amyloid-beta-peptides and Intracranial-Hemorrhages

Cerebrovascular pathology is a significant mediator in Alzheimer's disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2-83 years). Sections were immunostained against Aβ1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Case-Control Studies; Cerebral Amyloid Angiopathy; Child; Child, Preschool; Down Syndrome; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Intracranial Hemorrhages; Male; Middle Aged; Occipital Lobe; Peptide Fragments; Young Adult

Background and Purpose- Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods- We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1-38, Aβ1-40, and Aβ1-42 were assessed using ELISA. Results- Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1-42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, <0.001). Similarly, among persons in higher tertile of Aβ1-38, a strong association was observed between CRP and microbleed counts ( P interaction, 0.004). Conclusions- Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.

Topics: Aged; Amyloid beta-Peptides; Brain; C-Reactive Protein; Cerebral Small Vessel Diseases; Female; Glymphatic System; Gray Matter; Hippocampus; Humans; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Middle Aged; Neurodegenerative Diseases; Peptide Fragments; Stroke, Lacunar; White Matter

Alzheimer's disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA).. We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients.. Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers.. The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid β-protein 1-40 (Aβ40) and amyloid β-protein 1-42 (Aβ42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis.. CAA-related cortical microbleeds would be associated with lower CSF levels of Aβ40 and Aβ42 in AD, reflecting the deposition of both Aβ40 and Aβ42 in the cerebrovasculature.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Cerebral Amyloid Angiopathy; Female; Humans; Intracranial Hemorrhages; Leukoaraiosis; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Retrospective Studies; Risk Factors

New pre-clinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse responses that occurred during the clinical trials with AN-1792 vaccine formulation. Recently, we have pursued an alternative immunization strategy that replaces QS21 the Th1 type adjuvant used in the AN-1792 clinical trial with a molecular adjuvant, mannan that can promote a Th2-polarized immune response through interactions with mannose-binding and CD35/CD21 receptors of the innate immune system. Previously we established that immunization of wild-type mice with mannan-Abeta28 conjugate promoted Th2-mediated humoral and cellular immune responses. In the current study, we tested the efficacy of this vaccine configuration in amyloid precursor protein (APP) transgenic mice (Tg2576).. Mannan was purified, activated and chemically conjugated to Abeta28 peptide. Humoral immune responses induced by the immunization of mice with mannan-Abeta28 conjugate were analyzed using a standard ELISA. Abeta42 and Abeta40 amyloid burden, cerebral amyloid angiopathy (CAA), astrocytosis, and microgliosis in the brain of immunized and control mice were detected using immunohistochemistry. Additionally, cored plaques and cerebral vascular microhemorrhages in the brains of vaccinated mice were detected by standard histochemistry.. Immunizations with low doses of mannan-Abeta28 induced potent and long-lasting anti-Abeta humoral responses in Tg2576 mice. Even 11 months after the last injection, the immunized mice were still producing low levels of anti-Abeta antibodies, predominantly of the IgG1 isotype, indicative of a Th2 immune response. Vaccination with mannan-Abeta28 prevented Abeta plaque deposition, but unexpectedly increased the level of microhemorrhages in the brains of aged immunized mice compared to two groups of control animals of the same age either injected with molecular adjuvant fused with an irrelevant antigen, BSA (mannan-BSA) or non-immunized mice. Of note, mice immunized with mannan-Abeta28 showed a trend toward elevated levels of CAA in the neocortex and in the leptomeninges compared to that in mice of both control groups.. Mannan conjugated to Abeta28 provided sufficient adjuvant activity to induce potent anti-Abeta antibodies in APP transgenic mice, which have been shown to be hyporesponsive to immunization with Abeta self-antigen. However, in old Tg2576 mice there were increased levels of cerebral microhemorrhages in mannan-Abeta28 immunized mice. This effect was likely unrelated to the anti-mannan antibodies induced by the immunoconjugate, because control mice immunized with mannan-BSA also induced antibodies specific to mannan, but did not have increased levels of cerebral microhemorrhages compared with non-immunized mice. Whether these anti-mannan antibodies increased the permeability of the blood brain barrier thus allowing elevated levels of anti-Abeta antibodies entry into cerebral perivascular or brain parenchymal spaces and contributed to the increased incidence of microhemorrhages remains to be investigated in the future studies.

Topics: Adjuvants, Immunologic; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibody Formation; Blood-Brain Barrier; Cerebral Amyloid Angiopathy; Cerebral Arteries; Disease Models, Animal; Dose-Response Relationship, Drug; Intracranial Hemorrhages; Mannans; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Treatment Outcome; Vaccination; Vaccines, Conjugate