Reversible acute leukoencephalopathy as a form of presentation in cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) may present as cerebral haemorrhage, cerebral infarction and periventricular white matter lesions. Reversible leukoencephalopathy is a rare manifestation of CAA.Aims of the studyTo describe two patients with reversible acute leukoencephalopathy as the first manifestation of CAA.PatientsTwo consecutive patients were admitted to our neurology department with transient focal neurological symptoms. They showed reversible focal leukoencephalopathy on magnetic resonance imaging (MRI). CAA was finally diagnosed in both, and pathologically confirmed in one. The latter patient showed multiple foci of petechial bleeding in the cortex and subcortex in T2-weighted GRE sequences, suggestive of CAA.ConclusionReversible acute focal leukoencephalopathy may be an infrequent clinical and radiological pattern of CAA.     

Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease

Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta3) in cerebral vessels, has been implicated as a common cause of hemorrhagic stroke and other forms of vascular disease. CAA is also a frequent concomitant of Alzheimer disease (AD). While the longterm consequences of CAA are well recognized from clinical and pathologic studies, numerous questions remain unanswered regarding the progression of the disease. Examination of CAA in traditional histologic sections does not easily allow for characterization of CAA, particularly in leptomeningeal vessels. In order to approach this topic, we used low magnification imaging of intact, postmortem brains from transgenic mouse models of AD-like pathology to define the spatial and temporal characteristics of CAA in leptomeningeal vessels. Imaging of brains from 10- to 26-month-old animals demonstrated a stereotypical pattern to the development of CAA, with vessels over the dorsal surface of the brain showing an anterior-to-posterior and large-to-small vessel gradient of involvement. High magnification imaging revealed that CAA deposition began with a banding pattern determined by the organization of the vascular smooth muscle cells. Further analysis of the pattern of amyloid deposits showed shrinkage and disappearance of the gaps between clusters of amyloid bands, gradually reaching a confluent pattern. These data led to a classification system to describe the severity of CAA deposition and demonstrate the potential of using intact brains to generate maps defining the progression and kinetics of CAA. This approach should lead to more informed analysis of the consequences of evolving therapeutic options for AD on this related form of vascular pathology.     

A phase 2 study of tramiprosate for cerebral amyloid angiopathy

BACKGROUND AND PURPOSE: No treatments have been identified to lower the risk of intracerebral hemorrhage due to cerebral amyloid angiopathy (CAA). A potential approach to prevention is the use of agents that interfere with the pathogenic cascade initiated by the beta-amyloid peptide (Abeta). Tramiprosate (3-amino-1-propanesulfonic acid) is a candidate molecule shown in preclinical studies to reduce CAA in a transgenic mouse model. METHODS: We performed a 5-center phase 2 double-blinded trial to evaluate the safety, tolerability, and pharmacokinetics of tramiprosate in subjects with lobar intracerebral hemorrhage. Twenty-four subjects age > or =55 years with possible or probable CAA were randomized to receive 12 weeks of tramiprosate at 1 of 3 oral doses (50, 100, or 150 mg twice daily). Subjects were followed for clinical adverse effects, laboratory, vital sign, electrocardiogram, cognitive, or functional changes, appearance of new symptomatic or asymptomatic hemorrhages, and pharmacokinetic parameters. RESULTS: Enrolled subjects were younger (mean age 70.8+/-5.4, range 61 to 78) and had more advanced baseline disease (measured by number of previous hemorrhages) than consecutive subjects in a CAA natural history cohort. No concerning safety issues were encountered with treatment. Nausea and vomiting were the most common adverse events and were more frequent at high doses. Nine subjects had new symptomatic or asymptomatic hemorrhages during treatment; all occurred in subjects with advanced baseline disease, with no apparent effect of drug dosing assignment. CONCLUSIONS: These data suggest that tramiprosate can be given safely to subjects with suspected CAA and support future efficacy trials.     

Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy

Neprilysin (NEP) degrades amyloid-beta (Abeta) and is thought to contribute to its clearance from the brain. In Alzheimer disease (AD), downregulation of NEP has been suggested to contribute to the development of cerebral amyloid angiopathy (CAA). We examined the relationship among NEP, CAA, and APOE status in AD and elderly control cases. NEP was most abundant in the tunica media of cerebrocortical blood vessels and in pyramidal neurons. In homogenates of the frontal cortex, NEP protein levels were reduced in AD but not significantly; NEP enzymatic activity was significantly reduced in AD. Immunohistochemistry revealed a reduction of both vascular and parenchymal NEP. The loss of vessel-associated NEP in AD was inversely related to the severity of CAA, and analysis of cases with severe CAA showed that levels of vascular NEP were reduced to the same extent in Abeta-free and Abeta-laden vessels, strongly suggesting that the reduction in NEP is not simply secondary to CAA. Possession of APOE epsilon4 was associated with significantly lower levels of both parenchymal and vascular NEP. Colinearity of epsilon4 with the presence of moderate to severe CAA precluded assessment of the independence of this association from NEP levels. However, logistic regression analysis showed low NEP levels to be a significant independent predictor of moderate to severe CAA.     

