions due to ICH. Conclusions: Patients admitted for ICH with a secondary diagnosis of CAA are three times more likely to have readmissions for recurrent ICH compared to patients without CAA.

Spatial distribution of cerebral microbleeds reveals heterogeneous pathogenesis in CADASIL

ObjectivesRadiological diagnosis of subtypes of cerebral small vessel diseases remains challenging. This study aimed to explore the spatial distribution of cerebral microbleeds (CMBs) in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) in contrast to cerebral amyloid angiopathy (CAA) in the lobar regions.MethodsThirty-two patients with CADASIL and 33 patients with probable CAA were prospectively and consecutively included. On 3-Tesla susceptibility-weighted magnetic resonance images, CMBs were analyzed for incidence and volume within atlas-based regions of interest, followed by voxel-wise analysis using risk mapping. The distribution of CMBs was correlated with the status of hypertension. Correlation and group differences with a p-value less than 0.05 were considered to be significant.ResultsAs compared with the CAA group, the CADASIL group presents a larger CMB volume in hippocampus/amygdala and white matter (nonparametric analysis of covariance, p = 0.014 and 0.037, respectively), a smaller CMB volume in parietal lobe (p = 0.038), and a higher incidence in hippocampus/amygdala, white matter, and insula (logistic regression, p = 0.019, 0.024, and 0.30, respectively). As part of the exclusion criteria of probable CAA, thalamus, basal ganglia, and pons exhibit greater CMB volume/incidence in the CADASIL group. In CADASIL patients, hot spots of CMBs are identified in the putamen and posteromedial thalamus; hypertension is associated with larger CMB volumes in insula, basal ganglia, and pons.ConclusionsThe spatial distribution of CMBs is differentiable between CADASIL and CAA in lobar regions. In CADASIL patients, hypertension has a region-dependent mediating effect on the CMB volume.Key Points• The topological distribution of lobar CMBs is differentiable between CADASIL and CAA.• In CADASIL patients, hypertension mediates CMB volume and the mediation is region dependent.• CMB risk mapping allows for voxel-wise exploration of CMB distribution and reveals hot spots in the putamen and posteromedial thalamus in CADASIL.

Editors' Note: Detection of Cerebral Microbleeds With Venous Connection at 7-Tesla MRI

The etiology of cerebral microhemorrhages was further explored in the recently published observational cohort of 51 people who underwent 7T magnetic resonance imaging (MRI), as reported by Dr. Rotta et al . Using Quantitative Susceptibility Mapping of healthy elderly adults and adults with cerebral amyloid angiopathy (CAA) and hypertensive vasculopathy, the investigators observed a disproportionate burden of microbleeds with venous connections among patients with CAA vs control groups. This observation might suggest that some of these microbleeds have a venous origin. Although microbleeds in association with a venous connection represented a minority of microbleeds (only 14%), they were strongly tied to CAA over other conditions. Drs. Chen and Wang commented that cortical vessels may be mistaken for lobar microbleeds, leading to a misclassification bias. Furthermore, Drs. Chen and Wang observed a higher prevalence of deep microbleeds in association with a venous connection in their previous autopsy study. The investigators affirm that these results warrant validation using histopathology. Furthermore, one reason for their unique observations may be the higher sensitivity for detecting microbleeds when using an MRI with a greater magnet strength. The etiology of cerebral microhemorrhages was further explored in the recently published observational cohort of 51 people who underwent 7T magnetic resonance imaging (MRI), as reported by Dr. Rotta et al . Using Quantitative Susceptibility Mapping of healthy elderly adults and adults with cerebral amyloid angiopathy (CAA) and hypertensive vasculopathy, the investigators observed a disproportionate burden of microbleeds with venous connections among patients with CAA vs control groups. This observation might suggest that some of these microbleeds have a venous origin. Although microbleeds in association with a venous connection represented a minority of microbleeds (only 14%), they were strongly tied to CAA over other conditions. Drs. Chen and Wang commented that cortical vessels may be mistaken for lobar microbleeds, leading to a misclassification bias. Furthermore, Drs. Chen and Wang observed a higher prevalence of deep microbleeds in association with a venous connection in their previous autopsy study. The investigators affirm that these results warrant validation using histopathology. Furthermore, one reason for their unique observations may be the higher sensitivity for detecting microbleeds when using an MRI with a greater magnet strength.

Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy.

