Cerebral amyloid angiopathy: Neuropathological diagnosis, link to Alzheimer's disease and impact on clinics.

Cerebral amyloid angiopathy (CAA) is the most frequent cause of lobar hemorrhages in the brains of elderly individuals. It is characterized by the deposition of amyloidogenic proteins in the vessel wall of leptomeningeal and/or intracerebral blood vessels. Different proteins can cause CAA. Most frequently, the amyloid ß protein (Aß) is found to be deposited in CAA and indicates a link to Alzheimer's disease, because Aß is known to be deposited in amyloid plaques characteristic of Alzheimer's disease. Among other proteins that can also cause CAA, transthyretin (TTR) is the most important one because TTR amyloidosis can be successfully treated. Therefore, it is essential to diagnose TTR-related CAA even in biopsies taken in the context of cerebral hematoma evacuations if possible. The current "Boston criteria version 2.0" for the diagnosis of CAA highlight the importance of autopsy for the definite diagnosis of CAA and biopsies for the diagnosis of probable CAA. Here, we discuss the implications of Aß-related and non-Aß-related forms of CAA for their current diagnostic relevance also in the context of neurodegenerative diseases as well as the implications of the Boston criteria version 2.0 for neuropathological diagnosis.

Intracerebral Hemorrhage Among Blood Donors and Their Transfusion Recipients.

Importance: Recent reports have suggested that cerebral amyloid angiopathy, a common cause of multiple spontaneous intracerebral hemorrhages (ICHs), may be transmissible through parenteral injection of contaminated cadaveric pituitary hormone in humans. Objective: To determine whether spontaneous ICH in blood donors after blood donation is associated with development of spontaneous ICH in transfusion recipients. Design, Setting, and Participants: Exploratory retrospective cohort study using nationwide blood bank and health register data from Sweden (main cohort) and Denmark (validation cohort) and including all 1 089 370 patients aged 5 to 80 years recorded to have received a red blood cell transfusion from January 1, 1970 (Sweden), or January 1, 1980 (Denmark), until December 31, 2017. Exposures: Receipt of red blood cell transfusions from blood donors who subsequently developed (1) a single spontaneous ICH, (2) multiple spontaneous ICHs, or (3) no spontaneous ICH. Main Outcomes and Measures: Spontaneous ICH in transfusion recipients; ischemic stroke was a negative control outcome. Results: A total of 759 858 patients from Sweden (median age, 65 [IQR, 48-73] years; 59% female) and 329 512 from Denmark (median age, 64 [IQR, 50-73] years; 58% female) were included, with a median follow-up of 5.8 (IQR, 1.4-12.5) years and 6.1 (IQR, 1.5-11.6) years, respectively. Patients who underwent transfusion with red blood cell units from donors who developed multiple spontaneous ICHs had a significantly higher risk of a single spontaneous ICH themselves, compared with patients receiving transfusions from donors who did not develop spontaneous ICH, in both the Swedish cohort (unadjusted incidence rate [IR], 3.16 vs 1.12 per 1000 person-years; adjusted hazard ratio [HR], 2.73; 95% CI, 1.72-4.35; P < .001) and the Danish cohort (unadjusted IR, 2.82 vs 1.09 per 1000 person-years; adjusted HR, 2.32; 95% CI, 1.04-5.19; P = .04). No significant difference was found for patients receiving transfusions from donors who developed a single spontaneous ICH in the Swedish cohort (unadjusted IR, 1.35 vs 1.12 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.84-1.36; P = .62) nor the Danish cohort (unadjusted IR, 1.36 vs 1.09 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.70-1.60; P = .73), nor for ischemic stroke as a negative control outcome. Conclusions and Relevance: In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.

Evidence for human transmission of amyloid-ß pathology and cerebral amyloid angiopathy.

More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-ß (Aß) pathology. The Aß deposition in the grey matter was typical of that seen in Alzheimer's disease and Aß in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aß pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aß pathology and found marked Aß deposition in multiple cases. Experimental seeding of Aß pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aß in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aß pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aß and other proteopathic seeds associated with neurodegenerative and other human diseases.