Immunohistochemical study of constituents other than β-protein in canine senile plaques and cerebral amyloid angiopathy

To clarify the significance of the constituents of canine senile plaques (SPs) or cerebrovascular amyloid deposits, paraffin and cryostat sections of canine brains were examined by immunohistochemistry using antibodies against cathepsin B (CB), cathepsin D (CD), cystatin C (CC), α-1-antichymotrypsin (ACT), heat shock protein 70 (HSP70), ubiquitin (Ubq), and apolipoprotein E (Apo E). On the cryostat sections, all types of canine SPs and cerebrovascular amyloid deposits in both arterioles and capillaries were positive for Apo E. On paraffin sections, the Apo E immunoreactivity of diffuse plaques was weak and varied according to the method of fixation or pretreatment before immunostaining. Moreover, amyloid plaques were found to contain several elements that were positive for CC, ACT, CD, and Ubq, and a subset of vascular amyloid deposits around cortical capillaries showed significant immunoreactivity for CD, CC, and ACT. In addition, vascular amyloid deposits in the arterioles showed moderate CD immunoreactivity and were intensely Apo E positive. No significant labeling of canine SPs or vascular amyloid deposits was detected when the antibodies against CB and HSP 70 were applied to the cryostat and paraffin sections. These results indicated that, of the constituents examined, Apo E might be most closely related to canine β-amyloidosis in the early stage of this brain disorder. Received: 16 June 1996 / Revised: 28 May 1996, 24 June 1996, 8 August 1996 / Accepted: 8 August 1996     

The impact of cerebral amyloid angiopathy on the occurrence of cerebrovascular lesions in demented patients with Alzheimer features: a neuropathological study

Objective: The aim of this neuropathological study was to determine the prevalence of the different cerebrovascular lesions to be attributed to cerebral amyloid angiopathy (CAA) and of those associated with the severity of the Alzheimer dementia (AD) itself. Patients and methods: The cerebrovascular lesions were compared separately in 40 brains of patients with mild and 50 with severe AD features. In the two groups, the number of lesions were compared between the brains with severe and those with mild of absent CAA. Results: The age of the patients, the vascular risk factors and antithrombotic treatment were similar in all the compared groups. The brains with mild and severe AD features and with CAA contained more haematomas, cortical micro‐infarcts and micro‐bleeds, and more severe white matter changes, and cortico‐subcortical and white matter mini‐bleeds. In the CAA brains with severe AD features, also more cortical territorial infarcts were observed, compared to those with mild AD features. Conclusions: The increase in cortical infarcts cannot be attributed to the CAA alone, but also to the severity of the degenerative features, implying additional vascular factors in the pathogenesis of AD.     

Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease

Senile plaques (SPs) containing amyloid β peptide (Aβ) 1-42 are the major species present in Alzheimer disease (AD), whereas Aβ1-40 is the major constituent of arteriolar walls affected by cerebral amyloid angiopathy. The water channel proteins astrocytic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) are known to be abnormally expressed in AD brains, but the expression of AQPs surrounding SPs and cerebral amyloid angiopathy has not been described in detail. Here, we investigated whether AQP expression is associated with each species of Aβ deposited in human brains affected by either sporadic or familial AD. Immunohistochemical analysis demonstrated more numerous AQP1-positive reactive astrocytes in the AD cerebral cortex than in controls, located close to Aβ42- or Aβ40-positive SPs. In AD cases, however, AQP1-positive astrocytes were not often observed in Aβ-rich areas, and there was a significant negative correlation between the levels of AQP1 and Aβ42 assessed semiquantitatively. We also found that Aβ plaque-like AQP4 was distributed in association with Aβ42- or Aβ40-positive SPs and that the degree of AQP4 expression around Aβ40-positive vessels was variable. These findings suggest that a defined population of AQP1-positive reactive astrocytes may modify Aβ deposition in the AD brain, whereas the Aβ deposition process might alter astrocytic expression of AQP4.     

Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.     

