Current Alzheimer Research - Volume 15, Issue 5, 2018

Background: Among the myriad of factors modulating quality of life assessments estimated in patients presenting a variety of cognitive impairments, the distinctive and critical influence of diet and exercise cannot be overestimated. Objective: The objective of this study was to review the evidence to confirm the association between these health-endowering agents and cognitive performance in People With Dementia as well as providing a correlation between Mini Mental State Examination scores and available anthropometric data. Methods: The authors tested the hypothesized correlation on a sample of subjects with instrumentally confirmed cognitive impairment using parameters as Body Mass Index and calf circumference. Results: The results confirm the hypothesis and suggesting the possible use of anthropometric data in the process of objective evaluation of the patient with cognitive impairment that could also be used for forensic medicine.

Objective: Cognition is a complex trait representing a set of all mental abilities and processes related to knowledge. Although diverse brain regions are involved, most cognitive processes appear to engage cortical regions. The activity of dopaminergic neurons in prefrontal cortex represents a biological substrate underlying cognitive functions. Alzheimer's Disease (AD) is the most frequent dementia associated with cognitive impairments. Cognitive impairment in AD starts slowly with discrete deterioration in memory, language, thinking and reasoning, but it progresses into more severe and debilitating cognitive dysfunction. Cognitive function is affected by the complex interactions between various genetic, epigenetic, developmental and environmental factors. One of the most studied genes, associated with cognitive disturbances, is the gene coding for Catechol-O-methyltransferase (COMT), the enzyme with major role in dopamine metabolism and modulation of different brain functions. Therefore, COMT is studied as a target for many neuropsychiatric disorders, including dementias and AD. The COMT Val158/108Met functional polymorphism affects significantly the enzyme activity and consequently cognitive performance associated with altered dopamine function. The association of COMT Val158/108Met polymorphism with some cognitive domains and psychosis in AD was reported in some but not in all studies. Besides COMT Val158/108Met polymorphism, other risk genotypes or haplotypes should be evaluated to determine the association of COMT with cognitive decline in AD. Conclusion: Better understanding of the role of COMT in cognitive processes in AD, as well as integration of neurobiological, genetic, genomic and epigenetic data, might help in developing new potential therapies of cognitive impairments and psychotic symptoms, characteristic features of AD.

Background: Although mood and sleep disturbances are nearly universal among patients with Alzheimer's disease (AD), brain structures involved in non-cognitive processing remain under characterized in terms of AD pathology. Objectives: This study was designed to evaluate hallmarks of AD pathology in the brainstem of the APPswe/PS1dE9 mouse model of familial AD. Methods: Fresh-frozen sections from female, 12 month old, transgenic and control B6C3 mice (n=6/genotype) were examined for amyloid burden and neurofibrillary alterations, by using 6E10 immunohistochemistry and the Gallyas silver stain, respectively. Serotonin transporter (SERT) densities in the dorsal and the median raphe were quantified by [3H]DASB autoradiography. SERT mRNA expression was measured by RT-PCR and visualized by in situ hybridization. Neuroinflammation was evaluated by immunohistochemical staining for microglia and astrocytes, and by measuring mRNA levels of the proinflammatory cytokines TNF-α, IL-1β and IL-6. Results: No amyloid- and tau-associated lesions were observed in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. SERT binding levels were reduced in transgenic animals compared to age-matched controls, and SERT mRNA levels were decreased by at least 50% from control values. Intense microglial, but not astrocytic immunoreactivity was observed in APPswe/PS1dE9 vs. wild-type mice. Levels of TNF-α mRNA were two-fold higher than control and correlated positively with SERT mRNA expression levels in transgenic animals. Conclusions: There was no amyloid accumulation and tau-associated pathology in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. However, there was a local neuroinflammatory response with loss of serotonergic markers, which may partially account for some of the behavioral symptoms of AD.

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease.

Objective: The inferior parietal lobule (IPL) has been implicate in many higher cognitive processes, as visuo-motor transformations, tool use or tool making. In subjects with mild cognitive impairment (MCI) at major risk to develop Alzheimer' Disease (AD) an impairment of subtle visuomotor or praxic abilities is a well-known clinical feature. Enhance of the ratio of EEG alpha3/alpha2 frequency power was detected in subjects with MCI who will transform in Alzheimer's disease (AD). Methods: We explored of the association of alpha3/alpha2 power ratio with cortical size of IPL in patients with MCI. 74 subjects with MCI undergone EEG recording and MRI scans. Alpha3/alpha2 power ratio in addition to cortical size had been computed for each patient. Three MCI groups had been acquired in keeping with growing tertile values of alpha3/alpha2 ratio. Huge difference of cortical thickness among the groups was calculated. Higher alpha3/alpha2 power ratio group had broader cortical loss compared to other teams on the IPL, particularly in the Supramarginal Gyrus, and Precuneus on both hemispheres. Results: Our results unveil the possible part that the IPL could play in determining the classic alterations of early Alzheimer's disease (AD). Conclusion: Finally, the rise of alpha3/alpha2 power ratio detected a focused anatomo-functional association that could be a reliable marker of incipient AD.

