Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials.

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aß peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aß pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aß, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.

Potential caveats of putative microglia-specific markers for assessment of age-related cerebrovascular neuroinflammation.

BACKGROUND: The ability to distinguish resident microglia from infiltrating myeloid cells by flow cytometry-based surface phenotyping is an important technique for examining age-related neuroinflammation. The most commonly used surface markers for the identification of microglia include CD45 (low-intermediate expression), CD11b, Tmem119, and P2RY12. METHODS: In this study, we examined changes in expression levels of these putative microglia markers in in vivo animal models of stroke, cerebral amyloid angiopathy (CAA), and aging as well as in an ex vivo LPS-induced inflammation model. RESULTS: We demonstrate that Tmem119 and P2RY12 expression is evident within both CD45int and CD45high myeloid populations in models of stroke, CAA, and aging. Interestingly, LPS stimulation of FACS-sorted adult microglia suggested that these brain-resident myeloid cells can upregulate CD45 and downregulate Tmem119 and P2RY12, making them indistinguishable from peripherally derived myeloid populations. Importantly, our findings show that these changes in the molecular signatures of microglia can occur without a contribution from the other brain-resident or peripherally sourced immune cells. CONCLUSION: We recommend future studies approach microglia identification by flow cytometry with caution, particularly in the absence of the use of a combination of markers validated for the specific neuroinflammation model of interest. The subpopulation of resident microglia residing within the "infiltrating myeloid" population, albeit small, may be functionally important in maintaining immune vigilance in the brain thus should not be overlooked in neuroimmunological studies.

Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits.

Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-ß (Aß) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. SIGNIFICANCE STATEMENT: Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-ß-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

Systems proteomic analysis reveals that clusterin and tissue inhibitor of metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy.

AIMS: Amyloid beta (Aß) accumulation in the walls of leptomeningeal arteries as cerebral amyloid angiopathy (CAA) is a major feature of Alzheimer's disease. In this study, we used global quantitative proteomic analysis to examine the hypothesis that the leptomeningeal arteries derived from patients with CAA have a distinct endophenotypic profile compared to those from young and elderly controls. METHODS: Freshly dissected leptomeningeal arteries from the Newcastle Brain Tissue Resource and Edinburgh Sudden Death Brain Bank from seven elderly (82.9 ± 7.5 years) females with severe capillary and arterial CAA, as well as seven elderly (88.3 ± 8.6 years) and five young (45.4 ± 3.9 years) females without CAA were used in this study. Arteries from four patients with CAA, two young and two elderly controls were individually analysed using quantitative proteomics. Key proteomic findings were then validated using immunohistochemistry. RESULTS: Bioinformatics interpretation of the results showed a significant enrichment of the immune response/classical complement and extracellular matrix remodelling pathways (P < 0.05) in arteries affected by CAA vs. those from young and elderly controls. Clusterin (apolipoprotein J) and tissue inhibitor of metalloproteinases-3 (TIMP3), validated using immunohistochemistry, were shown to co-localize with Aß and to be up-regulated in leptomeningeal arteries from CAA patients compared to young and elderly controls. CONCLUSIONS: Global proteomic profiling of brain leptomeningeal arteries revealed that clusterin and TIMP3 increase in leptomeningeal arteries affected by CAA. We propose that clusterin and TIMP3 could facilitate perivascular clearance and may serve as novel candidate therapeutic targets for CAA.

Passive immunotherapy targeting amyloid-ß reduces cerebral amyloid angiopathy and improves vascular reactivity.

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-ß isoform(s) (predominantly amyloid-ß40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-ß40 selective antibody, to attenuate amyloid-ß accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-ß accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-ß biochemically. We hypothesized that the reduction in vascular amyloid-ß40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-ß40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-ß40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-ß species that may otherwise be detrimental to normal vessel function.

A human monoclonal IgG that binds aß assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo.

Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aß and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aß and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aß in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aß amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.

T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy.

Deposition of amyloid-ß (Aß) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aß trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aß1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aß vascular clearance receptor LRP-1, and protection from the deleterious effects of Aß on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions.

The Inflammatory Form of Cerebral Amyloid Angiopathy or "Cerebral Amyloid Angiopathy-Related Inflammation" (CAARI).

Cerebral amyloid angiopathy-related inflammation (CAARI) is a recently recognized syndrome of reversible encephalopathy seen in a subset of patients with cerebral amyloid angiopathy (CAA). CAA is a disorder of the elderly in which amyloid peptides are deposited in the walls of cerebral arteries, leading to microhemorrhages, macrohemorrhages, and eventually dementia. In a few cases, the amyloid deposition is accompanied by inflammation or edema. The clinical syndrome of CAARI is distinguished by subacute neurobehavioral symptoms, headaches, seizures, and stroke-like signs, contrasting the acute intracranial hemorrhage typically seen in CAA. Magnetic resonance imaging findings may be symmetric or asymmetric and involve patchy or confluent T2 hyperintense lesions in the cortex and subcortical white matter. Recent diagnostic criteria have been proposed which help distinguish CAARI from alternative diagnoses. Improvement has been reported in most cases with immunosuppression, although a few cases have had recurrent symptoms. Here, we review the clinical and radiologic features of CAARI and compare these with CAA.

