Severe Cerebral Amyloid Angiopathy Research Articles

Presence of co‐pathology in sporadic early‐onset Alzheimer disease versus dominantly inherited Alzheimer disease

A small proportion of Alzheimer disease (AD), known as early onset AD (EOAD), has symptomatic age at onset (AAO) before age 65. About 5-10% of EOAD is dominantly inherited (DIAD); the rest is termed to be sporadic (sEOAD). Although DIAD and sEOAD share the hallmark plaques and tangles that define AD neuropathologic change (ADNC), the relative burdens of these lesions and the frequencies of non-AD co-pathologies in sEOAD relative to DIAD remain unknown.We compared the neuropathological burden of AD and the frequency of AD and non-AD pathologies in 363 sEOAD cases from the National Alzheimer's Coordinating Center (NACC) and in 62 DIAD cases (45 from the Dominantly Inherited Alzheimer Network (DIAN); 17 from NACC). Operational criteria for the classification of AD and other co-pathologies followed accepted NACC guidelines. Only cases with AAO under 65 and a primary pathological diagnosis of 'high ADNC' were included.DIAD participants [mean AAO = 42.9 ± 8.1 years] had higher CERAD scores than sEOAD cases [mean AAO = 57.1 ±7.2 years] [p=0.03]. Braak stages were similar for both cohorts. The frequency and severity of cerebral amyloid angiopathy (CAA) was higher in DIAD versus sEOAD [CAA: 100% vs 83.7%, p=0.001; severe CAA: 40.3% versus 20.1%, p<0.001, respectively]. The frequency of at least one non-AD/non-CAA pathology was similar between DIAD and sEOAD [63.9% vs 59.7%, p=0.61], but the frequency of multiple pathologies (two or more) was lower in DIAD [3.2%] than in sEOAD [21.0%, p<0.001]. Lewy body disease (LBD) was the most prevalent non-AD/non-CAA pathology in both cohorts [58.1% in DIAD, 51.2% in sEOAD; p=0.39]. Hippocampal sclerosis [14.5%] and argyrophilic grain disease [2.5%], were observed in sEOAD, but were absent from DIAD.DIAD cases show greater neuritic plaque density and more severe CAA than sEOAD cases, but comparable Braak NFT stages. The similar frequencies of LBD in both cohorts may be linked to severe AD neuropathological change, rather than co-incident age-related pathologies. Future studies should include methodologically uniform assessments of both cohorts to explore age-related and non-age-related mechanisms that may account for differences in the burdens of ADNC lesions and non-AD co-pathologies.

Pharmacological inhibition of carbonic anhydrases ameliorates cognitive dysfunction, rescuing Aβ‐induced neurovascular pathology in vivo

Cerebrovascular dysfunction (CVD) is an early feature of Alzheimer's disease (AD), contributing to the pathology progression, and suggesting a strict association between CVD and neurodegeneration. The majority of AD cases present cerebral amyloid angiopathy (CAA), neuropathological feature characterized by abnormal vasculotropic deposition of amyloid beta, mainly Aβ40. Severe CAA is also induced by familial Aβ variants, such as the Dutch-Q22. Our previous in vitro studies demonstrated that brain vascular amyloidosis elicits mitochondrial dysregulation and caspase-mediated apoptosis, in cells composing the neurovascular unit, including neurons, endothelial, glial and smooth muscle cells. Additionally, we showed that acetazolamide (ATZ) and methazolamide (MTZ), FDA-approved carbonic anhydrase inhibitors (CAIs) which cross the blood-brain barrier (BBB), hamper these detrimental processes. Carbonic anhydrases (CAs) represent a family of metalloenzymes catalyzing the reversible hydration of carbon dioxide, and their inhibition improves cerebral blood flow, vasoreactivity and neuronal excitability, pointing to CAs as CVD targets in AD.We employed Tg-SwDI mice (expressing human amyloid precursor protein, APP, carrying the Swedish, Dutch and Iowa mutations), which develop fibrillar amyloid burden, primarily in the cerebral microvasculature, starting at 6 months. We fed the animals (from 8 to 16 months of age) a CAI-diet, following which we performed behavioral analysis, and harvested the brains for both biochemical and immunohistochemical examination.Compared to untreated Tg mice, ATZ- and MTZ-fed animals showed reduced cognitive impairment, along with decreased vascular Aβ overload and astrogliosis, main pathological hallmarks of the disease. Tg animals exhibited Aβ deposition in endothelial and glial cells, leading to cell-specific caspase-3 activation. Interestingly, CAI-diet reduced endothelial and astrocytic Aβ deposits, and Aβ-induced caspase activation. Interestingly, the augmented expression of cerebral TREM2 and CD68 in CAI-treated mice suggests an attenuated inflammatory response, concomitantly with a boost of the cerebral clearance and active Aβ removal from brain microglia/macrophages, respectively, which may underlie the observed Aβ reduction. Furthermore, preliminary data suggest that both ATZ and MTZ promote microglial endocytosis, possibly facilitating Aβ degradation.CAIs provide neuroprotection, fostering neurovascular and glial physiological functions and clearance mechanisms, and attenuating CVD.

