Incidence Of Cerebral Amyloid Angiopathy Research Articles

2.Cerebrovascular neuropathology in the brains of people with Down syndrome

AbstractBackgroundPeople with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), people with DS show an age‐related progression of cerebral amyloid angiopathy (CAA), white matter hyperintensities, microbleeds, micro infarcts, and enlarged perivascular spaces by neuroimaging. Interestingly, the incidence of CAA at autopsy is significantly higher in people with DS than patients with late onset AD. Our main objective is to investigate the cerebrovascular pathology in DS autopsy cases.MethodFree floating 30 µm thick sections from the occipital cortex of DS cases with or without AD pathology (DSAD and DS, respectively, n = 5/group) were compared to age matched cognitively normal controls (n = 5). Sections were immunostained for collagen IV (basement membranes) and for fibrinogen (protein extravasation).ResultPreliminary results show that compared to controls, DSAD brains have impaired vascular integrity, observed as reduced collagen IV basement membrane labeling and evidence of protein extravasation which may reflect microbleeds observed using in vivo neuroimaging.ConclusionOur preliminary data suggest a disruption of blood vessel basement membranes observed as losses in collagen IV immunostaining in DSAD brains. Moreover, fibrinogen extravasation was consistently observed in DSAD brains. We are currently characterizing the age of onset of collagen IV disruption/losses and fibrinogen leakage into the brain parenchyma in the context of an AT(N) framework to understand when in AD progression, cerebrovascular pathology evolves in DS.

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.

Human Apolipoprotein E4 Targeted Replacement Mice Show Increased Prevalence of Intracerebral Hemorrhage Associated with Vascular Amyloid Deposition

Previous studies show that APOE *4 carriers are at increased risk for ischemic stroke and intracerebral hemorrhage (ICH). The APOE *4 gene is also linked to increased incidence of cerebral amyloid angiopathy. It has been suggested that apolipoprotein E4 expression leads to increased vascular amyloid deposition, which may explain the increased incidence of ICH in APOE *4 carriers. Here we show a significant increase in ICH in apoE4 targeted replacement mice compared with apoE3 mice. In all, 89% of the vessels in the apoE4 mice that showed evidence for hemorrhage contained fibrillar amyloid beta based on thioflavine-S staining. Aged apoE4 mice contained predominantly vascular amyloid deposits in the frontal cortex and hippocampus, but also showed evidence for parenchymal amyloid deposits. Most of the parenchymal amyloid appeared diffuse in nature; however, a small fraction was thioflavine-S positive, indicating presence of fibrillar amyloid. Electron microscopy further revealed evidence for fibrillar deposits in the vessel walls of apoE4 mice, but not apoE3 mice. The apoE4 targeted replacement mice do not harbor any mutation in the amyloid precursor protein gene and, therefore, are similar to the majority of humans susceptible to cerebral amyloid angiopathy and ICH, where the APOE genetic polymorphism is the only known genetic risk factor.

Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology

Cerebral amyloid angiopathy (CAA) is defined by β-amyloid peptide (Aβ) depositions in cerebral vessels and is associated with Alzheimer disease (AD). It has been suggested that severe CAA is an independent risk factor for cognitive decline. 171 autopsy brains underwent standardized neuropathological assessment, the patients age ranged from 54 to 104 years (mean age: 83.9 years, +/− 9.2, 59.6% female, 56.1% clinically demented). Using immunohistochemistry, the severity of Aβ depositions in vessels was assessed semiquantitatively in the frontal, frontobasal, hippocampal, and occipital region, respectively. CAA was present in 117 cases (68.4%), with the occipital region being affected significantly stronger than other regions. The overall incidence of CAA was significantly higher in cases with high grade neuritic AD pathology (ADP) compared to those with low grade or no ADP. The severity of CAA significantly increased with increasing ADP, with CAA in the occipital region increasing significantly stronger than that in other regions. The association of CAA and clinical dementia failed to remain statistically significant when adjusting for concomitant ADP. However, in cases devoid of any ADP CAA was significantly associated with the presence of clinical dementia. These results indicate a strong association of AD with CAA, but do not unequivocally support reports suggesting CAA to be an independent risk factor for cognitive decline, except for a subgroup of demented patients lacking any ADP.

