Mild Cerebral Amyloid Angiopathy Research Articles

A case of probable cerebral amyloid angiopathy preceded by symmetrical diffusion‐weighted imaging lesions

AbstractPatients who initially have Alzheimer’s disease dementia with no or mild cerebral amyloid angiopathy (CAA) might later develop CAA‐related inflammation. We described a 76‐year‐old man with possible Alzheimer’s disease dementia and steroid‐responsive probable CAA‐related inflammation. Initial diffusion‐weighted imaging demonstrated symmetrical high signal intensities in the bilateral posterior region, which might suggest ischemia and predilection of CAA pathology for posterior brain regions. Magnetic resonance images thereafter demonstrated asymmetrical cortical swelling in the left temporo‐parieto‐occipital region with leptomeningeal enhancement, which might show subtle cerebrovascular immunological response may influence the subsequent distinct differences.

The Impact of Cerebral Amyloid Angiopathy in Various Neurodegenerative Dementia Syndromes: A Neuropathological Study

Purpose The Boston criteria for cerebral amyloid angiopathy (CAA) have to be confirmed by postmortem examination. The present study investigates the incidence and the cerebrovascular impact of the severity of CAA in various neurodegenerative dementia diseases. Material and Methods 208 patients underwent an autopsy. They consisted of 92 brains with Alzheimer's disease (AD), 46 with frontotemporal lobar degeneration (FTLD), 24 with progressive supranuclear palsy (PSP), 21 with Lewy body dementia (LBD), 5 with corticobasal degeneration (CBD), and 20 controls. In addition to the macroscopic examination, a whole coronal section of a cerebral hemisphere, at the level of the mamillary body, was taken for semiquantitative microscopic evaluation of the small cerebrovascular lesions. Results CAA is present in 2/3% of the AD brains of which half of them have a severe form, grade 3. Only the latter displays more cerebrovascular lesions. CAA is present in 45% of the LBD brains. Cortical microinfarcts are only more frequent in the CAA grade 3 group. In LBD additional AD pathology is present in 41% of the CAA grade 0, 83% in grade 1-2, and 100% in grade 3. In PSP only 21% had CAA grade 1-2. In FTLD, CBD, and normal controls no CAA pathology is observed. Conclusions The present study shows that CAA is most frequently associated to AD but that only the severe form displays more cerebrovascular lesions. LBD is the second most frequent disease associated to CAA with a clear correlation between the incidence of the associated AD features and the increasing severity of the CAA. In PSP only 21% display mild CAA features. PSP, tau-FTLD, and CBD are part of the Pick complex diseases, who are known to have a favourable vascular profile which can explain their low incidence of cerebrovascular lesions, in contrast to AD and LBD brains.

The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study

SummaryBackgroundIdentification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype.MethodsWe identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy.FindingsAmong 110 adults (median age 83 years [IQR 76–87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86–0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88–100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78–100).InterpretationThe CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage.FundingUK Medical Research Council, The Stroke Association, and The Wellcome Trust.

CT scanning to diagnose CAA: back to the future?

CT scanning to diagnose CAA: back to the future?

Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aβ deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aβ-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aβ deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aβ deposits in senile plaques. Furthermore, we demonstrated that both Aβ40 and Aβ42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aβ40. Knockdown of SRPX1, in contrast, reduced the formation of Aβ40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aβ deposits and that may increase Aβ-induced cerebrovascular degeneration in CAA.

CEREBRAL AMYLOID ANGIOPATHY AND ALZHEIMER'S DISEASE

Deposition of ß-amyloid peptide in the cerebral arterioles, small arteries, and capillaries, designated as cerebral amyloid angiopathy (CAA), is a nearly universal accompanying feature of Alzheimer's Disease (AD). Mild CAA appears to have little effect on vessels, but more advanced stages are associated with vascular rupture and intracerebral hemorrhage as well as with impaired vascular function, nonhemorrhagic brain lesions, and cognitive impairment. The Religious Orders Study, for example, demonstrated worse perceptual speed and episodic memory-independent of AD pathology and other covariates-among the one-fifth of individuals with moderate-to-very severe CAA. These findings suggest that AD and CAA might frequently act in concert to produce mixed dementia. A second link between AD and CAA are the striking similarities between the vasogenic edema-amyloid related imaging abnormalities (ARIA-E) seen in AD immunotherapy trials and the spontaneous syndrome of CAA-related inflammation. CAA-related inflammation appears to be driven by cerebrospinal production of anti-amyloid autoantibodies, indicating a shared mechanism for the two syndromes. Despite concerns about antibody-mediated adverse events, the key pathogenic role of ß-amyloid in CAA makes anti-amyloid immunotherapy a rational therapeutic approach for this largely untreatable disease.