Cell type-specific gene expression changes in Alzheimer's patients with varying levels of cerebral amyloid angiopathy.

Tau neurofibrillary tangles and senile plaques comprised of insoluble amyloid beta are the major histopathological hallmarks of Alzheimer's disease (AD). More than 85% of autopsy-confirmed AD cases also exhibit some degree of cerebral amyloid angiopathy (CAA), which is characterized by amyloid beta peptide deposits predominantly in blood vessels in the meningeal and intracerebral blood vessels. Consequently, CAA predisposes individuals with AD to cerebral infarction and hemorrhages, accounting for ∼20% of cases in the elderly, which could lead to faster cognitive decline through neurovascular pathway dysfunction. We sought to identify cellular composition changes and characterize cell type-specific expression associated with CAA pathology in AD patients. Using 10x Genomics single nuclei RNA sequencing, we profiled nuclei from frozen post-mortem temporal cortex tissue of 80 individuals with neuropathologic diagnosis of AD and varying levels of CAA, ranging from zero to severe CAA pathology. Braak and Thal measures were also obtained. Downstream analyses were performed in R using Seurat v3.2.3. Quality control filtering based on percentage of genes mapped to the mitochondrial genome and number of genes and UMIs detected resulted in 135,092 nuclei for analysis. Differential gene expression analyses were performed using R package MAST. We identified 30 clusters which were annotated using established cell type marker genes. There were 3 oligodendrocyte, 14 neuronal (2 excitatory and 3 inhibitory), 5 microglial, 3 endothelial, 4 astrocyte and 1 oligodendrocyte precursor cell cluster. We observed a significant increase in microglial cell proportions with increasing CAA severity, for 3 of the microglial clusters. Conversely, the excitatory neuronal proportion were decreased in individuals with more severe CAA. Further investigation is ongoing to identify the genes underlying the dysregulation of these cell types in CAA. We observed cellular proportion changes for multiple cell types with increasing CAA severity. Additional analyses to determine the effects of CAA independent of AD severity will be performed by adjusting for Braak and Thal measures. Deeper characterization of cell type-specific expression profiles is expected to provide novel insights into cell-type specific transcriptome changes associated with vascular risk factors in AD.

Transgenic rat models for cerebral amyloid angiopathy type‐1 and ‐2 and related vascular cognitive impairment and dementia (VCID)

