Current Alzheimer Research - Volume 12, Issue 2, 2015

The emergence of Alzheimer's disease as a systemic pathology shifted the research paradigm toward a better understanding of the molecular basis of the disease considering the pathophysiological changes in both brain and peripheral tissues. In the present study, we evaluated the impact of disease progression on physiological relevant features of skeletal muscle obtained from 3, 6 and 12 month-old 3xTg-AD mice, a model of Alzheimer's disease, and respective agematched nonTg mice. Our results showed that skeletal muscle functionality is already affected in 3-month-old 3xTg-AD mice as evidenced by deficient acetylcholinesterase and catalase activities as well as by alterations in fatty acid composition of mitochondrial membranes. Additionally, an age-dependent accumulation of amyloid-β1-40 peptide occurred in skeletal muscle of 3xTg-AD mice, an effect that preceded bioenergetics mitochondrial dysfunction, which was only detected at 12 months of age, characterized by decreased respiratory control ratio and ADP/O index and by an impairment of complex I activity. HPLC-MS/MS analyses revealed significant changes in phospholipid composition of skeletal muscle tissues from 3xTg-AD mice with 12 months of age when compared with age-matched nonTg mice. Increased levels of lyso-phosphatidylcholine associated with a decrease of phosphatidylcholine molecular species containing arachidonic acid were detected in 3xTg-AD mice, indicating an enhancement of phospholipase A2 activity and skeletal muscle inflammation. Additionally, a decrease of phosphatidylethanolamine plasmalogens content and an increase in phosphatidylinositol levels was observed in 3xTg-AD mice when compared with age-matched nonTg mice. Altogether, these observations suggest that the skeletal muscle of 3xTg-AD mice are more prone to oxidative and inflammatory events.

Alzheimer’s dis ease (AD) is a leading cause of mortality in the developed world with 70% risk attributable to genetics. The remaining 30% of AD risk is hypothesized to include environmental factors and human lifestyle patterns. Environmental factors possibly include inorganic and organic hazards, exposure to toxic metals (aluminium, copper), pesticides (organochlorine and organophosphate insecticides), industrial chemicals (flame retardants) and air pollutants (particulate matter). Long term exposures to these environmental contaminants together with bioaccumulation over an individual’s life-time are speculated to induce neuroinflammation and neuropathology paving the way for developing AD. Epidemiologic associations between environmental contaminant exposures and AD are still limited. However, many in vitro and animal studies have identified toxic effects of environmental contaminants at the cellular level, revealing alterations of pathways and metabolisms associated with AD that warrant further investigations. This review provides an overview of in vitro, animal and epidemiological studies on the etiology of AD, highlighting available data supportive of the long hypothesized link between toxic environmental exposures and development of AD pathology.

Resveratrol (trans-3, 5, 4’-trihydroxystilbene) is a polyphenolic phytoalexin known to exhibit antioxidant and neuroprotective effects in several experimental models. Amyloid β peptide (Aβ), a core component of extracellular senile plaques accumulates in the brains of patients with Alzheimer's disease and is related to the development of cognitive impairment and neuronal loss. The present study evaluates the neuroprotective action of resveratrol on Aβ-induced oxidative stress and memory loss. Cultured rat hippocampal H19-7 neuronal cell line was pretreated with 75 μM of resveratrol for 2 hrs followed by 25 μM of Aβ (1-40) for 24 hrs. H19-7 cells treated with Aβ exhibited increased lipid peroxide levels. Enzymatic antioxidants including superoxide dismutase, catalase, glutathione reductase, and non-enzymatic antioxidants such as tocopherol, ascorbic acid and glutathione were decreased in the Aβ treated group when compared to the control group. Aβ treatment also increased the expression of total tau as well as phosphorylated forms of tau (CP13, S202/205; PHF1, S396/404) and decreased the expression of insulin degrading enzyme (IDE), phosphoglycogen synthase kinase 3β involved in Aβ degradation and tau hyper phosphorylation. Expression of PSD-95 and Arc proteins, essential for synaptic maturity and plasticity, was decreased by Aβ treatment. Resveratrol treatment attenuated the accumulation of lipid peroxide levels, up-regulated the antioxidant activities and improved the expression of memory-associated proteins in Aβ treated H19-7 cells. These findings highlight the neuroprotective effect of resveratrol in preventing Aβ-induced oxidative damage and memory loss in vitro.

Introduction: This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. Methods: APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). Results: APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). Conclusion: APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.