Background:Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood.Objective:The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA.Methods:Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region.Results:Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) –0.047 mm, 95% confidence interval (CI) –0.088, –0.005, p = 0.03), and lower in AD compared to CAA (MD –0.104 mm, 95% CI –0.165, –0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD –0.07 mm, 95% CI –0.13 to –0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04).Conclusion:CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

Abstract 9: Peak Width of Skeletonized Mean Diffusivity and Cognition in Cerebral Amyloid Angiopathy

Background: We hypothesized that Peak Width of Skeletonized Mean Diffusivity (PSMD), an automated marker of cerebral microangiopathy representing microstructural disruption of white matter (WM), would be increased in patients with cerebral amyloid angiopathy (CAA) compared to healthy controls (HCs) and increased PSMD would be associated with lower processing speed scores (PSSs) in patients with CAA. Methods: Seventy-two nondemented probable CAA patients and 23 HCs prospectively underwent high-resolution brain MRIs and cognitive tests. PSMD scores were quantified from a probabilistic skeleton of the WM tracts as previously validated (http://www.psmd-marker.com). In subjects with intracerebral hemorrhage (ICH, n=27), ICH regions were masked and removed from the PSMD pipeline. The analyses were repeated in the non-ICH hemisphere. Raw scores of Trail Making Test-B and Symbol Substitution Test were transformed into standardized z -scores and averaged to obtain PSSs. Results: The mean age (p=0.366) and sex (p=0.811) were similar between CAA patients and HCs. PSMD was higher in the CAA group [(3.95±0.9) х 10 –4 mm 2 /s] compared to HCs [(3.32±0.6) х 10 –4 mm 2 /s] (p=0.003). This association remained significant in a linear regression model corrected for age and sex (β=0.700, 95%CI 0.3-1, p=0.001). Within the CAA cohort, higher PSMD was associated with higher WM hyperintensity volume in a multiple regression model adjusted for all relevant variables (β=0.890, 95%CI 0.7-1, p&lt;0.001). In a regression model corrected for age, sex, years of education and presence of ICH, a lower PSS was independently associated with increased PSMD (β=-0.405, 95%CI {-0.6}-{-0.2}, p&lt;0.001). These results did not change when the non-ICH hemisphere was used for PSMD processing. Conclusion: PSMD is increased in CAA and is associated with worse PSSs supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA.

The relationship between cerebral and retinal microbleeds in cerebral amyloid angiopathy (CAA): A pilot study

BackgroundThe standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients. MethodsWe used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients. ResultsWe found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements. ConclusionRetinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA.

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria 18F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aβ deposition. From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed P<0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values. Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism (P range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared. Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.

The microvascular extracellular matrix in brains with Alzheimer\u2019s disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA)

BackgroundThe microvasculature (MV) of brains with Alzheimer’s disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA), in the absence of concurrent pathologies (e.g., infarctions, Lewy bodies), is incompletely understood.ObjectiveTo analyze microvascular density, diameter and extracellular matrix (ECM) content in association with ADNC and CAA.MethodsWe examined samples of cerebral cortex and isolated brain microvasculature (MV) from subjects with the National Institute on Aging-Alzheimer's Association (NIA-AA) designations of not-, intermediate-, or high ADNC and from subjects with no CAA and moderate-severe CAA. Cases for all groups were selected with no major (territorial) strokes, ≤ 1 microinfarct in screening sections, and no Lewy body pathology. MV density and diameter were measured from cortical brain sections. Levels of basement membrane (BM) ECM components, the protein product of TNF-stimulated gene-6 (TSG-6), and the ubiquitous glycosaminoglycan hyaluronan (HA) were assayed by western blots or HA ELISA of MV lysates.ResultsWe found no significant changes in MV density or diameter among any of the groups. Levels of BM laminin and collagen IV (col IV) were lower in MV isolated from the high ADNC vs. not-ADNC groups. In contrast, BM laminin was significantly higher in MV from the moderate-severe CAA vs. the no CAA groups. TSG-6 and HA content were higher in the presence of both high ADNC and CAA, whereas levels of BM fibronectin and perlecan were similar among all groups.ConclusionsCortical MV density and diameter are not appreciably altered by ADNC or CAA. TSG-6 and HA are increased in both ADNC and CAA, with laminin and col IV decreased in the BM of high ADNC, but laminin increased in moderate-severe CAA. These results show that changes in the ECM occur in AD and CAA, but independently of one another, and likely reflect on the regional functioning of the brain microvasculature.

Utility of HAS-BLED and CHA2DS2-VASc Scores Among Patients With Atrial Fibrillation and Imaging Evidence of Cerebral Amyloid Angiopathy