The incidence of cerebral amyloid angiopathy in surgically treated intracranial hemorrhage in the Chinese population

Despite being widely accepted as an important cause of spontaneous intracranial hemorrhage (ICH), cerebral amyloid angiopathy (CAA) has seldom been studied in the Chinese population. The current study aims to investigate the incidence and features of CAA in surgically treated ICH patients in China. From May 2006 to April 2011, 974 patients admitted to 71 hospitals throughout China for acute spontaneous ICH were studied. Craniotomy for hematoma evacuation was performed. Brain tissue from the superficial side of the suspected residual hematoma cavity, as well as from the cortex and subcortex, was obtained. Congo Red stain and β-amyloid immunohistochemistry were used for the diagnosis. Each case was assigned a pathological severity score. Of the 974 involved patients, 37.7% were identified with CAA of different degrees. CAA had positive correlation with age and was independent of sex. Most patients had mild CAA with only the superficial vessels involved in lobes instead of the basal ganglia; the patients ≥65 years had more severe pathological score of CAA than those <65 years and had more lobes and cerebellum involved than the latter. More than one third of the surgically treated Chinese ICH patients may have CAA of different degrees.

Original article The association between cerebral amyloid angiopathy and atherosclerosis in patients with intracerebral hemorrhages

aim of the study: To analyze the incidence and grade of cerebral amyloid angiopathy (CAA) and atherosclerosis (AS) in cerebral vessels in patients who died from spontaneous intracerebral hemorrhage. The clinical diagnosis, based on CT scans of the brain, was made and immunohistochemic neuropathological examinations were performed in patients with intracerebral hemorrhages due to CAA. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria. The Vonsattel and Mountoy scales were used to assess the grade and score of CAA. Atherosclerosis was assessed according to a four-grade scale presented in the Coding Guide from Collaborative Study of Epidemiological Factors in Cerebral Vascular Disease. Of the 189 patients who died due to intracerebral hemorrhages 42 (22%) presented CAA. According to the Vonsattel scale this group comprised 32 (76%) patients who showed severe, 6 (14%) moderate and 4 (10%) mild CAA. Atherosclerosis was diagnosed in the CAA group of patients as follows: 6 (14%) with grade 1; 20 (49%) with grade 2; 9 (20%) with grade 3; and 7 (17%) patients with grade 4. There was no correlation between CAA and AS. The CAA was probably the direct cause of death in part of cases with advanced CAA. The different mechanisms presumably can cause CAA and AS.

Original article β-amyloid deposits in veins in patients with cerebral amyloid angiopathy and intracerebral haemorrhage

To review the incidence and grade of cerebral amyloid angiopathy (CAA) in veins in patients who died due to spontaneous intracerebral haemorrhage (ICH). Neuropathological examinations were performed in the study group of 189 patients. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria and confirmed during an autopsy. The Vonsattel and Mountjoy scales were used to assess the grade and scores of CAA. In the study group composed of 189 ICH patients, 42 presented CAA. In the microscopic examination, of the 42 patients 33 (78%) showed β-amyloid deposits in veins, which makes 17% of the total group of patients with ICH. In this group, the age ranged from 54 to 97 (mean age 80.18 ± 8.15 years). A group of 33 (27 women and 6 men) patients comprised 15 (45%) patients with severe CAA, 13 (40%) with moderate and 5 (15%) with mild CAA classified according to the Vonsattel scale. According to the Mountjoy scale 28 (85%) patients had a score of 4, which indicated the total involvement of the vessel. β-amyloid deposits in veins were found in 78% of patients with CAA and ICH, which makes 17% of the total group of patients with ICH. Interestingly, β-amyloid deposits in veins are not so rare in patients with CAA who died due to intracerebral haemorrhage. Cerebral amyloid angiopathy localization in the veins of the brain was observed more frequently than previously suspected. Veins may play a role in the elimination of β-amyloid from the brain.

Cerebral Microinfarcts Associated with Severe Cerebral β‐Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is common in elderly individuals, especially those affected with Alzheimer's disease. Eighteen brains with severe SCAA (SCAA) were compared with 21 brains with mild CAA (MCAA) to investigate whether the presence of SCAA in the brains of demented patients was associated with a higher burden of old microinfarcts than those with MCAA. Immunohistochemistry for CD68 was employed to highlight old microinfarcts in tissue blocks from various brain regions. Old microinfarcts, manually counted by light microscopy, were present in 14 of 18 SCAA brains and in 7 of 21 MCAA brains (P = 0.01, two-tailed Fisher's exact test). The average number of old microinfarcts across geographic regions in each brain ranged from 0 to 1.95 (mean rank 24.94, sum of ranks 449) in the SCAA group, and from 0 to 0.35 (mean rank 15.76, sum of ranks 331) in the MCAA group (P = 0.008, two-tailed Mann-Whitney U-test). Frequent old microinfarcts in demented individuals with severe CAA may contribute a vascular component to the cognitive impairment in these patients.