Objectives: Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions. Methods: We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline. Results: Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions. Conclusion: Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

Background: Insufficiency in vitamin D, a neurosteroid hormone, is associated with cognitive decline in older adults. The impact on the subjective perception of cognitive decline has not yet been examined. The objective of this cross-sectional hospital-based study was to determine whether vitamin D insufficiency was associated with subjective cognitive complaint amongst geriatric patients. Methods: Ninety-nine consecutive Caucasian in- and outpatients recruited in the ’Cognition and LIPophilic vitamins’ (CLIP) study, who had no advanced cognitive disorders (ie, Mini-Mental State Examination score≥20) and who took no vitamin D supplements, were categorized into 2 groups based on vitamin D insufficiency (ie, serum 25-hydroxyvitamin D≥75nmol/L). Subjective cognitive complaint was examined using the Memory Complaint Questionnaire (MAC-Q; score 0-30, best). MAC-Q score<15 out of 30 defined severe cognitive complaint. Age, gender, body mass index, education level, comorbidity burden, functional autonomy, mood, and serum concentrations of parathyroid hormone, calcium, thyroid-stimulating hormone and vitamin B12, and estimated glomerular filtration rate were used as potential confounders. Results: Compared to participants with serum 25OHD>75nmol/L, those with vitamin D insufficiency (n=89) had a lower mean MAC-Q score (14.9±2.9 versus 17.1±1.6, P=0.02) and more often a MAC-Q score<15 (52.8% versus 10.0%, P=0.01). Vitamin D insufficiency was inversely associated with the MAC-Q score (adjusted β=-2.84, P=0.03), and positively associated with severe cognitive complaint (adjusted OR=10.07, P=0.03). Conclusion: Vitamin D insufficiency was associated with subjective cognitive complaint in the studied cohort of geriatric patients.

Background: Fl oor effects are present in most dementia assessment tools as dementia progresses and the in–depth assessment of patients considered more or less on vegetative state is questionable. Objective: To develop a questionnaire (the “Gatos Clinical Test-GCT”) for the assessment of end-stage demented patients. Methods: Five hundred patients with dementia of various causes and an MMSE score between 0 and 2 were enrolled in the study. The GCT consists of 14 closed type questions rated on a Likert scale. The total score is used to evaluate patient’s dementia. Various aspects of validity and reliability (including face, content and structural validity as well as test-retest reliability) were examined. Results: Three subscales “Autonomy/Alertness”, “Gnosias” and “Somatokinetic function” were defined, with a Cronbach equal to 0.851, 0.756 and 0.598 respectively. The GCT subscales and total score were statistically significant higher in patients with MMSE score 1 or 2 compared with those with MMSE score 0 (p<0.0005). Patients with GCT total score less than 12.5 had 75% probability to have zero MMSE score. Conclusion: The “GATOS” questionnaire is a valid and reliable test for patients with severe dementia, aiming at identification of those patients who could sustain some quality of life. It is a relatively short and easy to administer tool. As dementia prevalence is expected to rise further worldwide we believe that GCT could offer valuable services to health professionals, caregivers and patients.

Prevalence estimates of depression in AD vary greatly across studies, and a reliable result is crucial for further interventions. A systematic review and meta-analysis was conducted to identify the prevalence of depression in AD patients. We searched PubMed and Embase, followed by data extraction, quality assessment, prevalence estimates and subgroup analyses. A total of 63 studies were included in the review. The prevalences of depression were 12.7% (CI, 8.8-17.8) and 42% (CI, 38-45) according to the DSM criteria for major depression and the specific criteria for dementia respectively. Subgroup analyses stratified by case identification showed that the prevalences of population-based stud ies were 5% (CI: 2-15) and 35% (CI: 29-41) according to the DSM criteria and the specific criteria respectively, while those of single source were 17% (CI: 11-25) and 43% (CI: 37-49). Subgroup analyses stratified by MMSE score revealed that the prevalences of severe AD were 8% (CI: 5-15) and 48% (CI: 41-54) according to the DSM criteria and the specific criteria respectively, while those of mild AD were 14% (CI: 8-24) and 40% (CI: 32- 47). In conclusion, the prevalence of depression according to the DSM criteria was lower than that of the specific criteria. Prevalence estimates conducted in population-based studies were lower compared with those in single-source studies irrespective of the screening tools. Patients with severe AD tended to have higher prevalence of depression according to the specific criteria, while the trend was opposite according to the DSM criteria. Thus, different settings and diagnostic approaches should be taken into account before estimates of depression and further interventions.