ObjectiveTo determine the utility of the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly) and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack–VAScular disease) scores among patients on anticoagulation (AC) therapy for atrial fibrillation (AF) who have evidence of cerebral amyloid angiopathy (CAA). Patients and MethodsPatients older than 55 years with a diagnosis of AF who had a nontraumatic intracerebral hemorrhage (ICH) while on AC therapy between 1995 and 2016 were identified using the Rochester Epidemiology Project Database. Medical records were reviewed, including imaging of the brain, to identify baseline characteristics, AC use, and outcomes. ResultsA total of 65 patients were identified (mean age, 81.3 years); 35 (53.8%) had evidence of possible/probable CAA. Mean HAS-BLED score in the CAA group was significantly lower (2.1) than that of the non-CAA group (2.9; P<.001). Mortality after ICH, adjusted for HAS-BLED scores, was not significantly different among patients with and without CAA. Sixteen patients restarted on AC therapy after ICH; CHA2DS2-VASc scores were no different between this group and those who were not restarted. Among patients with CAA, the overall rate of ICH recurrence was 8.6% over 93.5 person-years of follow-up. Among patients with CAA, the rate of ICH recurrence was 3.2 per 100 patient-years, higher than their HAS-BLED scores would predict (1.9 bleeds/100 patient-years). ConclusionHAS-BLED scores were lower in patients who had evidence of CAA compared with those without, suggesting underestimation of ICH risk in patients with CAA. CHA2DS2-VASc scores did not affect resumption of AC therapy. ICH recurrence was higher in patients with CAA than their HAS-BLED scores predicted. Current risk assessment scoring systems do not accurately account for CAA in patients with AF on AC.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.

Background:There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).Objective:To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.Methods:We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.Results:We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile.Conclusion:CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.

Abstract TP213: Diagnostic Score to Differentiate the Etiology of Cortical Microinfarcts on 3-Tesla MRI

Background and Purpose: Cortical microinfarcts (CMIs) are small ischemic lesions found in cerebral amyloid angiopathy (CAA) patients, which are also associated with embolic stroke. This study aimed to differentiate cortical microinfarcts caused by CAA from those caused by microembolism, using 3-tesla magnetic resonance imaging. Methods: We retrospectively investigated 119 patients with at least 1 cortical infarct &lt;10 mm on 3D double inversion recovery imaging. Forty-three patients with an embolic stroke history were included as the emboli group (Emboli-G) and 27 patients with CAA were included as the CAA group (CAA-G), based on the modified Boston criteria. We compared the size, number, location, and distribution of CMIs between groups to assess CMI etiology. Using this information, we designed a radiological diagnostic score, which incorporated data on the location, size, distribution, and numbers of CMIs. Results: CAA-G patients showed significantly more lesions &lt;5 mm, which were restricted to the cortex (p&lt;0.01). Cortical lesion number was significantly higher in Emboli-G than in CAA-G patients (4 vs 2; p&lt;0.01). The diameter of cortical lesions was significantly larger in Emboli-G than in CAA-G patients (3.8 mm vs 3.0 mm; p&lt;0.01). Lesions in CAA-G and Emboli-G patients were disproportionately located in the occipital lobe (p&lt;0.01) and frontal or parietal lobe (p=0.04), respectively. In diagnostic scoring, a score of ≥3 points strongly predicted microembolism (sensitivity, 63%; specificity, 92%) or CAA (sensitivity, 63%; specificity, 91%). The area under the curve was 0.85 and 0.87 for microembolism and CAA, respectively. Conclusions: Our radiological diagnostic score may be a powerful tool for differentiating the etiology of CMIs.

Cross-sectional and longitudinal differences in peak skeletonized white matter mean diffusivity in cerebral amyloid angiopathy

ObjectivesTo test the hypotheses that peak skeletonized mean diffusivity (PSMD), a measure of cerebral white matter microstructural disruption, is 1) increased in patients with cerebral amyloid angiopathy (CAA) compared to normal control (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD); 2) associated with neuropsychological test performance among CAA patients; and 3) increased more quickly over one year in CAA than in AD, MCI, and NC. MethodsNinety-two participants provided a medical history, completed a neuropsychological assessment, and had a magnetic resonance (MR) exam including diffusion tensor imaging (DTI) from which PSMD was calculated. A 75-minute neuropsychological test battery was used to derive domain scores for memory, executive function, and processing speed. Multivariable analyses controlling for age and sex (and education, for cognitive outcomes) were used to test the study hypotheses. ResultsPSMD was higher in the CAA group (mean 4.97 × 10−4 mm2/s) compared to NC (3.25 × 10−4 mm2/s), MCI (3.62 × 10−4 mm2/s) and AD (3.89 × 10−4 mm2/s) groups (p < .01). Among CAA patients, higher PSMD was associated with slower processing speed (estimated −0.22 standard deviation (SD) change in processing speed z score per SD increase in PSMD, 95% CI −0.42 to −0.03, p = .03), higher WMH volume [β = 0.74, CI 0.48 to 1.00], and higher CAA SVD score [β = 0.68, CI 0.24 to 1.21] but was not associated with MMSE, executive function, memory, CMB count, or cortical thickness. PSMD increased over 1-year in all groups (p < .01) but without rate differences between groups (p = .66). ConclusionsPSMD, a simple marker of diffuse global white matter heterogeneity, is increased in CAA. Our findings further support a role for white matter disruption in causing cognitive impairment in CAA.