Follow-up study of a patient with early onset cerebral amyloid angiopathy following childhood cadaveric dural graft.

We retrospectively studied the T2 star (T2*)-weighted magnetic resonance imaging (MRI) of a 40-year-old patient diagnosed with symptomatic early-onset cerebral amyloid angiopathy (CAA), occurring 34 years following childhood neurosurgery using a cadaveric dural patch. Our findings revealed that CAA associated with cadaveric dural transplantation could progress rapidly, sometimes with bilateral bleeding. This microbleed evolution is suggestive of water-soluble amyloid-ß transmission via cerebrospinal fluid alongside perivascular drainage pathways with deposition in the cerebral artery walls due to clearance disturbances. Multiple intracerebral hemorrhages associated with CAA with a childhood cadaveric dural graft should be considered a life-threatening medical complication.

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid ß (Aß) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aß deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aß cytotoxicity, Aß fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aß deposits and molecules that accumulate with Aß may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy.

Accumulation of fibrillar amyloid ß protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid ß protein in brain and faithfully recapitulates many of the pathologic aspects of human small-vessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions.

Primary central nervous system vasculitis mimicking brain tumor: Comprehensive analysis of 13 cases from a single institutional cohort of 191 cases.

OBJECTIVE: To describe the clinical, laboratory, and imaging features and course of patients with primary central nervous system vasculitis (PCNSV) presenting with an intracranial tumor-like mass (TLM). METHODS: We retrospectively studied a cohort of 191 consecutive patients with PCNSV seen at the Mayo Clinic, Rochester, MN over a 35-year period (1982-2017). 13/191 patients presented with a TLM. We compared the findings in these 13 patients with those from the 178 without this presentation. RESULTS: In 13 of 191 (6.8%) patients with TLM the diagnosis of PCNSV was established by cerebral biopsy. Granulomatous vasculitis was found in 11/13 patients, accompanied by vascular deposits of ß-amyloid peptide in 7. Compared to the 178 patients without TLM, the patients with TLM were more likely to be male (p = 0.04), and less likely to have a transient ischemic attack (p = 0.023), bilateral cerebral infarcts (p = 0.018), or vasculitic lesions on angiography (p = 0.045). They were more likely to have seizures (p = 0.022), gadolinium-enhanced lesions (p = 0.007), and amyloid angiopathy (p = 0.046). All 13 patients responded to therapy and 8/13 (61.5%) had a Rankin disability score of 0 at last visit. Overall, high disability scores (Rankin scores 4-6) at last follow-up were associated with increasing age (odds ratio, OR, 1.49) and cerebral infarction (OR, 3.47), but were less likely in patients with gadolinium-enhanced lesions (OR, 0.36) and amyloid angiopathy (OR, 0.21). CONCLUSION: In PCNSV a TLM at presentation represents a definable subgroup of patients with a favourable treatment response.

Chronic treatment with five vascular risk factors causes cerebral amyloid angiopathy but no Alzheimer pathology in C57BL6 mice.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most common form of dementia coming along with cerebral amyloid angiopathy (CAA) in more than 70% of all cases. However, CAA occurs also in pure form without AD pathology. Vascular life style risk factors such as obesity, hypertension, hypercholesterolemia, diabetes, stress or an old age play an important role in the progression of CAA. So far, no animal model for sporadic CAA has been reported, thus the aim of the present study was to create and characterize a new mouse model for sporadic CAA by treatment with different vascular risk factors. Healthy C57BL6 mice were treated with lifestyle vascular risk factors for 35 or 56 weeks: lipopolysaccharide, social stress, streptozotozin, high cholesterol diet and copper in the drinking water. Four behavioral tests (black-white box, classical maze, cheeseboard maze and plus-maze discriminative avoidance task) showed impaired learning, memory and executive functions as well as anxiety with increased age. The treated animals exhibited increased plasma levels of cortisol, insulin, interleukin-1ß, glucose and cholesterol, confirming the effectiveness of the treatment. Confocal microscopy analysis displayed severe vessel damage already after 35 weeks of treatment. IgG positive staining points to a severe blood-brain barrier (BBB) disruption and furthermore, cerebral bleedings were observed in a much higher amount in the treatment group. Importantly, inclusions of beta-amyloid in the vessels indicated the development of CAA, but no deposition of beta-amyloid plaques and tau pathology in the brains were seen. Taken together, we characterized a novel sporadic CAA mouse model, which offers a strategy to study the progression of the disease and therapeutic and diagnostic interventions.