Anti-amyloid ß autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid ß (Aß) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aß autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aß40, Aß42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti-Aß autoantibodies were specifically increased and directly correlated with Aß mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aß and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aß, directly related to autoantibody concentration and soluble Aß. The CSF dosage of anti-Aß autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aß autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Immune activation in amyloid-ß-related angiitis correlates with decreased parenchymal amyloid-ß plaque load.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-ß (Aß) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aß-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aß as the trigger of vasculitis. OBJECTIVE: To investigate whether the inflammatory response to Aß has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aß from brain parenchyma. METHODS: We studied immune activation and Aß load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. RESULTS: ABRA patients showed significantly increased immune activation and decreased Aß loads in the brain parenchyma adjacent to affected vessels. CONCLUSION: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aß and show that this can lead to enhanced clearance of Aß from the brain parenchyma by immune-mediated mechanisms.

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities.

Therapeutic antibodies have been developed to target amyloid-beta (Aß), and some of these slow the progression of Alzheimer's disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aß antibody binding to cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue to study whether this related to the ARIA-E frequencies previously reported by clinical trials. The binding of Aß antibodies to CAA Aß fibrils was evaluated in vitro using immunoprecipitation, surface plasmon resonance, and direct binding assay. Marked differences in Aß antibody binding to CAA fibrils were observed. Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aß present. The findings of this study support the proposal that Aß antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aß-based immunotherapies.

Chitosan enhances the stability and targeting of immuno-nanovehicles to cerebro-vascular deposits of Alzheimer's disease amyloid protein.

Alzheimer's disease amyloid ß (Aß) proteins accumulate in the cerebral vasculature and cause cerebral amyloid angiopathy (CAA). The objective of this study was to resolve critical formulation issues in developing nanoparticles (NPs) capable of permeating the blood brain barrier (BBB) and targeting cerebrovascular Aß proteins. To achieve this objective we designed immuno-nanovehicles, which are chitosan-coated poly lactic-co-glycolic acid (PLGA) NPs conjugated with a novel anti-Aß antibody. Measurements made according to Derjaguin-Landau-Verwey-Overbeek (DLVO) theory indicated that the immuno-nanovehicles have a much lower propensity to aggregate than the control nanovehicles. Immuno-nanovehicles showed enhanced uptake at the BBB and better targeting of the Aß proteins deposited in the CAA model in vitro in comparison with the control nanovehicles. In addition, chitosan enhanced aqueous dispersibility and increased the stability of immuno-nanovehicles during lyophilization, thus transforming them into ideal vehicles for delivering therapeutic and diagnostic agents to the cerebral vasculature ridden with vascular amyloid. FROM THE CLINICAL EDITOR: In this study, the authors report the development of chitosan-coated PLGA nanoparticles conjugated with anti-amyloid antibody to be used as immuno-nanovehicles to image cerebral amyloid angiopathy deposits in vivo. This method enables delivering therapeutic and diagnostic agents to the cerebral vasculature ridden with vascular amyloid.

Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: The aging brain demonstrates frequent MRI and pathological evidence of cerebral microbleeds, which are often associated with cerebral amyloid angiopathy. To develop new therapeutic strategies for this disorder, we studied cerebral microhemorrhage in a well-characterized mouse model of cerebral amyloid angiopathy. METHODS: Tg2576 mice were studied at ages ranging from 2 to 21 months. Spontaneous and induced microscopic bleeding was analyzed with and without a passive anti-amyloid immunization regimen and dietary supplementation of ischemic stroke prevention medication dipyridamole. RESULTS: Areas of microhemorrhage were easily demonstrated and were significantly more prominent in the oldest mice and in animals treated with anti-amyloid immunotherapy. Dipyridamole supplementation in the diet generated plasma levels >790 ng/mL within the range seen clinically. Dipyridamole treatment did not worsen frequency and size of cerebral microscopic bleeding. CONCLUSIONS: The Tg2576 mouse is a useful model to study progression and modification of spontaneous and immunotherapy-induced cerebral microhemorrhage. Absence of microhemorrhage worsening with dipyridamole treatment suggests a potential therapeutic role of this agent when ischemic and microhemorrhagic lesions coexist.

Posterior reversible encephalopathy syndrome (PRES) with immune system activation, VEGF up-regulation, and cerebral amyloid angiopathy.

The case of a 75-year-old man with a history of lymphoma, recent upper respiratory tract infection, and a protracted course of encephalopathy is presented. Radiologically, findings were consistent with posterior reversible encephalopathy syndrome. A brain biopsy revealed evidence of endothelial activation, T-cell trafficking, and vascular endothelial growth factor expression, suggesting that systemic immune system activation may be involved with triggering posterior reversible encephalopathy syndrome. In addition, underlying cerebral amyloid angiopathy may have contributed to the initial nonclassical edema distribution by compromising autoregulatory blood flow mechanisms.

