Amyloid Deposition In Blood Vessels Research Articles

AB1601 Phase 2 Study of ABvac40, an Anti‐Aβ40 Vaccine: Safety and Immunogenicity of a Cross‐Over Extension

AbstractBackgroundAmyloid‐β (Aβ) immunotherapy is a promising strategy for treating Alzheimer’s disease (AD). Previous studies suggested that Aβ40 could have an important role in AD, especially in relation to amyloid deposition in blood vessels in AD. The AB1601 (NCT03461276) is a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study in patients with amnestic mild cognitive impairment (a‐MCI) or very mild AD (vm‐AD) which investigated the safety, tolerability and immunogenicity of repeated subcutaneous injections of ABvac40, a vaccine targeting Aβ40. The 24‐month study (Part A) showed that ABvac40 was safe, well‐tolerated and highly immunogenic. Here, an additional 18‐month cross‐over study (Part B) was conducted to evaluate safety, tolerability and immunogenicity of ABvac40 in patients randomized to placebo in Part A (Delayed start group), and to assess safety and immunogenicity of a delayed booster of ABvac40 in ABvac40‐treated patients in Part A (Booster group).MethodA total of 124 patients with a‐MCI (N = 80) or vm‐AD (N = 44) were initially included in Part A. Seventy‐seven out of 101 patients who completed Part A transitioned to Part B. Safety assessments included the frequency of amyloid‐related imaging abnormalities (ARIA). Immune response was assessed by quantification of specific anti‐Aβ40 antibodies in plasma samples.ResultABvac40 continued to show a favorable safety profile. Specifically, no ARIA‐E was reported and ARIA‐H incidence was low, equally distributed in both groups, and similar to the placebo group (Part A). Delayed start group showed a strong and specific immune response, with a time course equivalent to the ABvac40 group in Part A. A delayed booster of ABvac40 elicited a large increase in anti‐Aβ40 antibody plasma levels, exceeding the concentrations observed throughout the active dosing phase of Part A.ConclusionThe cross‐over extension of the AB1601 Phase 2 study confirmed the excellent safety and tolerability profile of ABvac40, making this vaccine a potential candidate to be combined with other disease‐modifying therapies. Results on immunogenicity supported those obtained in Part A, demonstrating that ABvac40 elicited a strong, specific, sustained and boostable immune response. This could have important implications for long‐term treatments, especially in the context of preventive approaches. Additional exploratory efficacy results of Part B are expected in Q4‐2023.

Intermediate Antiparallel Fibrils in Aβ40 Dutch Mutant Aggregation: Insights from Nanoscale Infrared Spectroscopy.

Cerebral amyloid angiopathy (CAA), which involves amyloid deposition in blood vessels leading to fatal cerebral hemorrhage and recurring strokes, is present in the majority Alzheimer's disease (AD) cases. Familial mutations in the amyloid β peptide are correlated to higher risks of CAA and are mostly comprised of mutations at residues 22 and 23. While the structure of the wild-type Aβ peptide has been investigated in great detail, less is known about the structure of mutants involved in CAA and evolutions thereof. This is particularly true for mutations at residue 22, for which detailed molecular structures, as typically determined from Nuclear Magnetic Resonance (NMR) spectroscopy or electron microscopy, do not exist. In this report, we have used nanoscale infrared (IR) spectroscopy augmented with atomic force microscopy (AFM-IR) to investigate structural evolution of the Aβ Dutch mutant (E22Q) at the single aggregate level. We show that in the oligomeric stage, the structural ensemble is distinctly bimodal, with the two subtypes differing with respect to population of parallel β sheets. Fibrils on the other hand are structurally homogeneous, with early-stage fibrils distinctly antiparallel in character, which develop parallel β sheets upon maturation. Furthermore, the antiparallel structure is found to be a persistent feature across different stages of aggregation.