病理证实的淀粉样脑血管病26例临床分析

目的 总结26例尸检证实的淀粉样脑血管病的临床资料特点,以提高对本病的认识和诊断水平.方法 回顾性分析我院1983--1999年收治的经尸检证实的26例淀粉样脑血管病患者,总结其既往史、临床表现、实验室检查等临床资料.结果 26例淀粉样脑血管病中男17例,女9例,年龄45 ～78岁,有高血压病史者8例(30.7％),糖尿病病史者6例(23.1％).2例患者(7.6％)正服用抗凝或扰血小板剂,均为多发脑叶出血.26例中脑出血20例,其中单发脑叶出血2例,多灶性脑叶出血8例,壳核出血5例,丘脑及小脑出血各2例,脑干出血1例.蛛网膜下腔出血2例,出血性脑梗死、基底节区梗死、椎基底动脉闭塞及硬膜下血肿各1例.20例淀粉样脑血管病脑出血患者临床表现为头痛、肢体瘫痪、昏迷、抽搐等.结论 淀粉样脑血管病临床上常以脑血管病表现形式起病,伴有或不伴有高血压.脑叶出血是淀粉样脑血管病最常见临床表现,但少数也可见基底节、小脑和脑干出血.淀粉样脑血管病也可表现为脑梗死、蛛网膜下腔出血.抗凝剂(如华法林)及抗血小板药物(如阿司匹林)的应用对淀粉样脑血管病脑出血可能具有一定的促发作用.     

Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study.

To identify those factors associated with cerebral hemorrhage among brains with cerebral amyloid angiopathy (CAA), we undertook a comparative postmortem histopathological study of amyloid-containing vessels in the brains of patients with and without hemorrhage. Those without hemorrhage were represented by the following two groups: (1) elderly patients from a large general hospital (n = 66; age range, 75-107 years) and (2) patients with various neuropsychiatric disorders (n = 70; age range, 27-96 years). CAA was found in 45% of the first group and in 54% of the second group. The findings in these patients were compared with those in 17 brains in which both CAA and cerebral hemorrhage were present. We found that CAA was more severe in the brains with cerebral hemorrhage than in those without, and that fibrinoid necrosis was seen only in the brains with cerebral hemorrhage (12 of the 17 brains). Microaneurysms occurred only in the presence of severe, rather than moderate or mild, CAA. Serial sections in 2 brains of patients with cerebral hemorrhage showed fibrinoid necrosis, microaneurysms, and vascular rupture in close association with the hemorrhage. In 2 patients, hemorrhage was precipitated by trauma, and in 1, it was secondary to metastatic carcinoma. The features of brains from patients with CAA that are most consistently related to cerebral hemorrhage are (1) a severe degree of CAA and (2) the presence of fibrinoid necrosis, with or without microaneurysms.     

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study

BackgroundAge-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA.ObjectiveTo compare the prevalence of CAA in patients with or without AMD matched for age.MethodsWe conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD).ResultsOur analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669).ConclusionsAMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.     

Aquaporin expression in the brains of patients with or without cerebral amyloid angiopathy

Aquaporins have recently been identified as protein channels involved in water transport. These channels may play a role in the edema formation and alterations in microvascular function observed in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). We investigated the expression of aquaporin 1 (AQP1) and aquaporin 4 (AQP4) in 24 human autopsy brains consisting of 18 with AD and varying degrees of CAA and 6 with no pathologic abnormalities using immunohistochemistry. In cases of AD and CAA, there was enhanced AQP4 expression compared with the age- and sex-matched controls. Aquaporin 4 immunoreactivity was prominent at the cerebrospinal fluid and brain interfaces, including subpial, subependymal, pericapillary, and periarteriolar spaces. Aquaporin 1 expression in AD and CAA cases was not different from that in age- and sex-matched controls. Double labeling studies demonstrated that both AQP1 and 4 were localized to astrocytes. Both enhanced AQP4 expression and its unique staining pattern suggest that these proteins may be important in the impaired water transport observed in AD and CAA.     

Recurrent intracerebral lobar hematoma in cerebral amyloid angiopathy. A clinicopathologic case

The clinico-pathological case of a 71 year-old woman who presented 5 lobar intracerebral hematomas in 27 months is reported. There were no familial factor nor arterial hypertension. Amyloid deposits in cortical and meningeal arteries were present at post-mortem examination. There were no lesions of the Alzheimer type.     

Cerebral amyloid angiopathy in Alzheimer disease is associated with apolipoprotein E4 and cortical neuron loss

Pathological correlations were sought between cerebral amyloid angiopathy (CAA) and other classical neurodegenerative changes in 101 consecutive cases of autopsy-confirmed Alzheimer disease (AD). Some degree of CAA was found in at least one area of the brain in 81% of the cases; severe CAA was found in at least one brain region in 29% of the cases. In a subset of 42 cases for which genomic DNA was available, greater severity of CAA was associated more with cases that were homozygous for apolipoprotein epsilon4 than in cases with only one or no epsilon4 alleles (Fisher's exact test, p = 0.005). In all brain regions, severity of CAA was inversely correlated with numbers of neurons. This correlation was statistically significant in the temporal lobe (r = -0.29,p = 0.004) and the frontal lobe (r = -0.22, p = 0.02). Our findings suggest that two factors may modify the severity of AD pathology: Apolipoprotein E4 may accentuate the vascular deposition of beta-amyloid, and severe CAA may accelerate neuronal loss.