Incidence Of Microhemorrhage Research Articles

CD59 Protects Primary Human Cerebrovascular Smooth Muscle Cells from Cytolytic Membrane Attack Complex.

Cerebral amyloid angiopathy is characterized by a weakening of the small- and medium-sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid β, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and varying cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody, and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in a total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. The overexpression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reductions in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated.

Prevalence and Incidence of Microhemorrhages in Adolescent Football Players

SWI is an advanced imaging modality that is especially useful in cerebral microhemorrhage detection. Such microhemorrhages have been identified in adult contact sport athletes, and the sequelae of these focal bleeds are thought to contribute to neurodegeneration. The purpose of this study was to utilize SWI to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are significantly greater than those of adolescent noncontact athletes. Preseason and postseason SWI was performed and evaluated on 78 adolescent football players. SWI was also performed on 27 adolescent athletes who reported no contact sport history. Two separate one-tailed Fisher exact tests were performed to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are greater than those of noncontact athlete controls. Microhemorrhages were observed in 12 football players. No microhemorrhages were observed in any controls. Adolescent football players demonstrated a significantly greater prevalence of microhemorrhages than adolescent noncontact controls (P = .02). Although 2 football players developed new microhemorrhages during the season, microhemorrhage incidence during 1 football season was not statistically greater in the football population than in noncontact control athletes (P = .55). Adolescent football players have a greater prevalence of microhemorrhages compared with adolescent athletes who have never engaged in contact sports. While microhemorrhage incidence during 1 season is not significantly greater in adolescent football players compared to adolescent controls, there is a temporal association between playing football and the appearance of new microhemorrhages.

Value of Advanced MR Imaging Techniques in Mild Traumatic Brain Injury.

This commentary addresses the article, “Prevalence and Incidence of Microhemorrhages in Adolescent Football Players.”[1][1] The authors performed SWI in 78 adolescent football players before and after the season. The number of examined football players was fairly large. They found a prevalence

Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice

BackgroundIt is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response.ResultsWe have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A) was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP), and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden) in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens.ConclusionThese results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects.

Molecular characterization and preclinical efficacy

Passive immunotherapy with anti-Abeta antibodies is currently investigated for the treatment of Alzheimer's Disease with several candidates in preclinical or clinical development. BIIB037 was generated using the Reverse Translational Medicine method (RTM). Binding properties of BIIB037 were measured in vitro against soluble and fibrillar Abeta. In vivo studies using Tg2576 mice were conducted to assess brain penetration and binding to amyloid plaques, as well as PK profile of the antibody. Preclinical efficacy was determined after chronic dosing using biochemical and histopathological endpoints. BIIB037 is a fully human IgG1 monoclonal antibody derived from an AD patient with an unusual stable clinical course. The RTM approach was used to isolate, clone and recombinantly express the antibody. In vitro characterization shows a high affinity for insoluble fibrillar human Abeta using an ELISA format assay with fibrillar Abeta1-42 immobilized on the plate, and BIIB037 doesn't bind to soluble Abeta1-40 in an inverted ELISA assay format. Binding was also evaluated using a TAPIR assay and staining of amyloid plaques in both AD brain and transgenic mice brain tissues was observed. BIIB037 enters the brain and binds to amyloid plaques after systemic administration in Tg2576 transgenic mice. The amount of drug detected into the brain is dose-dependent. Chronic dosing for 6 months led to a significant amyloid load reduction as measured by ELISA and histopathology, but didn't lead to increased plasma Abeta1-40, Abeta1-42 levels. Incidence of microhemorrhage and inflammation was not increased compared to vehicle treated group. A novel fully human antibody recognizing fibrillar human Abeta was characterized and its preclinical efficacy was demonstrated in vivo.

Immunotherapy Reduces Vascular Amyloid- 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.

O1-06-07: Immunotherapy with antibodies to N-terminal amyloid-β peptides reduces cerebral amyloid angiopathy in PDAPP mice

Passive immunotherapy with amyloid–β (Aβ) antibodies reduces a number of AD pathologies including parenchymal Aβ plaques, neuritic dystrophy, synaptic loss, and memory function in mouse models, and many of these effects are beginning to be seen in AD patients. In addition to parenchymal deposition of amyloid, AD is also characterized by amyloid fibrils in the cerebral vasculature in the majority of patients, a condition called cerebral amyloid angiopathy (CAA). Previous studies have suggested that immunotherapy does not clear and may increase CAA and the incidence of microhemorrhage. In the present study we demonstrate that certain immunotherapies are surprisingly highly efficacious in removing CAA and that the incidence of microhemorrhage can be modulated by dosage. We examined the effects of passive immunization on CAA in 2 PDAPP mouse studies: one a comparison of antibodies to different Aβ epitopes (3D6, Aβ1–5; 12A11 and 10D5, Aβ3–7; 266 Aβ16–23) at one dose, and a 3D6 dose–response study at 3 doses. CAA clearance and microhemorrhage incidence were assessed after 6 months using Aβ IHC and hemosiderin detection. We found that 3D6 at the highest dose completely cleared CAA, with nearly 100% clearance observed in both studies. In addition, partial clearance was evident at both lower doses as well as with 10D5 and 12A11 treatments. 266 showed no effect on CAA or plaque clearance. Sites of hemosiderin staining were limited to focal, perivascular regions and were almost entirely restricted to meningeal vasculature and sagittal sinus vessels. Lower dose 3D6 groups had significantly reduced hemosiderin ratings compared to the highest dose group, and the 266 and 10D5 groups did not significantly differ from the control. Hemosiderin staining co–localized with Aβ at sites of ongoing clearance in the lower dose 3D6, 12A11, and 10D5 groups. Collectively, these observations showed that removal of CAA at lower doses of 3D6 minimized microhemorrhage over the 6–month study period. These observations suggest that passive immunization can reduce CAA, and modulating antibody dose and duration can significantly mitigate the incidence of microhemorrhage. Immunotherapy can then potentially remove or reverse the CAA that is thought to lead to dysfunction of the microvasculature in AD.