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease commonly found in the elderly population and in patients with Alzheimer's disease and is significant driver of vascular cognitive impairment and dementia (VCID). CAA exists in two forms: type-1 which affects small microvessels and capillaries and type-2 which primarily affects small arteries and arterioles. Our understanding of how these different forms of CAA promote VCID is hampered by reliable preclinical models. Recently, we generated novel transgenic rat models of CAA type-1 and CAA type-2 to investigate the development and pathological consequences of each type of CAA and their impact on VCID. Cohorts of CAA type-1 and CAA type-2 transgenic rats and wild-type rats were aged from three to twenty four months of age. Magnetic resonance imaging (MRI) was performed to determine the effects of progressive CAA pathology on white matter changes and emergence of cerebral microbleeds. Quantitative histological analyses were performed to measure progressive severity of CAA, neuroinflammation and cerebral microbleeds. A battery of behavioral task assessments was performed to reveal the impact of CAA on cognitive performance. CAA type-1 rats developed microvascular CAA starting at ≈3 months of age that became severe at 12 months leading to a moribund state. CAA type-2 rats developed CAA pathology later starting ≈12 months of age and progressed to 24 months. Histological analysis showed CAA type-1 rats exhibited early-onset perivascular neuroinflammation and microvascular pathology including capillary occlusions and microbleeds. In contrast, CAA type-2 rats presented little evidence of perivascular neuroinflammation and less extensive microbleeds. MR imaging showed that CAA type-1 rats presented with white matter loss at ≈6 months of age. Behavioral analysis revealed that CAA type-1 rats displayed a distinct form sensorimotor slowing that was not observed in CAA type-2 rats. CAA type-1 rats recapitulate many of the pathological features of human microvascular CAA including perivascular neuroinflammation and white matter loss and exhibit cognitive changes. In contrast, CAA type-2 rats lack these particular pathological features and did not display cognitive changes. These findings suggest that CAA-associated neuroinflammation and white matter loss may play an important role in VCID.

Current findings on the coincidence of cerebral amyloid angiopathy and Alzheimer's disease

Die zerebrale Amyloidangiopathie (CAA) tritt trotz verschiedener Pathomechanismen häufig koinzident zur Alzheimer-Demenz auf. Sie moduliert kognitive Defizite im Rahmen der Alzheimer-Erkrankung (AD) annehmbar durch additive Effekte, auch wenn die diesbezüglichen Zusammenhänge komplex sind. Die pathophysiologische Gemeinsamkeit beider Erkrankungen besteht in einem gestörten Amyloidmetabolismus, distinkt ist jedoch die pathologische Prozessierung von Amyloidvorläuferproteinen. Die CAA mit ihren verschiedenen Subtypen ist eine pathomechanistisch heterogene Gefäßerkrankung des Gehirns. Vaskuläre und parenchymatöse Amyloidablagerungen kommen gemeinsam, aber auch isoliert und unabhängig voneinander vor. Um den spezifischen Beitrag der CAA zu kognitiven Defiziten im Rahmen der AD zu untersuchen, bedarf es daher geeigneter diagnostischer Methoden, die der Komplexität der histopathologischen bzw. bildmorphologischen Charakteristika der CAA gerecht werden, sowie differenzierender testpsychometrischer Verfahren, anhand derer der Beitrag der CAA zu kognitiven Defiziten deskriptiv erfasst und damit ätiologisch besser zuordenbar wird.

Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer’s Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor

Background:Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome.Objective:We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and vessel density.Methods:We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques.Results:The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density.Conclusion:Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.

First identification of ITM2B interactome in the human retina

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

Deep learning assisted quantitative assessment of histopathological markers of Alzheimer\u2019s disease and cerebral amyloid angiopathy

Traditionally, analysis of neuropathological markers in neurodegenerative diseases has relied on visual assessments of stained sections. Resulting semiquantitative scores often vary between individual raters and research centers, limiting statistical approaches. To overcome these issues, we have developed six deep learning-based models, that identify some of the most characteristic markers of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). The deep learning-based models are trained to differentially detect parenchymal amyloid β (Aβ)-plaques, vascular Aβ-deposition, iron and calcium deposition, reactive astrocytes, microglia, as well as fibrin extravasation. The models were trained on digitized histopathological slides from brains of patients with AD and CAA, using a workflow that allows neuropathology experts to train convolutional neural networks (CNNs) on a cloud-based graphical interface. Validation of all models indicated a very good to excellent performance compared to three independent expert human raters. Furthermore, the Aβ and iron models were consistent with previously acquired semiquantitative scores in the same dataset and allowed the use of more complex statistical approaches. For example, linear mixed effects models could be used to confirm the previously described relationship between leptomeningeal CAA severity and cortical iron accumulation. A similar approach enabled us to explore the association between neuroinflammation and disparate Aβ pathologies. The presented workflow is easy for researchers with pathological expertise to implement and is customizable for additional histopathological markers. The implementation of deep learning-assisted analyses of histopathological slides is likely to promote standardization of the assessment of neuropathological markers across research centers, which will allow specific pathophysiological questions in neurodegenerative disease to be addressed in a harmonized way and on a larger scale.

