Cerebral Amyloid Angiopathy in Stroke Medicine.
Ontology highlight
ABSTRACT:
SUBMITTER: Block F
PROVIDER: S-EPMC5541242 | biostudies-other | 2017 Jan
REPOSITORIES: biostudies-other
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Project description:Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.
| S-EPMC4325636 | biostudies-literature
Project description:Amyloid-? (A?) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). A? pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early A? pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that A? pathology may be transmissible, as prion disease is, through neurosurgical procedures.
| S-EPMC5904220 | biostudies-literature
Project description:Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid protein in the walls of cerebral blood vessels. This deposition of amyloid causes damage to the cerebral vasculature, resulting in blood-brain barrier disruption, cerebral hemorrhage, cognitive decline, and dementia. The role of the immune system in CAA is complex and not fully understood. While the immune system has a clear role in the rare inflammatory variants of CAA (CAA related inflammation and Abeta related angiitis), the more common variants of CAA also have immune system involvement. In a protective role, immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. The immune system can also contribute to CAA pathology, promoting vascular injury, blood-brain barrier breakdown, inflammation, and progression of CAA. In this review, we summarize the role of the immune system in CAA, including the potential of immune based treatment strategies to slow vascular disease in CAA and associated cognitive impairment, white matter disease progression, and reduce the risk of cerebral hemorrhage. HIGHLIGHTS: The immune system has a role in cerebral amyloid angiopathy (CAA) which is summarized in this review. There is an inflammatory response to beta-amyloid that may contribute to brain injury and cognitive impairment. Immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. Improved understanding of the immune system in CAA may afford novel treatment to improve outcomes in patients with CAA.
| S-EPMC11247707 | biostudies-literature
Project description:BackgroundThere is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).ObjectiveTo determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.MethodsWe 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.ResultsWe 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.ConclusionCAA 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.
| S-EPMC7242825 | biostudies-literature
Project description:Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm(2) in mild, 0.584/cm(2) in moderate, and 4.370/cm(2) in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
| S-EPMC3282897 | biostudies-literature
Project description:We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17-44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.
| S-EPMC8028507 | biostudies-literature
Project description:Background and Purpose- Hematoma location within the cerebellum may help identify the dominant small vessel disease type (cerebral amyloid angiopathy [CAA] versus nonamyloid small vessel disease). However, it is unknown whether this holds true for cerebral microbleeds (CMBs) within the cerebellum. We tested the hypothesis that cerebellar CMBs restricted to the cortex and vermis (defined as superficial regions) are associated with clinically diagnosed and pathology-verified CAA. Methods- Three hundred and seven consecutive spontaneous intracerebral hemorrhage (ICH) patients with a baseline magnetic resonance imaging that included susceptibility-weighted imaging or angiography were enrolled. Using a topographical template, cerebellar CMB patterns were defined as strictly superficial versus deep (cerebellar gray nuclei and white matter) or mixed (both regions involved). Thirty-six ICH patients with cerebellar CMBs and neuropathology data available were evaluated for the presence of CAA. Results- One hundred and thirty-five (44%) ICH patients had CMBs in the cerebellum. In the patient group with cerebellar CMBs, 85 (63%) showed a superficial pattern, and 50 (37%) had a deep/mixed pattern. Strictly superficial cerebellar CMBs were independently associated with a supratentorial pattern of probable CAA-ICH according to the Boston criteria (odds ratio, 1.6; CI, 1.03-2.5) and deep/mixed cerebellar CMBs with a pattern of deep/mixed ICH (odds ratio, 1.8; CI, 1.2-2.7). Pathologically verified CAA was present in 23 of 24 (96%) patients with superficial cerebellar CMBs versus 3 of 12 (25%) patients with deep/mixed cerebellar CMBs ( P<0.001). Conclusions- In ICH patients, cerebellar CMBs are relatively common and often restricted to superficial regions. A strictly superficial distribution of cerebellar CMBs is associated with clinically diagnosed and pathologically verified CAA.
| S-EPMC6599711 | biostudies-literature
Project description:OBJECTIVE:To determine whether common genetic variants in UNC5C, a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes. METHODS:We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the UNC5C gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, ?-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) UNC5C RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies. RESULTS:A set of UNC5C SNPs tagged by rs28660566T was associated with a higher CAA score (p = 2.3 × 10-6): each additional rs28660566T allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of APOE ?4. rs28660566T was weakly associated with lower UNC5C expression in the human DLPFC (p = 0.036). Moreover, rs28660566T had a synergistic interaction with APOE ?4 on their association with higher CAA severity (p = 0.027) and was associated with more severe arteriolosclerosis (p = 0.0065). CONCLUSIONS:Targeted analysis of the UNC5C region uncovered a set of SNPs associated with CAA.
| S-EPMC5515600 | biostudies-literature
Project description:Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions.
| S-EPMC3581946 | biostudies-literature
Project description:Cerebral amyloid angiopathy (CAA) corresponds to the deposition of amyloid material in the cerebral vasculature, leading to structural modifications of blood vessel walls. The most frequent form of sporadic CAA involves fibrillar β-amyloid peptide (Aβ) deposits, mainly the 40 amino acid form (Aβ1-40), which are commonly found in the elderly with or without Alzheimer's disease. Sporadic CAA usually remains clinically silent. However, in some cases, acute complications either hemorrhagic or inflammatory can occur. Similar complications occurred after active or passive immunization against Aβ in experimental animal models exhibiting CAA, and in subjects with Alzheimer's disease during clinical trials. The triggering of these adverse events by active immunization and monoclonal antibody administration in CAA-bearing individuals suggests that analogous mechanisms could be involved during spontaneous CAA complications, drawing particular attention to the role of anti-Aβ antibodies. However, antibodies that react with several monomeric and aggregated forms of Aβ spontaneously occur in virtually all human individuals, hence being part of the "natural antibody" repertoire. Natural antibodies are usually described as having low-affinity and high cross-reactivity toward microbial components and autoantigens. Although frequently of the IgM class, they also belong to IgG and IgA isotypes. They likely display homeostatic functions and protective roles in aging. Until recently, the peculiar properties of these natural antibodies have hindered proper analysis of the Aβ-reactive antibody repertoire and the study of their implication in CAA complications. Herein, we review and comment the evidences of an auto-immune nature of spontaneous CAA complications, and discuss implications for forthcoming research and clinical practice.
| S-EPMC6620823 | biostudies-literature