Characterization of amyloid angiopathy in the retina

AbstractBackgroundCerebral amyloid angiopathy (CAA) is a vascular brain disease with risk of severe complications, and high prevalence in those with Alzheimer’s disease (AD). Characteristic amyloid beta deposits in blood vessels in the cerebrum are challenging to diagnose. Amyloid deposits in blood vessels in human retinas have been previously reported. Here, we characterize postmortem, retinal amyloid angiopathy (RAA) in individuals with AD and/or CAA brain pathology. We propose a staging of RAA which could be extended to in vivo imaging, modified from CAA staging in the brain.MethodCorrelation of severity of brain pathology for AD and CAA was assessed for 52 individuals. Formalin fixed retinas from 6 of these individuals were whole‐mounted and stained with thioflavin S and DAPI, then imaged in polarized light and confocal microscopy with 3 florescence channels. While following blood vessels systematically, images of RAA were collected.ResultBrain pathology due to CAA increased in severity with increasing severity of AD pathology as previously reported (Figure 1). RAA was present in all donors with evidence of brain CAA and in two donors with no evidence of brain CAA (Figure 2). Amyloid present in vessels can be imaged dye‐free in polarized light. Our proposed staging of RAA severity is modified from two used in the brain (Figures 3‐6). Stage 1): Amyloid within the vessel and not filling the lumen of the vessel: 1A) Amyloid is not circumferential; 1B) Amyloid is circumferential. Stage 2): Amyloid completely fills the lumen of the vessel. Stage 3): Amyloid both within and touching the outside of the vessel, analogous to dysphoric CAA.ConclusionAmyloid angiopathy in the retina (RAA) may occur concurrently with and potentially prior to brain CAA. Further, severity of RAA could be monitored through the proposed staging which in turn could allow comparison of severities of CAA and RAA. This would elucidate whether RAA severity is a good predictor of CAA severity. Our data confirm the previously reported correlation between brain CAA and AD. Further development of RAA imaging in the living eye may allow earlier and improved diagnosis of brain CAA, facilitating the development and testing of new treatments.

The Clinical Impact of Proteomics in Amyloid Typing

The Clinical Impact of Proteomics in Amyloid Typing

Apolipoprotein E genotype does not influence the risk of symptomatic hemorrhage in acute ischemic stroke

BackgroundAPOE ε4 is independently associated with lobar intracranial hemorrhages (ICH). Although the ε4 allele enhances amyloid deposition in blood vessels, the ε2 allele predisposes to vasculopathic changes leading to rupture of amyloid laden vessels. Thus, ε4 and ε2 carriers might have increased susceptibility to ICH.We aimed to study the impact of the apolipoprotein E alleles in the development of symptomatic ICH (sICH). MethodsWe included 384 consecutive ischemic anterior circulation stroke patients submitted to thrombolysis between January 2014 and March 2016. Admission CT-scans were reviewed to calculate the ASPECTS. Patients were followed for up to at least 6 months post-stroke or until death. Outcome was development of sICH, defined according to the ECASS III. ResultsConsidering APOE genotyping, three patients had ε2/ε2, four had ε2/ε4, 38 had ε2/ε3, 284 had ε3/ε3, 51 had ε3/ε4 and four had ε4/ε4. sICH was associated with sex and diabetes. In multivariate analysis, sICH was not associated with carrying one or more ε4 alleles (OR: 0.483, 95%CI = [0.059, 3.939], p = 0.497) nor with carrying one or more ε2 alleles (OR: 1.369, 95%CI = [0.278, 6.734], p = 0.699). ConclusionNo association was found between APOE genotype and the development of symptomatic intracranial hemorrhage.

Low Levels of Serum N-3 Polyunsaturated Fatty Acids are Associated with Lower Heart Failure Free Survival after Acute Myocardial Infarction

Introduction: Cardiac involvement in systemic amyloidosis causes detrimental prognosis, therefore early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Methods: We retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Results: Amyloid deposition was observed in 11 patients (79%). Histopathological analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compare to senile systemic amyloidosis and familial amyloidosis (60% vs. 0%; p50.03). During the follow-up period (median 297 days, range 3-761 days), 7 patients died or were admitted to the hospital due to worsening heart failure. Among them, 6 patients (86%) were positive for amyloid deposition in blood vessels. The incidence of death and composite outcome, including heart failure hospitalization and death, was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p50.03, p50.006; respectively). Conclusions: Amyloid subtype could be diagnosed by analyzing the degree of amyloid deposition in blood vessels and adipose tissue using subcutaneous tissue biopsy samples in patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Effect of Exercise Training on Nitric Oxide Synthasesin the Cardiovasculature and Kidney of Rats with Chronic Heart Failure

