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.

[A case of inflammatory cerebral amyloid angiopathy with white matter lesions appearing after brain biopsy].

A 76-year-old woman with a 7-year history of dementia presented to our hospital with generalized convulsive seizure for the first time. Contrast-enhanced brain magnetic resonance imaging revealed leptomeningeal enhancement mainly in the right occipital lobe and multiple lobar microbleeds in the bilateral cerebral and cerebellar subcortex. No white matter lesions were observed. A brain biopsy of the right parieto-occipital lobe revealed cerebral amyloid angiopathy (CAA). White matter lesions appeared in the right parieto-occipital lobe three days after the biopsy, and we considered inflammatory CAA. Three courses of methylprednisolone pulse followed by oral prednisolone therapy gradually reduced leptomeningeal and white matter lesions. An apolipoprotein E genotype investigation identified the ε2/ε3 genotype. In patients with inflammatory CAA, a risk of exacerbation should be considered after brain biopsy, in which the ε2 allele might play a role.

Braak Stage, Cerebral Amyloid Angiopathy, and Cognitive Decline in Early Alzheimer's Disease.

The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. The study used a total of 141 subjects consisting of 72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer's disease (AD) cases displaying Braak stages 0-II and III from the Rush Religious Order Study cohort. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOEɛ4 status, and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (ß = -0.58, SE = 0.25, p = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (ß= -0.75, SE = 0.35, p = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum.

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.

Hiding in plain sight: a brain lesion in a patient with a history of colon and breast cancer.

We present a case of a 76-year-old woman who was admitted to our hospital with a low Glasgow Coma Scale score. She had a medical history of breast and colon cancer. The CT scan showed possible diagnosis of brain metastasis. However, the MRI scan showed this to be a completely different diagnosis.

Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry.Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA.

Intravenous injection of beta-amyloid seeds promotes cerebral amyloid angiopathy (CAA).

Seeding and spread of beta-amyloid (Aß) pathologies have been considered to be based on prion-like mechanisms. However, limited transmissibility of Aß seeding activity upon peripheral exposure would represent a key difference to prions, not only in terms of pathogenesis but also in terms of potential transmission of disease. We partially characterized the seeded Aß amyloidosis after intracerebral injection of various brain homogenates in APP/PS1 mice. One particularly seed-laden homogenate was selected to investigate the development of Aß pathologies after intravenous exposure. We report here that a single intravenous injection of an Alzheimer disease patient's-brain extract into APP/PS1 recipient mice led to cerebral amyloid angiopathy within 180 days post injection. Thus, vascular proteinopathies such as CAA are transmissible in mice via the intravenous route of peripheral exposure.

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.

Generation of Alzheimer's Disease Transgenic Zebrafish Expressing Human APP Mutation Under Control of Zebrafish appb Promotor.

BACKGROUND: Amyloid peptide precursor (APP) as the precursor protein of peptide betaamyloid (ß-amyloid, Aß), which is thought to play a central role in the pathogenesis of Alzheimer's disease (AD), also has an important effect on the development and progression of AD. Through knocking-in APP gene in animals, numerous transgenic AD models have been set up for the investigation of the mechanisms behind AD pathogenesis and the screening of anti-AD drugs. However, there are some limitations to these models and here is a need for such an AD model that is economic as well as has satisfactory genetic homology with human. METHODS: We generated a new AD transgenic model by knocking a mutant human APP gene (APPsw) in zebrafish with appb promoter of zebrafish to drive the expression of APPsw. RESULTS: Fluorescent image and immunochemistry stain showed and RT-PCR and western blot assay confirmed that APPsw was successfully expressed in the brain, heart, eyes and vasculature of the transgenic zebrafish. Behavioral observation demonstrated that the transgenic zebrafish had AD-like symptoms. Histopathological observation found that there were cerebral ß-amyloidosis and angiopathy (CAA), which induced neuron loss and enlarged pervascular space. CONCLUSION: These results suggest that APPsw transgenic zebrafish well simulate the pathological characters of AD and can be used as an economic AD transgenic model. Furthermore, the new model suggested that APP can express in microvasculatures and cause the Aß generation and deposition in cerebral vessel which further destroys cerebral vascular structure resulting in the development and/or the progress of AD.