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre‐codon 200 (n = 10), PSEN1 post‐codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid‐beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub‐group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post‐codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post‐codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.

Metformin attenuates vascular pathology by increasing expression of insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 2 diabetes mellitus

Sporadic cerebral amyloid angiopathy (CAA), which is characterized by cerebrovascular amyloid β (Aβ) deposits, causes cerebral hemorrhages and dementia in elderly people. Metformin has been used to treat patients with type 2 diabetes mellitus (T2DM), and animal and clinical studies have reported therapeutic effects of metformin in Alzheimer’s disease (AD). However, the therapeutic effects of metformin in CAA are unclear. Here, we used a mixed mouse model of CAA and T2DM (APP23-ob/ob) to investigate whether metformin has therapeutic effects on cerebrovascular Aβ deposits. We dissolved metformin hydrochloride in water and administered it orally at 350 mg/kg/day. Treatments started when mice were 6 weeks old and continued until they were 15 months old. After we treated APP23-ob/ob mice with metformin, we counted the numbers of vessels with Aβ and measured levels of Aβ40 and Aβ42 (soluble and insoluble), amyloid precursor protein (APP), APP-processing enzymes (α-, β-, and γ-secretases), and Aβ-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Metformin significantly reduced cerebrovascular Aβ deposits in APP23-ob/ob mice (p < .05). Compared with controls, metformin-treated APP23-ob/ob mice had significantly reduced Aβ levels in the cerebral cortex (p < .05) and hippocampus (p < .05) and increased levels of IDE in the hippocampus (p < .01). Our results indicate that metformin attenuates the severity of CAA by enhancing Aβ-cleaving IDE expression. The clinical application of metformin may lead to a novel therapeutic strategy in CAA treatment, especially in patients with T2DM.

Significance of cerebral amyloid angiopathy and other co-morbidities in Lewy body diseases.

Lewy body dementia (LBD) and Parkinson's disease-dementia (PDD) are two major neurocognitive disorders with Lewy bodies (LB) of unknown etiology. There is considerable clinical and pathological overlap between these two conditions that are clinically distinguished based on the duration of Parkinsonism prior to development of dementia. Their morphology is characterized by a variable combination of LB and Alzheimer's disease (AD) pathologies. Cerebral amyloid angiopathy (CAA), very common in aged persons and particularly in AD, is increasingly recognized for its association with both pathologies and dementia. To investigate neuropathological differences between LB diseases with and without dementia, 110 PDD and 60 LBD cases were compared with 60 Parkinson's disease (PD) cases without dementia (PDND). The major demographic and neuropathological data were assessed retrospectively. PDD patients were significantly older than PDND ones (83.9 vs 77.8years; p < 0.05); the age of LB patients was in between both groups (mean 80.2years), while the duration of disease was LBD < PDD < PDND (mean 6.7 vs 12.5 and 14.3years). LBD patients had higher neuritic Braak stages (mean 5.1 vs 4.5 and 4.0, respectively), LB scores (mean 5.3 vs 4.2 and 4.0, respectively), and Thal amyloid phases (mean 4.1 vs 3.0 and 2.3, respectively) than the two other groups. CAA was more common in LBD than in the PDD and PDND groups (93 vs 50 and 21.7%, respectively). Its severity was significantly greater in LBD than in PDD and PDND (p < 0.01), involving mainly the occipital lobes. Moreover, striatal Aβ deposition highly differentiated LBD brains from PDD. Braak neurofibrillary tangle (NFT) stages, CAA, and less Thal Aβ phases were positively correlated with LB pathology (p < 0.05), which was significantly higher in LBD than in PDD < PDND. Survival analysis showed worse prognosis in LBD than in PDD (and PDND), which was linked to both increased Braak tau stages and more severe CAA. These and other recent studies imply the association of CAA-and both tau and LB pathologies-with cognitive decline and more rapid disease progression that distinguishes LBD from PDD (and PDND).