Introduction: Cardiac involvement in systemic amyloidosis causes detrimental prognosis, therefore early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Methods: We retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Results: Amyloid deposition was observed in 11 patients (79%). Histopathological analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compare to senile systemic amyloidosis and familial amyloidosis (60% vs. 0%; p50.03). During the follow-up period (median 297 days, range 3-761 days), 7 patients died or were admitted to the hospital due to worsening heart failure. Among them, 6 patients (86%) were positive for amyloid deposition in blood vessels. The incidence of death and composite outcome, including heart failure hospitalization and death, was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p50.03, p50.006; respectively). Conclusions: Amyloid subtype could be diagnosed by analyzing the degree of amyloid deposition in blood vessels and adipose tissue using subcutaneous tissue biopsy samples in patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Diagnostic and Prognostic Value of Subcutaneous Tissue Biopsy in Patients With Cardiac Amyloidosis

Cardiac involvement in systemic amyloidosis causes detrimental prognosis; therefore, early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening procedure for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Thus, we investigated the value of subcutaneous tissue biopsy in cardiac amyloidosis. In 22 patients with cardiac amyloidosis, we retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Amyloid deposition was observed in 11 patients (79%). Histopathologic analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compared to senile systemic amyloidosis and familial amyloidosis (60% vs 0%, p = 0.03). During the follow-up period (median 297 days, range 3 to 761), 7 patients (5 with monoclonal immunoglobulin light-chain amyloidosis and 2 with senile systemic amyloidosis) died or were admitted to the hospital because of worsening heart failure. Of them, 6 patients (86%) were positive for amyloid deposition in blood vessels in subcutaneous tissue biopsy. Incidence of death and composite outcome including heart failure hospitalization and death was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p = 0.03, p = 0.006, respectively). These results suggest that amyloid subtype could be diagnosed by assessing the degree of amyloid deposition in blood vessels and adipose tissue in subcutaneous tissue biopsy samples from patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Extensive Amyloid Deposit in Bone Marrow Aspirate

A 62-year-old female presented in the Hepatology OPD with progressive weakness, loss of appetite and dyspnoea. On examination she had icterus, anasarca and hepatomegaly. The liver was enlarged 8 cm below the right costal margin and hard on palpation with vague nodularity. There was no splenomegaly or lymphadenopathy. She was a known case of hypothyroidism. X-ray chest showed bilateral pleural and pericardial effusion. Echocardiography was suggestive of restrictive cardiomyopathy. MRI showed hyperintensity of liver on T2. Liver function tests were deranged. Kidney function tests were normal. Complete hemogram showed Hb of 11 gm/dl, total leukocyte count 7.8 × 109/L and platelets were 178 × 109/L. Liver biopsy performed for the workup revealed extensive amyloid deposit in the vessels and the sinusoids near completely replacing hepatic parenchymal cells. Endoscopic biopsies from duodenum and rectum showed amyloid deposition in blood vessels. Serum and urine electrophoresis and immunofixation did not showed monoclonal M band. Serum Ig-free light chain showed κ to λ ratio of 4.12 (normal 0.26–1.65) and β2 microglobulin was raised. Bone marrow aspirate and biopsy was performed to rule out multiple myeloma. Aspirate showed hypocellular marrow particles with extensive deposits of blue-pink acellular amorphous (Fig. 1A, B) extracellular congophilic material (Fig. 1C) displaying green bireferingence under polarised light. There was mild erythroid hyperplasia with adequate representation of myeloid and erythroid series of cells with normal maturation and no dysplastic changes. The plasma cells were approximately 6 % out of 500 cell count. A few isolated small aggregates of 4–6 plasma cells were also seen. Bone marrow biopsy also revealed homogenous pale eosinophilic acellular deposits of amyloid in the interstium and vessel walls (Fig. 1D). Plasma cell group or nodules were not seen. Immunohistochemistry for kappa and lambda was performed on the bone marrow biopsy which showed plasma cells showing positivity predominantly for kappa and focally for lambda. A final clinico-pathological diagnosis of plasma cell dyscrasia with AL (kappa) systemic amyloidosis was made. Fig. 1 Bone marrow aspirate showing extensive deposits of blue-pink acellular amorphous extracellular material (A, B) congophilic with congo red stain (C). Bone marrow biopsy also revealed homogenous pale eosinophilic acellular deposits of amyloid in the interstium ... Primary or AL amyloidosis is the commonest cause of systemic amyloidosis worldwide [1,2]. Bone marrow examination in these cases is performed in order to evaluate plasma cell infiltration. Plasma cells may be increased to the level of overt multiple myeloma or the number could be <10 % in which case it is classified as plasma cell dyscrasia or monoclonal gammopathy of unknown significance (MGUS). Amyloid is usually is not seen or is very sparse if present in aspirate, however biopsy usually shows amyloid deposition on vessel wall and rarely in interstitium [3]. In a study by Swan et al. the bone marrow core biopsy demonstrate amyloid deposition in 60 % cases out of 100 biopsies of patients with AL (primary) amyloidosis studied [2]. In their series plasma cell dyscrasia was observed in 83 cases with majority of lambda (65 cases) light chain disease. They also observed that interstitial amyloid deposition was significantly more commonly associated with patients with a monoclonal kappa light chain gammopathy, like in our case. Few studies have shown mean plasma cell percentages ranging from 7 to 14 % by analyzing the bone marrow core biopsy specimen in AL amyloidosis using immunohistochemical stains for light chain immunoglobulins [2, 4]. However, the finding of extensive bone marrow amyloid deposition in the aspirate smears is very unusual and rarely reported to the best of our knowledge.

