Private costs almost equal health care costs when intervening in mild Alzheimer's: a cohort study alongside the DAISY trial

Udgivelsesdato: Nov 25, 200

Gender- and Age-Dependent γ-Secretase Activity in Mouse Brain and Its Implication in Sporadic Alzheimer Disease

Alzheimer disease (AD) is an age-related disorder. Aging and female gender are two important risk factors associated with sporadic AD. However, the mechanism by which aging and gender contribute to the pathogenesis of sporadic AD is unclear. It is well known that genetic mutations in γ-secretase result in rare forms of early onset AD due to the aberrant production of Aβ42 peptides, which are the major constituents of senile plaques. However, the effect of age and gender on γ-secretase has not been fully investigated. Here, using normal wild-type mice, we show mouse brain γ-secretase exhibits gender- and age-dependent activity. Both male and female mice exhibit increased Aβ42∶Aβ40 ratios in aged brain, which mimics the effect of familial mutations of Presenilin-1, Presenlin-2, and the amyloid precursor protein on Aβ production. Additionally, female mice exhibit much higher γ-secretase activity in aged brain compared to male mice. Furthermore, both male and female mice exhibit a steady decline in Notch1 γ-secretase activity with aging. Using a small molecule affinity probe we demonstrate that male mice have less active γ-secretase complexes than female mice, which may account for the gender-associated differences in activity in aged brain. These findings demonstrate that aging can affect γ-secretase activity and specificity, suggesting a role for γ-secretase in sporadic AD. Furthermore, the increased APP γ-secretase activity seen in aged females may contribute to the increased incidence of sporadic AD in women and the aggressive Aβ plaque pathology seen in female mouse models of AD. In addition, deceased Notch γ-secretase activity may also contribute to neurodegeneration. Therefore, this study implicates altered γ-secretase activity and specificity as a possible mechanism of sporadic AD during aging

Sexual Dimorphism in Healthy Aging and Mild Cognitive Impairment: A DTI Study

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Bioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions.Metabolic characteristics of human glioma cell models - including mitochondrial function, glycolytic pathway and energy substrate oxidation - in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry.U251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation).Our findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas

Choice of observational study design impacts on measurement of antipsychotic risks in the elderly: a systematic review

BACKGROUND: Antipsychotics are frequently and increasingly prescribed to treat the behavioural symptoms associated with dementia despite their modest efficacy. Evidence regarding the potential adverse events of antipsychotics is limited and little is known about the longer-term safety of these medicines in the elderly. The aim of this review was to determine the impact of the choice of observational study design and methods used to control for confounding on the measurement of antipsychotic risks in elderly patients. METHODS: We searched PUBMED and the Cochrane controlled trials register for double-blind randomised controlled trials (RCTs), meta-analyses and published observational studies of antipsychotics. RESULTS: Forty four studies were identified for the endpoints; death, cerebrovascular events, hip fracture and pneumonia. RCTs found a 20% to 30% increased risk of death, or an absolute increase of 1extra death per 100 patients with atypical antipsychotics compared to non-use. Cohort and instrumental variable analyses estimated between 2 to 7 extra deaths per 100 patients with conventional compared to atypical antipsychotics. RCTs found a 2 to 3 times increased risk of all cerebrovascular events with atypical antipsychotics compared to placebo and no association with serious stroke that required hospitalisation. Observational studies using cohort and self-controlled case-series designs reported similar results; no association where the endpoint was stroke causing hospitalisation and a doubling of risk when minor stroke was included. No RCTs were available for the outcome of hip fracture or pneumonia. Observational studies reported a 20% to 40% increased risk of hip fracture with both antipsychotic classes compared to non-use. The risk of pneumonia was a 2 to 3 times greater with both classes compared to non-use while a self-controlled case-series study estimated a 60% increased risk. Conventional antipsychotics were associated with a 50% greater hip fracture risk than atypical antipsychotics, while the risk of pneumonia was similar between the classes. CONCLUSIONS: Choice of observational study design is critical in studying the adverse effects of antispychotics. Cohort and instrumental variable analyses gave more consistent results to clinical studies for mortality outcomes as have self-controlled case-series for the risk of cerebrovascular events and stroke. Observational evidence has highlighted the potential for antipsychotics to be associated with serious adverse events that were not reported in RCTs including hip fracture and pneumonia. Good quality observational studies are required, that employ appropriate study designs that are robust towards unmeasured confounding, to confirm the potential excess risk of hip fracture and pneumonia with antipsychotics.Nicole Pratt, Elizabeth E. Roughead, Amy Salter and Philip Rya

Characterization of metabolites in infiltrating gliomas using ex vivo 1H high-resolution magic angle spinning spectroscopy

Gliomas are routinely graded according to histopathological criteria established by the World Health Organization. Although this classification can be used to understand some of the variance in the clinical outcome of patients, there is still substantial