Recurrent Hemorrhagic Transformation of Cardioembolic Stroke in an Elderly Patient: A Case Report and Literature Review

Proper therapy for secondary stroke prevention is crucial in the management of cardioembolic stroke. Although oral anticoagulants were the superior strategy for patients with atrial fibrillation and stroke per current evidence, many patients with cardioembolic stroke were prescribed with antiplatelet therapy due to concern for the risk of bleeding from anticoagulation therapy. We presented a case of an 84-years-old male patient who had sudden-onset left hemiparesis from cardioembolic stroke. Past medical history was significant for paroxysmal atrial fibrillation, hypertension and uncontrolled diabetes. Severe white matter hyperintensity (WMH) was identified with the brain imaging. The local hospital initiated antiplatelet therapy with Aspirin 100 mg daily for secondary stroke prevention. Subsequently he was found to have recurrent asymptomatic hemorrhagic transformation involving each of the infarctions. The case report highlighted that severe WMH and possible cerebral amyloid angiopathy could be a risk factor of hemorrhagic transformation and antiplatelet therapy should be used prudently in such condition.

158 Management of Atrial Fibrillation in Patients with Cerebral Amyloid Angiopathy: Multidisciplinary Neuro-Cardiology Approach

Abstract We present two cases that highlight the clinical challenge of anti coagulation in patients with intracerebral haemorrhage (ICH) due to Cerebral Amyloid Angiopathy (CAA) and co-existent non-valvular Atrial Fibrillation (AF). Case 1 78 -Years right-handed functionally independent gentleman presented with right parietal intracerebral haemorrhage (ICH) on Dabigatran that required reversal. He had a background history of hypertension, persistent AF and a previous ICH on warfarin. Post atrial septal defect repair, he had multiple unsuccessful cardioversions for AF, and a failed catheter ablation after the first stroke. Magnetic Resonance Imaging (MRI) brain showed Cerebral Amyloid Angiopathy (CAA), the cause of his recurrent bleeds. Anticoagulation was not started due to severe CAA on imaging and recurrent bleeds. He was referred for left atrial closure device. Case 2 79-Years female presented with left parietal haemorrhage and new onset atrial fibrillation. Work up for ICH showed normal BP readings and clotting profile. Her MRI brain showed a large lobar bleed with mild small vessel disease and evidence of no other imaging features suggestive of CAA. As optimal timing to start anticoagulation after ICH is unknown, she was suggested to take part in a clinical trial. Her family declined the offer of clinical trial and also anti coagulation due to few falls. Her CHAD-VaSc and HAS-BLED score were 4 and 2 respectively. She was then referred to tertiary centre for left atrial appendage closure device. Conclusion Safety and timing to initiate DOAC for AF in this group is not established yet, understanding hemorrhagic risk using Boston Criteria for CAA diagnosis should be considered in addition to HAS-BLED score. Shared decision making and comprehensive discussions with cardiologist are of paramount importance. Non pharmacological intervention studies WATCHMAN and PREVAIL have proven procedural efficacy, however, in elderly population, decision making is complex due to frailty, dementia and co-morbidities.

Abstract P342: Histopathological Correlates of MRI-Visible Perivascular Spaces in Cerebral Amyloid Angiopathy

Perivascular spaces (PVS) are fluid-filled spaces surrounding cerebral blood vessels. MRI-visible, supposedly enlarged, PVS in the centrum semiovale (CSO) have been associated with cerebral amyloid angiopathy (CAA). PVS enlargement may be due to perivascular clearance impairments, potentially caused by increased amyloid-β (Aβ) accumulation in the walls of vessels in the overlying cortex. We test this hypothesis, using MRI-guided histopathological examination of PVS in CAA autopsy cases. The cohort included 19 CAA (74.1±8.2y, 7F) and 5 non-CAA control cases (88.0±4.9y, 3F). Formalin-fixed hemispheres were scanned on a 3T MRI scanner, including a 500μm T2-weighted sequence. PVS enlargement was assessed in the CSO on in vivo and ex vivo MRI. In addition, local score of PVS enlargement was assessed in four pre-defined juxtacortical areas (Fig.A), using a semiquantitative score and on the corresponding histological sections (Fig.B). Severity of leptomeningeal and cortical CAA were assessed on adjacent Aβ-stained sections, using a semiquantitative scale.PVS enlargement was more severe in CAA cases compared to controls, both on in vivo and ex vivo MRI (p&lt;0.05). PVS enlargement on ex vivo MRI positively correlated with the severity of PVS enlargement on the corresponding histopathological samples (Fig.C). Within CAA cases, the degree of PVS enlargement on ex vivo MRI was positively associated with leptomeningeal CAA severity (n=52 samples, ρ=0.35, p=0.011), but not cortical CAA severity (n=52 samples, ρ=0.10, p=0.472). These preliminary findings confirm that the degree of MRI-visible PVS in juxtacortical brain areas reflects enlargement on histopathology. Moreover, they suggest that PVS enlargement in cases with CAA corresponds to increased CAA severity in the overlying leptomeningeal vessels, possibly as a result of impaired perivascular clearance. Future directions include characterization of individual blood vessels associated with PVS enlargement.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and microvascular pathologies in community-dwelling older persons.