Angiotensin‐converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE‐1 to cerebral amyloid angiopathy

Several observations point to the involvement of angiotensin-converting enzyme-1 (ACE-1) in Alzheimer's disease (AD): ACE-1 cleaves amyloid-beta peptide (Abeta) in vitro, the level and activity of ACE-1 are reportedly increased in AD, and variations in the ACE-1 gene are associated with AD. We analysed ACE-1 activity and expression in AD and control brains, particularly in relation to Abeta load and cerebral amyloid angiopathy (CAA). ACE-1 activity was measured in the frontal cortex from 58 control and 114 AD cases of known Abeta load and CAA severity. The distribution of ACE-1 was examined immunohistochemically. In five AD cases with absent or mild CAA, five with moderate to severe CAA and five controls with absent or mild CAA, levels of vascular ACE-1 were assessed by quantitative immunofluorescence. ACE-1 activity was increased in AD (P < 0.001) and correlated directly with parenchymal Abeta load (P = 0.05). Immunohistochemistry revealed ACE-1 in neurones and cortical blood vessels - in the intima but most abundant perivascularly. Cases with moderate to severe CAA had significantly more vessel-associated ACE-1 than did those with little or no CAA. Perivascular ACE-1 did not colocalize with Abeta, smooth muscle actin, glial fibrillary acidic protein, collagen IV, vimentin or laminin, but was similarly distributed to extracellular matrix (ECM) proteins fibronectin and decorin. Our findings indicate that ACE-1 activity is increased in AD, in direct relationship to parenchymal Abeta load. Increased ACE-1, probably of neuronal origin, accumulates perivascularly in severe CAA and colocalizes with vascular ECM. The possible relationship of ACE-1 to the deposition of perivascular ECM remains to be determined.

Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype

There is growing evidence that in Alzheimer's disease (AD) amyloid beta-protein (Abeta) triggers a chronic inflammatory reaction in cerebral amyloid plaques, including complement proteins. Abeta also accumulates cerebrovascularly in age- and AD-associated cerebral amyloid angiopathy (CAA). We investigated complement proteins in CAA in a population-based series using histological and immunohistochemical staining methods. The 74 subjects, aged 95 years or more, had undergone clinical neurological examination and apolipoprotein E (ApoE) genotyping. The brains had been studied for AD post-mortem, allowing us to relate the histopathological findings to clinical and genetic conditions. CAA with congophilic amyloid was found in 36/74 individuals (48.6%). The vascular amyloid deposits immunoreacted with antibodies to Abeta and complements 3d (C3d) and 9 (C9). The positivity in complement stains increased with growing severity of CAA (P = 0.001). The presence of CAA associated with ApoE epsilon4 (P = 0.0005) and overrepresentation of epsilon4 among those with moderate or severe vs. mild CAA (P = 0.03) was demonstrated. The presence of CAA associated with dementia (P = 0.01), which was contributed by both epsilon4+ (P = 0.02) and epsilon4- (P = 0.06) subjects. Our study shows that complement proteins are deposited in the affected vessels in Abeta-associated CAA. They may solely represent the cerebral Abeta- burden associated to inflammatory stimuli, or signal a contribution in the clearance of cerebral Abeta, thereby contributing to the events associated with evolution of clinical dementia. Our results demonstrate a strong association between CAA and ApoE epsilon4 as well as dementia and suggest that the contribution of CAA to dementia is largely independent of ApoE epsilon4.

Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy.

Examination of cortical tissue obtained surgically is an important tool for diagnosis of cerebral amyloid angiopathy (CAA) during life. Analysis of a single sample of cortical tissue, however, might lead to conclusions that are either falsely positive (because of the high frequency of CAA in the healthy elderly) or falsely negative (because of the patchy distribution of CAA pathology). We therefore attempted to estimate the sensitivity and specificity of cortical biopsy for diagnosis of CAA as the cause of intracerebral hemorrhage. To simulate biopsy in CAA, we took biopsy-sized cortical samples from postmortem brains with known extents of CAA: either CAA-related hemorrhage or mild to severe CAA without hemorrhage. Samples were stained with the use of methods routinely available in surgical pathology laboratories and blindly examined for vascular amyloid and amyloid-related vasculopathic changes. The presence of vascular amyloid was a sensitive marker for CAA-related hemorrhage, occurring in all 28 specimens from brains with hemorrhage. Conversely, the appearance of fibrinoid necrosis in amyloid-laden vessels was relatively specific for CAA-related hemorrhage. This finding occurred in 13 of the 28 specimens (46%) from brains with hemorrhage but in none of 27 sections from brains with mild CAA and in only 4 of 42 specimens with moderate to severe CAA without hemorrhage. These data help to define criteria for the diagnosis of CAA-related hemorrhage from surgical specimens.