Primary amyloidosis presenting as “dropped head syndrome”

A 77-year-old man, with a history of lymphoma, presented with isolated neck extensor weakness and a 2-year history of bilateral carpal tunnel syndrome (CTS). Needle electromyography showed myopathic changes, and biopsy of cervical paraspinal muscles showed amyloid deposition in blood vessels. Amyloidosis should be considered in the differential diagnosis of dropped head syndrome.

Cerebral Amyloid Angiopathy, Blood-Brain Barrier Disruption and Amyloid Accumulation in SAMP8 Mice

Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer’s disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors.

Increased incidence of anti- β-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer's disease

During the past several years, evidence has been accumulated to support the thesis that immunological factors may play some role in Alzheimer's disease (AD). We have characterized the reactive antigens detected by certain monoclonal antibodies secreted by Epstein-Barr virus (EBV)-transformed B cell lines from the peripheral blood of AD patients and controls. Autoantibodies against β-amyloid protein ( β-A) in amyloid plaques and blood vessels and in enzyme-linked immunosorbent assays (ELISA) have been reported in four cell lines derived from an AD patient. In this study, over 3300 EBV-transformed B cell lines from thirteen individuals were tested in ELISAs for antibodies against β-A peptides. Significantly more autoantibodies against β-A (1–40) were found in the AD group, 2.26±0.62% (39/1794 cell lines) than in the control group, 0.28±0.36% (5/1552 cell lines) with P<0.005. These new antibodies did not react with plaques or amyloid deposits in blood vessels. In contrast to the four plaque-reactive autoantibodies which reacted better with β-A (1–40) than with β-A (1–28), 70% of these anti- β-A (1–40) antibodies reacted as well or better with β-A (1–28). Many of them were also reactive with β-A (1–16). Tested against a panel of cytoskeletal proteins and Hela cells, many of these anti- β-A (1–40) antibodies appear to be polyreactive. The higher incidence of anti- β-A antibody secreting B cells in AD patients provides further evidence that autoimmunity may play a role in AD.

Peripheral nerve pathological findings in familial amyloid polyneuropathy: A correlative study of proximal sciatic nerve and sural nerve lesions

To analyze the peripheral nerve pathological abnormalities in familial amyloid polyneuropathy, a correlative pathological study was carried out on the spinal nerve roots, proximal sciatic nerves, sural nerves, and brachial plexuses from 3 patients with the disease in Japan. The spinal nerve roots appeared to be unaffected except for amyloid deposition on the epineurium. In sciatic nerves and brachial plexuses the nerve lesions had a multifocal distribution, showing prominent interstitial edema in the endoneurium frequently adjacent to deposits of amyloid; in these regions the nerve fibers were severely depleted. A teased-fiber study revealed that segmental demyelination was the predominant type of nerve fiber abnormality. However, these findings were not seen in the sural nerves; instead a diffuse fiber loss with axonal degeneration was observed. It is suggested that multifocal lesions in the proximal portions of the long extremity nerves could summate distally to produce a symmetrical polyneuropathy in the disease. In addition to a space-occupying effect of amyloid deposits in the endoneurium, severe endoneurial edema associated with amyloid deposition in blood vessels and the endoneurial interstitium may induce ischemia in nerve fibers, thus causing the progressive polyneuropathy in this disorder.