Limbic‐predominant age‐related transactive response DNA‐binding protein 43 (TDP‐43) encephalopathy neuropathologic change (LATE‐NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE‐NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co‐occurring LATE‐NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE‐NC in brains from community‐dwelling older persons. Analyses included 749 deceased participants with completed data on LATE‐NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE‐NC. LATE‐NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate‐severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate‐severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01–1.25) after controlling for demographics, AD, and other age‐related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE‐NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13–2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE‐NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE‐NC in the aging brain.

Cerebrospinal fluid biomarkers and apolipoprotein E genotype in cerebral amyloid angiopathy. A narrative review

Sporadic cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease, characterized by the deposition of β-amyloid within the cortical and leptomeningeal blood vessel walls. It has attracted interest concerning new therapeutic perspectives. However, there are scarce data regarding the cerebrospinal fluid biomarkers (CSF) and genetic factors in sporadic CAA. In this narrative review, we investigated the literature regarding the cerebrospinal fluid core biomarkers profile of patients with probable or possible CAA and its subtype, the CAA- related inflammation (CAA-ri), taking into account the clinical and radiological characteristics of the patients. We also analyzed the Apolipoprotein E (APOE) genotype differentiations among the different subtypes of cerebral amyloid angiopathy. Our results demonstrate specific CSF patterns of β-amyloid (Aβ42 and Aβ40) and tau-proteins (t-tau and p-tau) which may serve as molecular biomarkers for CAA/ CAA-ri and could prove helpful for novel therapeutic procedures. Specifically, decreased levels of Aβ40 and Aβ42 in both CAA and CAA-ri, mildly increased concentrations of tau protein in patients with CAA-ri and a strong association between APOE ε4/ε4 genotype and CAA-ri are the main findings.

Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.

Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy

AbstractBackgroundCortical superficial siderosis (cSS) is an established hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA) and emerging as a strong independent risk factor for future lobar intracerebral hemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cSS remain elusive.MethodFourteen autopsy cases with CAA (mean age at death 73 years, 9 males) and three controls (mean age at death 91 years, 1 male) were included. Intact formalin‐fixed cerebral hemispheres were scanned on a 3 tesla MRI scanner. cSS was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, eleven representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI‐defined cSS. In addition, samples were taken from pre‐defined standard areas of the brain, blinded to MRI findings. Serial sections were stained for H&amp;E and Perls’ Prussian blue, and immunohistochemistry was performed against Aβ and GFAP.ResultcSS was present on ex vivo MRI in 8/14 cases and 0/3 controls. Histopathologically, cSS corresponded to Iron‐positive hemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels (Figure 1). Increased severity of cSS was associated with upregulation of reactive astrocytes. Next, cSS and CAA pathology were assessed on a total of 65 sections from MRI‐targeted and untargeted samples. Moderate‐to‐severe cSS was associated with concentric splitting (an advanced form of CAA‐related vascular damage) of the walls of leptomeningeal vessels (p&lt;0.0001), but reduced CAA severity in cortical vessels (p=0.048). Moderate‐to‐severe cSS was associated with the presence of microinfarcts (p=0.025), though not microbleeds (p=0.973).ConclusioncSS on MRI corresponds to Iron‐positive depositions in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. cSS appears to be the result predominantly of advanced CAA of the leptomeningeal vessels and may trigger secondary ischemic injury in affected areas.

A practical approach to the management of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-β deposition. Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults. This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflammation, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for potential future interventions.