High levels of homocysteine results in cerebral amyloid angiopathy in mice.

High levels of homocysteine is a risk factor for developing Alzheimer's disease (AD), and the effect that this amino acid has on amyloid-ß (Aß) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aß deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, mice with high homocysteine showed a significant increase in the amount of Aß deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aß chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aß clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA.

Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

Accumulation of amyloid beta-peptide (Aß) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aß vaccination removes Aß deposits from the brain. Aß immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aß deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aß fragments produced by catalytic antibodies are less likely to form aggregates, Aß-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aß antibodies. Additionally, catalytic antibodies may remove Aß more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aß molecules. We previously isolated Aß-specific catalytic antibody, IgVL5D3, with strong Aß-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aß load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aß catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

Amyloid-ß oligomers as a template for secondary amyloidosis in Alzheimer's disease.

Alzheimer's disease is a complex disease characterized by overlapping phenotypes with different neurodegenerative disorders. Oligomers are considered the most toxic species in amyloid pathologies. We examined human AD brain samples using an anti-oligomer antibody generated in our laboratory and detected potential hybrid oligomers composed of amyloid-ß, prion protein, α-synuclein, and TDP-43 phosphorylated at serines 409 and 410. These data and in vitro results suggest that Aß oligomer seeds act as a template for the aggregation of other proteins and generate an overlapping phenotype with other neuronal disorders. Furthermore, these results could explain why anti-amyloid-ß therapy has been unsuccessful.

Telmisartan treatment ameliorates memory deficits in streptozotocin-induced diabetic mice via attenuating cerebral amyloidosis.

Telmisartan, an angiotensin II type 1-receptor blocker (ARBs), has been reported to exert beneficial effects on the central nervous system (CNS). However, the effect of telmisartan on cognitive impairment associated with type 1 diabetes is not well known. Here, we examined the possibility that telmisartan could improve memory function in a type 1 diabetic mouse model, streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice subjected to the Morris Water Maze (MWM) task exhibited a significant decline of spatial learning and memory. Oral administration of telmisartan at two nonhypotensive doses (0.7 or 0.35 mg/kg) significantly improved memory deficits in STZ-induced diabetic mice. Telmisartan treatment markedly reduced Aß42, APP, BACE1, RAGE, and NF-κB p65 of the hippocampus and cortex, but did not beneficially affect hyperglycemia and hypoinsulinemia in the STZ-induced diabetic mice compared with untreated diabetic mice. Taken together, our findings suggest that telmisartan ameliorates memory deficits in type 1 diabetic mice, at least partly because of attenuation of amyloidosis in the brain.

[Cerebral amyloid angiopathy with familial transthyretin-derived oculoleptomeningeal amyloidosis].

Cerebral amyloid angiopathy (CAA) is caused by the accumulation of amyloid fibrils on vascular walls and is a well-known cause of cerebral hemorrhages in the elderly. This disease manifests as recurrent or multiple simultaneous subcortical hematomas, occasionally leading to fatal hemorrhages. Additionally, it is noteworthy that CAA-related hemorrhages can develop in individuals aged around 50 years. Although a few different amyloid fibril proteins have been isolated from patients with CAA, the most common protein is Aß, which is also the main component of senile plaques in Alzheimer's disease. Recent studies have suggested that corticosteroid therapy is effective for preventing the recurrence of CAA-related hemorrhages. Hereditary generalized amyloidosis usually manifests as familial amyloid polyneuropathy (FAP), showing severe involvement of peripheral somatic and autonomic nerves. Many variant forms of transthyretin (TTR) with a single amino acid substitution have been identified as causative amyloid precursor proteins in FAP. Moreover, a small number of TTR gene mutations causes a rare phenotype of systemic amyloidosis characterized by preferential deposition of TTR-derived amyloid proteins in the vitreous body in the eye, as well as the leptomeninges and subarachnoidal vessels in the central nervous system (CNS). This disorder is called familial oculoleptomeningeal or leptomeningeal amyloidosis and is characterized clinically by CNS symptoms, including progressive dementia, seizures, ataxia, spastic paresis, and stroke-like episodes. Since the variant forms of TTR in this amyloidosis are derived from the retinal epithelium or choroid plexus, liver transplantation-an effective treatment for FAP-is considered less effective for treating this rare form of TTR-related systemic amyloidosis.