Role of Peroxynitrite in the Vasoactive and Cytotoxic Effects of Alzheimer's β-Amyloid1–40Peptide

Increasing evidence implicates oxidative stress as partially responsible for the neurodegenerative process of Alzheimer's disease (AD). Recent reports show an increased production of nitrotyrosine in AD brains, suggesting that peroxynitrite is produced in excess in this disease. Furthermore, incidence of cerebral amyloid angiopathy in AD cases is very frequent (83%), strongly suggesting a vascular component of AD pathogenesis. We have evaluated the hypothesis that peroxynitrite could be responsible for mediating the cytotoxicity and vasoactivity induced by the amyloid-β1–40(Aβ) peptide. Rat brain endothelial cells (RBE-4) appear to be sensitive to Aβ-induced toxicity but not to the cytotoxicity induced by peroxynitrite. Addition of Cu/Zn superoxide dismutase to cell culture media, which is only able to clear extracellular superoxide, was not effective in blocking Aβ-induced toxicity. However, we were able to partially block Aβ-induced cytotoxicity by using Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) which dismutes superoxide intracellularily. Yet, MnTBAP was not able to prevent the vasoactivity triggered by Aβ. Moreover, addition of peroxynitrite to rat aortae did not modulate the vasotension induced by Aβ. We conclude that intracellular superoxide radicals may contribute to Aβ-induced cytotoxicity. Our results also indicate that peroxynitrite does not significantly contribute to Aβ-induced cytotoxicity in rat brain endothelial cells (RBE-4) or vasoactivity in rat aortae. These results suggest that therapeutic efforts aimed at removal of reactive oxygen species with SOD is unlikely to be beneficial for treatment of Aβ-induced endothelial dysfunction. However, compounds that clear free radicals intracellularly may well be beneficial.

Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan.

The incidence of cerebral amyloid angiopathy in a general population was evaluated in brains of 400 consecutive autopsies of residents of Hisayama, Japan (November 1971-October 1983). Six samples taken from frontal lobe, parietal lobe, temporal lobe, occipital lobe, hippocampus, and basal ganglia of the same side of each brain were stained with both hematoxylin and eosin and Congo red. The specimens were surveyed microscopically with polarized light for deposition of amyloid in the vascular wall. In 26 cases with brain hemorrhage, the region surrounding the hemorrhagic sites was further examined to study the probable causal relation between cerebral amyloid angiopathy and brain hemorrhage. Cerebral amyloid angiopathy was found in 40 of 218 men (18.3%) and 51 of 182 women (28.0%). The incidence increased with age in both sexes. The frontal lobe was most frequently affected (66 cases), followed by parietal lobe (65), occipital lobe (49), temporal lobe (44), and hippocampus (32); the putamen was never affected. The incidence of cerebral amyloid angiopathy did not correlate with blood pressure or with the severity of cerebral atherosclerosis. Among the 26 cases in which there was brain hemorrhage, only one cerebellar hemorrhage, in an 85-year-old man, was attributed to cerebral amyloid angiopathy. This case showed four microaneurysms in vessels, with cerebral amyloid angiopathy surrounding the hemorrhagic site. Thirty similar lesions were observed in eight cases without brain hemorrhage. Cerebral amyloid angiopathy may play an etiologic role in the development of brain hemorrhage through formation of angionecrosis and microaneurysm.

Cerebral amyloid angiopathy in dementia and old age.

A necropsy study of 159 elderly patients drawn mainly from a prospectively assessed geriatric hospital population was carried out to investigate the relationship of cerebral amyloid angiopathy to Alzheimer's disease, other CNS disease and ageing. About half the patients were demented and the majority of these had Alzheimer's disease. In Alzheimer's disease there was an incidence of cerebral amyloid angiopathy of 82%. Among the other groups of patients, both demented and non-demented, the incidence of cerebral amyloid angiopathy was a little over 30%, and remained constant between 60 and 102 years of age.

The incidence of cerebral amyloid angiopathy in Alzheimer's disease.

The incidence and forms of cerebral amyloid angiopathy were studied in 15 cases of Alzheimer's disease using Congo red staining and polarization. Thirteen cases showed slight to severe involvement; two contained no amyloid vascular degeneration. There was a correlation between the presence of amyloid-rich plaques and cerebral amyloid angiopathy (especially the plaque-like angiopathy) but no correlation with "amyloid-poor" senile plaques or Alzheimer's neurofibrillary degeneration.