Multiple Cerebral Hemorrhagic Lesions Depicted by Susceptibility-Weighted Imaging in a Patient with Down Syndrome: Case Report.

Our objective is to study a 53-year-old woman with Down syndrome presented with massive lobar hematoma in the left fronto-parietal lobe, and who underwent craniotomy and hematoma evacuation. Histopathological diagnosis of surgical specimen was amyloid angiopathy. Postoperative magnetic resonance studies were performed. The lesion this time showed mixed intensity on susceptibility-weighted imaging. In addition, multiple hypointense lesions were evident. An old previously unidentified hemorrhage in the right temporo-parietal lobe was accompanied by superficial cortical siderosis. Old bleeds were apparent in subcortical areas. These various kinds of hemorrhagic lesion were consistent with findings of amyloid angiopathy reported in the elderly. Most reported cases of Down syndrome associated with intracerebral hemorrhage have involved middle-aged patients. Magnetic resonance studies for Down syndrome patients before old age may disclose the degree to which amyloid angiopathy progresses in the brain of these patients.

Evidence of amyloid-ß cerebral amyloid angiopathy transmission through neurosurgery.

Amyloid-ß (Aß) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aß 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 Aß 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 Aß pathology may be transmissible, as prion disease is, through neurosurgical procedures.

The etiology of spontaneous intracerebralhemorrhage: Insights from a neuropathological series.

The etiology of intracerebral hemorrhage (ICH) is frequently undetermined. We aimed to assess the impact of the neuropathological study on the etiologic diagnosis of ICH. Patients with ICH admitted to a tertiary hospital in the last 14 years were identified, and histological samples of surgically-drained ICH were retrieved. Blinded from neuropathological results, a clinical etiology was hypothesized. Pathological samples were reviewed, and immunohistochemistry study for ß-amyloid was performed in all the cases where structural abnormalities were not identified. From 2002 - 2016, 113 patients with ICH underwent surgical drainage and had specimens taken for histology. The mean age was 51.6 years (SD = 19.2). Clinical and imaging data defined a presumable etiology in 47 patients (44.2%), including 30 patients with suspected structural pathology, 11 patients under anticoagulation, and 8 patients with probable hypertensive hemorrhage, while most had an undetermined etiology. Using neuropathological analysis, a definitive diagnosis was possible in 88.5% of the patients. Arteriovenous malformations (38.1%) and cavernous hemangiomas (16.8%) represented the most common findings. In 9.7%, the blood vessels showed cerebral amyloid angiopathy (CAA). The neuropathological study established a definite etiology in an additional 44.3% of patients other than only using the clinical and imaging data.
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Chronic cerebral hypoperfusion alters amyloid-ß peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice.

Cerebral hypoperfusion is an early feature of Alzheimer's disease (AD) that influences the progression from mild cognitive impairment to dementia. Understanding the mechanism is of critical importance in the search for new effective therapies. We hypothesized that cerebral hypoperfusion promotes the accumulation of amyloid-ß (Aß) and degenerative changes in the brain and is a potential mechanism contributing to development of dementia. To address this, we studied the effects of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis on Aß peptide pools in a transgenic mouse model of AD (transgenic mice with Swedish, Dutch and Iowa mutations in human amyloid precursor protein (APP) (Tg-SwDI)). Cerebrovascular integrity was characterized by quantifying the occurrence of microinfarcts and haemorrhages and compared with wild-type mice without Aß. A significant increase in soluble Aß peptides (Aß40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated APP and APP proteolytic products. Following 3 months, a significant increase in insoluble Aß40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared with wild-type mice and further exacerbated by hypoperfusion at 1 and 3 months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared with hypoperfused wild-type mice. Soluble parenchymal Aß was associated with elevated NADPH oxidase-2 (NOX2) which was exacerbated by 1-month hypoperfusion. We suggest that in response to hypoperfusion, increased Aß production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts.