Background: Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD). Objective: To assess the effectiveness of a CT program designed to improve cognition in AD patients. Method: This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal-learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates. Results: Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time. Conclusion: Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline.

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

Background: The longitudinal change of neuropsychological tests (NPTs) in treated Alzheimer's disease (AD) is essential to understand the interplay of a therapeutic response from medication and a disease decline due to degenerative processes. The aim of our study is to investigate the annual cognitive progression as measured by commonly used NPTs in treated AD patients and to assess the potential predictors of disease progression. Methods: Participants (N=455) diagnosed with AD and treated with cholinesterase inhibitors (ChEIs) or memantine at memory clinics in three hospitals in southern Taiwan from January 2009 to December 2014 were enrolled in this prospectively registered study. The mean follow-up duration was 3.2 ± 0.9 years. The patients' severity of AD ranged from very mild (clinical dementia rating (CDR) scales = 0.5) to moderate (CDR = 2.0). At baseline and for each year, participants were assessed by various NPTs commonly used in clinical practice, including the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), CDR and CDR-sum of boxes (CDR-SB). All enrolled participants were assessed for at least two years during follow-up. We used mixed-effect models to examine annual progression in the whole group and to compare the cognitive progression between the subgroups with very mild AD and mild to moderate AD. Potential predictors of disease progression, including age, gender, the type of ChEI, and Apolipoprotein E (APOE) genotype, were also analyzed. Results: Among the study population, the rate of change in MMSE scores were -1.15 points per year, CASI scores were -4.27 points per year, and CDR-SB scores were 0.81 points per year. The slope of annual changes of NPTs differed significantly between the CDR 0.5 group and the CDR 1 to 2 group. The most significant predictors of the faster progression were increasing age and higher CDR stage at entry; however, different types of ChEI therapy (donepezil vs. rivastigmine users), and APOE genotype were not associated with the rate of disease progression. Conclusions: This longitudinal data shows the mean annual change of the MMSE, CASI, CDR, and CDR-SB in treated AD patients. The data may provide clinicians with information regarding to the cognitive decline rate in every year while their AD patients receive approved pharmacological therapy in real-world practice. Increasing age and severity of dementia when receiving therapy are the main factors that associated with faster deterioration.

Background: Oxidative stress is one of the causative factors in the pathogenesis of neurodegenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant. Objective: We assess the effects of drinking H2-water (water infused with H2) on oxidative stress model mice and subjects with MCI. Methods: Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink H2-water. For a randomized double-blind placebo-controlled clinical study, 73 subjects with MCI drank ~300 mL of H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year. Results: In mice, drinking H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water group was longer than that of the control group. In MCI subjects, although there was no significant difference between the H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score). Conclusion: H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.

Background: Accumulating evidence suggests that dietary factors are associated with Alzheimer's disease, cognition, and brain health in older adults. It is however unclear whether inflammation explains this association. Objective: To examine whether an inflammation-related nutrient pattern (INP) was associated with neuroimaging and cognitive measures of brain health. Method: The current cross-sectional study included 330 non-demented elderly (mean age 79 years at MRI scan) participants in a multi-ethnic, community-based cohort study who had information on nutritional intake (estimated from food frequency questionnaire), circulating C-reactive protein and interleukin- 6 (measured by ELISA), MRI scans, and cognition. Diet and blood samples were collected approximately 5.3 years prior to the MRI and cognitive test visit. We used a reduced rank regression model to derive an INP based on 24 nutrients' relationship with CRP and interleukin-6. We examined the association of the INP with brain and cognitive measures using regression models adjusted for age, sex, race/ethnicity, education, caloric intake, APOE genotype, body mass index, and vascular burden, as well as intracranial volume for the brain MRI measures. Results: The INP was characterized by low intake (effect loading <-0.15) of calcium, vitamins (D, E, A, B1, B2, B3, B5, B6), folate, Ω-3 poly-unsaturated fatty acids, and high intake (>0.15) of cholesterol. As designed, this INP was positively correlated with CRP (Pearson's r=0.25 p=0.005) and interleukin-6 (r=0.30, p<0.0001). Each unit increase in INP was associated with 36.8 cm3 (p=0.023) smaller total brain volume and 0.21 (p=0.038) lower visuospatial z-score. Mediation analysis showed that TGMV (b=0.002, p=0.003) was associated with visuospatial cognitive function, and there was a significant mediation effect by TGMV (indirect effect: -0.049, 95% CI: -0.1121 ~ -0.0131) for the association between INP and visuospatial cognitive score. Conclusions: Among older adults, a diet with high inflammatory potential is associated with less favorable brain and cognitive health.