Low avidity and level of serum anti-Aß antibodies in patients with cerebral amyloid angiopathy-related cerebral hemorrhage.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the beta-amyloid protein (Aß) in small cerebral vessels, which is considered a common cause of intracerebral hemorrhage (CAAH) in elderly people. Little is known about the properties of serum naturally occurring anti-Aß antibodies in patients with CAAH. We investigated the avidity and levels of anti-Aß antibodies in 20 patients and 20 age-matched healthy controls by an enzyme-linked immunosorbent assay with thiocyanate elution. Our study revealed that both the levels and the avidity of these endogenous anti-Aß antibodies were lower in patients with CAAH than in controls, which may be a new mechanism for the impaired clearance of cerebral Aß and have important implications for the development of immune-based therapeutic strategies for CAA.

Immunotherapy reduces vascular amyloid-beta in PDAPP mice.

In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.

Novel isolated cerebral ALlambda amyloid angiopathy with widespread subcortical distribution and leukoencephalopathy due to atypical monoclonal plasma cell proliferation, and terminal systemic gammopathy.

Neuropathologic and biochemical findings in a 34-year-old man whose disease began 2 years before death appearing as chronic progressive encephalitis and culminated in mutism are reported. Cerebrospinal fluid and serum of the patient showed a brain-restricted monoclonal lambda-light chain apparently produced by a small monoclonal immunoglobulin Glambda plasma cell population. In the preterminal stage, there was a systemic monoclonal gammopathy, the source of which could not be identified. At autopsy, there was extensive amyloid deposition in most vessels throughout the cerebral and cerebellar white matter, basal ganglia, and thalamus and diffuse leukoencephalopathy; cerebral and cerebellar cortices, other portions of the CNS, and non-CNS tissues were spared. Partial amino acid sequence analysis demonstrated that the amyloidogenic protein originated from immunoglobulin lambda-light chains which were produced by monoclonal plasma cells. There are 2 similar cases reported in the literature. The distribution of ALlambda deposits in these 3 cases indicates that widespread subcortical vascular amyloidosis with leukoencephalopathy is a novel clinicopathologic entity distinguished from other cerebral diseases with local amyloid light chain deposition, including amyloidoma, leptomeningeal vascular amyloidosis, solitary intracerebral plasmacytoma, primary intracerebral lymphoma with plasmacytic differentiation, and multiple sclerosis with demyelination-associated amyloid deposition.

Cerebral immunoglobulin light chain amyloid angiopathy-related hemorrhages.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage (ICH) particularly in elderly patients. In CAA-related hemorrhages, amyloid deposits in the brain vessel walls mainly contain amyloid beta-protein (A-beta). Rarely other forms of amyloid substances have been reported in sporadic CAA-related hemorrhages. METHODS: We report the case of a 44-year-old patient with recurrent ICH who had surgical evacuation of a large frontal hematoma. Following surgery, samples from the hematoma and adjacent cerebral cortex were obtained for histopathological examination. RESULTS: Within the recent hemorrhage, a few arteriolar walls were thickened with an amyloid deposit that was immunostained for immunoglobulin (Ig) M and light chain lambda. In the wall of some vessels, around the amyloid deposits, as well as in the adjacent cerebral cortex, there was an infiltration by monotypic lymphocytes and plasma cells expressing IgM and light chain lambda. No amyloid deposition was found outside the hemorrhage. There was no evidence of multiple myeloma, B-cell malignancy, or systemic amyloidosis. CONCLUSIONS: Recurrent ICH may be due to amyloid deposition of IgM lambda produced by monotypic proliferation of lymphocytes and plasma cells purely localized to the brain.

Aß43 in human Alzheimer's disease: effects of active Aß42 immunization.

Neuropathological follow-up of patients with Alzheimer's disease (AD) who participated in the first clinical trial of Amyloid-ß 42 (Aß42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of Aß42 and Aß40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these Aß peptides in cerebral amyloid angiopathy (CAA). Aß43 has been less frequently studied in AD, but its aggregation propensity and neurotoxic properties suggest it may have an important pathogenic role. In the current study we show by using immunohistochemistry that in unimmunized AD patients Aß43 is a frequent constituent of plaques (6.0% immunostained area), similar to Aß42 (3.9% immunostained area). Aß43 immunostained area was significantly higher than that of Aß40 (2.3%, p = 0.006). In addition, we show that Aß43 is only a minor component of CAA in both parenchymal vessels (1.5 Aß43-positive vessels per cm2 cortex vs. 5.3 Aß42-positive vessels, p = 0.03, and 6.2 Aß40-positive vessels, p = 0.045) and leptomeningeal vessels (5.6% Aß43-positive vessels vs. 17.3% Aß42-positive vessels, p = 0.007, and 27.4% Aß40-positive vessels, p = 0.003). Furthermore, we have shown that Aß43 is cleared from plaques after Aß immunotherapy, similar to Aß42 and Aß40. Cerebrovascular Aß43 levels did not change after immunotherapy.