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice.

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aß levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1ß and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aß in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aß pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aß pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

Recurrent lobar intracerebral hemorrhage in Tangier disease.

We report a patient with familial α-lipoprotein deficiency (Tangier disease) who presented with recurrent lobar intracerebral hemorrhages and accumulating microbleeds on T*2-weighted magnetic resonance imaging, suggestive of probable cerebral amyloid angiopathy. This case provides new insight into the links between the adenotriphosphate-binding cassette A1 (ABCA1) transporter gene mutation in Tangier disease and apolipoprotein-E expression in the brain and supports further investigation of the potential role of ABCA1 transporter in cerebral amyloid angiopathy.

Brain abscess associated with cerebral amyloid angiopathy and hemorrhage.

PURPOSE: We want to report an extremely rare condition, brain abscess associated with cerebral amylid angiopathy and hemorrhage. CASE REPORT: We report on a 64-year-old woman who presented initially with moderate fever and headache. She was initially misdiagnosed with a bleeding tumor or arteriovenous malformation rupture and treated without antibiotic therapy. The mass was surgically drained due to neurological deterioration on day 14 after admission. Streptococcus virdians was isolated from the pus culture. The pathology evaluation showed cerebral amyloid angiopathy. She received intravenous antibiotic therapy for 4 weeks. She was eventually discharged home with left quadrantanopia. CONCLUSION: This case reminds us early recognition of brain abscess formation at the site of intracerebral hemorrhage is very important for prompt and appropriate treatment to improve the overall prognosis.

Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer's disease: a long-term follow up study.

Cerebral amyloid angiopathy is manifested as accumulation of amyloid ß (Aß) peptide in the wall of meningeal and cerebral arteries, arterioles and capillaries and is frequently found postmortem in sporadic Alzheimer's disease (sAD) patients. It is difficult to assess when and how cerebral amyloid angiopathy develops and progresses in humans in vivo, which is why animal AD models are used. Streptozotocin-intracerebroventricularly (STZ-icv) treated rats have been recently proposed as the model of sAD which develops insulin resistant brain state preceding Aß pathology development. Vascular Aß deposits in the brain of STZ-icv-treated rats (3 months old at the time of icv treatment) were visualized by Thioflavine-S staining, Congo red staining and Aß immunohistochemistry. Thioflavine-S and Congo red staining revealed diffuse congophilic deposits in the wall of meningeal and cortical blood vessels both 6 and 9 months after the STZ-icv treatment. Preliminary Aß1-42 and Aß1-16 immunohistochemistry experiments showed positive staining in blood vessels 3 and 9 months after the STZ-icv treatment, respectively. Results suggest that cerebral amyloid angiopathy observed 6 and 9 months after the STZ-icv treatment seems to be a continuation and progression of the amyloid pathology observed already 3 months following the STZ-icv treatment in this non-transgenic sAD animal model.

Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy.

Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages (ICHs), microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical secondary role in many neurodegenerative diseases, including Alzheimer's disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood-brain barrier (BBB) lesions. The accumulation of amyloid beta (Aß) in the cerebrovascular system is a significant risk factor for ICH and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aß immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits but have been plagued by CAA-associated adverse events. Although management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of ß-amyloidosis in the cerebral vasculature.