Chronic Intranasal Treatment with an Anti-Aβ30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aβ-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aβ fibril formation and Aβ-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aβ from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice

The ε3 and ε4 Alleles of Human APOE Differentially Affect Tau Phosphorylation in Hyperinsulinemic and Pioglitazone Treated Mice

Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD). The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM). Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD) or low fat diet (LFD) for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone

On Your Feet to Earn Your Seat: pilot RCT of a theory-based sedentary behaviour reduction intervention for older adults

Background: Of all age groups, older adults spend most of the time sitting and are least physically active. This sequential, mixed-methods feasibility study used a randomised controlled trial design to assess methods for trialling a habit-based intervention to displace older adults’ sedentary behaviour with light activity and explore impact on behavioural outcomes. Methods: Eligibility criteria were age 60–74 years, retired, and ≥6 h/day leisure sitting. Data were collected across four sites in England. The intervention comprised a booklet outlining 15 ‘tips’ for disrupting sedentary habits and integrating activity habits into normally inactive settings, and eight weekly self-monitoring sheets. The control was a non-habit-based factsheet promoting activity and sedentary reduction. A computer-generated 1:1 blockrandomisation schedule was used, with participants blinded to allocation. Participants self-reported sedentary behaviour (two indices), sedentary habit, physical activity (walking, moderate, vigorous activity) and activity habit, at pre-treatment baseline, 8- and 12-week follow-ups and were interviewed at 12 weeks. Primary feasibility outcomes were attrition, adverse events and intervention adherence. The secondary outcome was behavioural change. Results: Of 104 participants consented, 103 were randomised (intervention N = 52, control N = 51). Of 98 receiving allocated treatment, 91 (93%; intervention N = 45; control N = 46) completed the trial. One related adverse event was reported in the intervention group. Mean per-tip adherence across 7 weeks was ≥50% for 9/15 tips. Qualitative data suggested acceptability of procedures, and, particularly among intervention recipients, the allocated treatment. Both groups appeared to reduce sedentary behaviour and increase their physical activity, but there were no apparent differences between groups in the extent of change. Conclusions: Trial methods were acceptable and feasible, but the intervention conferred no apparent advantage over control, though it was not trialled among the most sedentary and inactive population for whom it was developed. Further development of the intervention may be necessary prior to a large-scale definitive trial. One possible refinement would combine elements of the intervention with an informational approach to enhance effectiveness

Cognitive Neuropsychology of HIV-Associated Neurocognitive Disorders

Advances in the treatment of the human immunodeficiency virus (HIV) have dramatically improved survival rates over the past 10 years, but HIV-associated neurocognitive disorders (HAND) remain highly prevalent and continue to represent a significant public health problem. This review provides an update on the nature, extent, and diagnosis of HAND. Particular emphasis is placed on critically evaluating research within the realm of cognitive neuropsychology that aims to elucidate the component processes of HAND across the domains of executive functions, motor skills, speeded information processing, episodic memory, attention/working memory, language, and visuoperception. In addition to clarifying the cognitive mechanisms of HAND (e.g., impaired cognitive control), the cognitive neuropsychology approach may enhance the ecological validity of neuroAIDS research and inform the development of much needed novel, targeted cognitive and behavioral therapies

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Health-related quality of life dynamics of HIV-positive South African women up to ART initiation : evidence from the CAPRISA 002 acute infection cohort study.

CAPRISA, 2014.Few studies have investigated the long-term dynamics in health-related quality of life (HRQoL) among HIV-positive persons from acute infection. From 2004, 160 women were enrolled into the CAPRISA 002 Acute Infection study at two sites in the province of KwaZulu-Natal and underwent 3–6 monthly HRQoL assessments using the functional assessment of HIV infection (FAHI) instrument. Overall and 5 sub-scale FAHI scores [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were calculated up to antiretroviral therapy (ART) initiation and scores at enrollment were compared to the acute, early and established infection phases. Mixed-effects regression models adjusting for behavioral and clinical factors were applied to assess HRQoL trends and the proportion of women meeting minimally important differences was calculated. Our analyses revealed that overall/sub-scale scores improved over time, except from PWB and CF. A higher educational status, contraceptive use and a higher BMI were the strongest predictors of higher overall/sub-scale FAHI scores. CD4 count and HIV viral load were strongly associated with PWB and CF, but not overall FAHI and other sub-scales. Women newly diagnosed with acute HIV infection face profound HRQoL challenges. While early ART delivery may be important for PWB and CF, factors such as education, contraception provision and good nutritional status should be promoted to maximize HRQoL in HIV positive individuals