CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer\u27s Disease

The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer\u27s disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-)mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble A beta production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble A beta 42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(1/1) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce A beta; however, the results suggest that interventions may have a divergent effect on tau pathology

Psychotic Alzheimer\u27s disease is associated with gender-specific tau phosphorylation abnormalities

Converging evidence suggests that psychotic Alzheimer\u27s disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of alpha-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration. (C) 2014 Elsevier Inc. All rights reserved

Distraction and Older Drivers: An Emerging Problem?

Distracted driving is widely recognised as a significant threat to the safety of all road users. Age-related declines in a range of sensory, cognitive and physical processes can, however, make older drivers particularly vulnerable to risks associated with distraction. While traditionally viewed as a younger driver issue, distracted driving among the older driver cohort is predicted to increase as future generations of older drivers drive more often, and for longer, and embrace technology in increasing numbers. This paper discusses current knowledge regarding why older drivers are particularly vulnerable to the effects of distracted driving and reviews recent research on older driver distraction engagement and its impact on their driving performance. Also presented, is an Australian case study of older driver secondary task engagement using data from the recently completed Australian Naturalistic Driving Study (ANDS). This case study examined patterns of secondary task engagement during everyday trips among 48 older (60+), middle-aged (43-49 years) and young (22-31 years) drivers. The findings suggest that Australian older drivers do engage in a large number of secondary tasks when driving; however, there is evidence that they self-regulate the type and timing of these tasks.Kristie L. Young, Judith Charlton, Sjaan Koppel, Raphael Grzebieta, Ann Williamson, Jeremy Woolley, and Teresa Senserric

Psychosis in Alzheimer\u27s Disease is Associated with Frontal Metabolic Impairment and Accelerated Decline in Working Memory: Findings from the Alzheimer\u27s Disease Neuroimaging Initiative

Objective: An ascendant body of evidence suggests that Alzheimer disease with psychosis (AD+P) is a distinct variant of illness with its own genetic diathesis and a unique clinical course. Impaired frontal lobe function has been previously implicated in AD+P. The current exploratory study, presented in two parts, evaluates both the regional brain metabolic and psychometric correlates of psychosis in a longitudinal sample of subjects with AD, made available by the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI). Methods: In Part 1 of the study, 21 ADNI participants with AD who developed psychotic symptoms during the study but were not psychotic at baseline were matched with 21 participants with AD who never became psychotic during the study period, and mean brain [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) Cerebral metabolic rate for glucose (CMRgl) by regions of interest (ROIs) were compared Additionally, 39 participants with active psychosis at the time of image acquisition were matched with 39 participants who were never psychotic during the study period, and mean brain FDG-PET CMRgl by sROI were compared. In Part 2 of the study, 354 ADNI participants with AD who were followed for 24 months with serial psychometric testing were identified, and cognitive performance and decline were evaluated for correlation with psychotic symptoms. Results: Part 1: There were no regional brain metabolic differences between those with AD destined to become psychotic and those who did not become psychotic. There was a significant reduction in mean orbitofrontal brain metabolism in those with active psychosis. Part 2: Over the course of study follow-up, psychosis was associated with accelerated decline in functional performance as measured by the Functional Assessment Questionnaire, the Mini-Mental State Examination, and Forward Digit Span. Conclusion: In a sample drawn from the ADNI dataset, our exploratory FDG-PET findings and longitudinal cognitive outcomes support the hypofrontality model of AD+P. Focal frontal vulnerability may mediate the accelerated decline seen in AD+P

Individual, interpersonal, incident and community level variables associated with adult homicide and availability in the Victorian Homicide Register.

Individual, interpersonal, incident and community level variables associated with adult homicide and availability in the Victorian Homicide Register.</p

Definitions of terms in this protocol.

BackgroundThere is a need for both descriptive and analytical evidence on the factors associated with older adult homicide. The current landscape is insufficient because most published research is confined to the United States, and contains insufficient data about the homicide context. This study protocol describes the proposed method for examining the characteristics and factors associated with older adult homicide in the Australian state of Victoria, using data generated for the criminal and coronial investigation into these deaths stored in the Victorian Homicide Register (VHR). Outcomes will support practitioners, policy makers and other key stakeholders to strengthen prevention strategies to reduce the risk of future homicides among older Victorians.MethodsThis study will comprise a single-jurisdiction population-based cross-sectional design to analyse consecutive cases of homicide among community-dwelling older adults in Victoria, Australia for the period 2001 to 2015. All homicides of adults aged 18 years and older, and where the Coroner’s investigation is completed at data extraction will be included. Variables will be selected in accordance with elements of the social-ecological model (i.e., individual, interpersonal, incident, and community). This will include: socio-demographic characteristics; presence of mental or physical illness; deceased-offender relationship; nature of any abuse between the deceased and offender; incident location and weapon used; the presence of alcohol or drugs; and criminal justice outcomes. Homicide rates per 100,000 population will be calculated for older adults (aged 65 years and older) and younger adults (aged 18–64 years), and compared as rate ratios using Poisson regression. Descriptive statistics and cross-tabulation will be generated for factors associated with homicide for older compared to younger adults. Homicide typologies based on deceased-offender relationship and motive will be explored within group and family homicides will be compared between older and younger adults.</div

Modified social-ecological model–older adult homicide.

Modified social-ecological model–older adult homicide.</p