Cerebral amyloid angiopathy in a young man with a history of traumatic brain injury: a case report and review of the literature.

Cerebral amyloid angiopathy (CAA), a cause of recurrent and multiple lobar hemorrhages, characteristically occurs in persons aged ≥55 years. We report a case of a 32-year-old male who had recurrent hemorrhage in the left multiple lobes, with a history of traumatic brain injury and hematoma evacuation at the age of 1 year. He underwent surgical treatment and was histopathologically diagnosed as having CAA. The literature review yielded six CAA cases, including ours, aged less than 55 years. All were male and four had histories of severe TBI, suggesting that male sex and TBI may be associated with CAA in young persons.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

Prenatal high-fat diet alters the cerebrovasculature and clearance of ß-amyloid in adult offspring.

Alzheimer's disease (AD) is characterized by the accumulation of ß-amyloid (Aß) peptides in the extracellular spaces of the brain as plaques and in the walls of blood vessels as cerebral amyloid angiopathy (CAA). Failure of perivascular drainage of Aß along cerebrovascular basement membranes contributes to the development of CAA. Mid-life hypercholesterolaemia is a risk factor for the development of AD. Maternal obesity is associated with the development of obesity, hypertension and hypercholesterolaemia in adulthood, suggesting that the risk for AD and CAA may also be influenced by the early-life environment. In the present study, we tested the hypothesis that early-life exposure to a high-fat diet results in changes to the cerebrovasculature and failure of Aß clearance from the brain. We also assessed whether vascular Aß deposition is greater in the brains of aged humans with a history of hyperlipidaemia, compared to age-matched controls with normal lipidaemia. Using a mouse model of maternal obesity, we found that exposure to a high-fat diet during gestation and lactation induced changes in multiple components of the neurovascular unit, including a down-regulation in collagen IV, fibronectin and apolipoprotein E, an up-regulation in markers of astrocytes and perivascular macrophages and altered blood vessel morphology in the brains of adult mice. Sustained high-fat diet over the entire lifespan resulted in additional decreases in levels of pericytes and impaired perivascular clearance of Aß from the brain. In humans, vascular Aß load was significantly increased in the brains of aged individuals with a history of hypercholesterolaemia. These results support a critical role for early dietary influence on the brain vasculature across the lifespan, with consequences for the development of age-related cerebrovascular and neurodegenerative diseases.

Intracerebral hemorrhage due to cerebral amyloid angiopathy after head injury: Report of a case and review of the literature.

Cerebral amyloid angiopathy (CAA) is an important cause of spontaneous intracerebral hemorrhage in the elderly. A few case reports of CAA-related intracerebral hemorrhage after head injury, usually following a fall, have been published. More rarely, it may occur in the setting of a traffic accident, with only four cases having been reported. We describe a case of CAA-related intracerebral hemorrhage in an 88-year-old man injured in a road traffic accident. The patient died 14 h after the accident. Autopsy examination revealed a left frontoparietal hematoma and CAA of most of the small leptomeningeal and cortical arteries, as well as several capillaries, predominantly in the parietal and occipital lobes. Except for bruises in the frontal and zygomatic regions, elbow and forearm, to the left, there were no skull fractures or traumatic lesions in other parts of the body. We review the literature on CAA-related intracerebral hemorrhage associated with head injury. CAA-related intracerebral hemorrhage after head injury may occur due to a minor trauma, minor and severe falls, or in the setting of a traffic accident. However, even in this last condition, it seems to happen mostly in patients who had a mild to moderate head injury. These facts show that replacement of the contractile components of the arterial tunica media by amyloid renders the affected cerebral blood vessels more vulnerable to head injury associated with acceleration and deceleration, independently of the severity of the dynamic loading acting on the head.