stilbenes and Cerebral-Amyloid-Angiopathy

Free and Cued Selective Reminding Test (FCSRT) is a reliable cognitive marker for Alzheimer's disease (AD), and the identification of neuropsychological tests sensitive to the early signs of AD pathology is crucial both in research and clinical practice.. The study aimed to ascertain the ability of FCSRT in predicting the amyloid load as determined from amyloid PET imaging (Amy-PET) in patients with cognitive disorders.. For our purpose, 79 patients (71 MCI, 8 mild dementia) underwent a complete workup for dementia, including the FCSRT assessment and a [18F]florbetaben PET scan. FCSRT subitem scores were used as predictors in different binomial regression models.. Immediate free recall and delayed free recall were the best predictors overall in the whole sample; whereas in patients <76 years, all models further improved with immediate total recall (ITR) and Index of Sensitivity of Cueing (ISC) resulting the most accurate in anticipating Amy-PET results, with a likelihood of being Amy-PET positive greater than 85% for ITR and ISC scores of less than 25 and 0.5, respectively.. FCSRT proved itself to be a valid tool in dementia diagnosis, also being able to correlate with amyloid pathology. The possibility to predict Amy-PET results through a simple and reliable neuropsychological test might be helpful for clinicians in the dementia field, adding value to a paper and pencil tool compared to most costly biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Aniline Compounds; Body Burden; Cerebral Amyloid Angiopathy; Cognitive Dysfunction; Cues; Dementia; Disease Progression; Female; Humans; Male; Mental Recall; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Prospective Studies; Psychomotor Performance; Radiopharmaceuticals; Reproducibility of Results; Stilbenes

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben).. To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients.. CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients.. A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers.. In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cerebral Amyloid Angiopathy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Positron-Emission Tomography; Prospective Studies; Stilbenes; tau Proteins; Vasculitis, Central Nervous System

Topics: Aged; Amyloid; Aniline Compounds; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Humans; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Stilbenes

In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aniline Compounds; Animals; Case-Control Studies; Cerebral Amyloid Angiopathy; Disease Models, Animal; Female; Longitudinal Studies; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Stilbenes

Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver therapeutic agents and endogenous therapeutic molecules to the brain leading to plaque reduction and improved behavior. However, prior to moving to clinic, questions regarding how the compromised vasculature in Alzheimer's disease responds to FUS need to be addressed. Here, we used two-photon microscopy to study changes in FUS-mediated BBB permeability in transgenic (TgCRND8) mice and their non-transgenic littermates. A custom-built ultrasound transducer was attached to the skull, covering a cranial window. Methoxy-X04 was used to visualize amyloid deposits in vivo. Fluorescent intravascular dyes were used to identify leakage from the vasculature after the application of FUS. Dye leakage occurred in both transgenic and non-transgenic mice at similar acoustic pressures but exhibited different leakage kinetics. Calculation of the permeability constant demonstrated that the vasculature in the transgenic mice was much less permeable after FUS than the non-transgenic littermates. Further analysis demonstrated that the change in vessel diameter following FUS was lessened in amyloid coated vessels. These data suggest that changes in vessel diameter may be directly related to permeability and the presence of amyloid plaque may reduce the permeability of a vessel after FUS. This study indicates that the FUS parameters used for the delivery of therapeutic agents to the brain may need to be adjusted for application in Alzheimer's disease.

Topics: Alkenes; Alzheimer Disease; Animals; Benzene Derivatives; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Drug Delivery Systems; Female; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Permeability; Plaque, Amyloid; Stilbenes; Ultrasonics

Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microscopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

Topics: Alkenes; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzene Derivatives; Cerebral Amyloid Angiopathy; Cyclic N-Oxides; Dipeptides; Fluorescent Dyes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Transgenic; Minocycline; Oxidative Stress; Presenilin-1; Protease Inhibitors; Reactive Oxygen Species; Simvastatin; Statistics as Topic; Stilbenes; Time Factors

Aggregation of amyloid-beta (Abeta) peptide in the brain in the form of neuritic plaques and cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD). Microglial cells surround aggregated Abeta and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-Abeta antibodies. One mechanism by which certain anti-Abeta antibodies have been proposed to exert their effects is via antibody-mediated microglial activation. Whether, when, or to what extent microglial activation occurs after systemic administration of anti-Abeta antibodies has not been fully assessed. We administered an anti-Abeta antibody (m3D6) that binds aggregated Abeta to PDAPP mice, an AD mouse model that was bred to contain fluorescent microglia. Three days after systemic administration of m3D6, there was a marked increase in both the number of microglial cells and processes per cell visualized in vivo by multiphoton microscopy. These changes required the Fc domain of m3D6 and were not observed with an antibody specific to soluble Abeta. These findings demonstrate that some effects of antibodies that recognize aggregated Abeta are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD.

Topics: Age Factors; Alkenes; Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Animals; Antibodies; Benzene Derivatives; Calcium-Binding Proteins; Cell Count; Cell Movement; Cerebral Amyloid Angiopathy; CX3C Chemokine Receptor 1; Disease Models, Animal; Green Fluorescent Proteins; Leukocyte Common Antigens; Mice; Mice, Transgenic; Microfilament Proteins; Microglia; Plaque, Amyloid; Receptors, Chemokine; Stilbenes

Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.

Topics: Alkenes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzene Derivatives; Cerebral Amyloid Angiopathy; Craniotomy; Disease Models, Animal; Disease Progression; Fluorescent Dyes; Humans; Image Processing, Computer-Assisted; Kinetics; Meninges; Mice; Mice, Transgenic; Plaque, Amyloid; Skin Window Technique; Stilbenes