Current Alzheimer Research - Volume 14, Issue 12, 2017

Background: Alzheimer's dementia is characterized by significant cortical and subcortical atrophy, causing diverse neuropsychological deficits. According to the somatic marker hypothesis, the areas responsible for generating the somatic markers that anticipate the consequences of a decision and thereby optimize the process would be affected in these patients. Objective: The aim of this experiment is to study the decision-making processes in Alzheimer type dementia patients to determine potential deficits in these processes as a result of the disease, aside from the cognitive impairment that is typical of aging. In addition, we wish to determine the defining characteristics of decision-making in these patients, on the basis of the prospect valence-learning parameters. Method: We evaluated 30 patients with Alzheimer's disease and a control group of 30 healthy subjects. A short version of the Iowa Gambling Task was used. Results: The results showed that patients made less advantageous choices than did controls. Group differences were quantitative and qualitative, as significant differences in cognitive mechanisms identified in the prospect valence-learning decisions were observed. These results are consistent with evidence from neuroimaging studies as well as with work carried out with amnesic patients. Conclusion: That problems in our patients' decision-making could be due to the characteristic memory deficits of this disease, which prevents them from establishing new stimulus-reward relationships and eliminating previously learned responses as a result of the parietal and temporal atrophy they present.

Background: Frailty is a state of increased vulnerability to poor resolution of homeostasis as a consequence of age-related decreased physiological reserves. Although physical frailty and cognitive impairment have been shown to be associated, evidence on the prevalence of frailty in Alzheimer's disease is scarce. Objective: To conduct a systematic review on the prevalence of frailty and to combine the data to synthesize the pooled prevalence of physical frailty among patients with Alzheimer's disease. Method: Five electronic databases (Embase, MEDLINE, CINAHL Plus, PsycINFO, and the Cochrane Library) were searched for studies providing cross-sectional data on physical frailty among patients with Alzheimer's disease published from 2000 to January 2016. Results: Of 2,564 studies identified through the systematic review, five studies incorporating 534 patients with Alzheimer's disease were included for the meta-analysis. The prevalence of frailty varied with a wide range from 11.1% to 50.0% and the pooled prevalence was 31.9% (five studies, 95% confidence interval (CI)=15.7%-48.5%). The high degree of heterogeneity was observed in all analyses. A borderline publication bias was detected. Conclusion: The current study showed that frailty is highly prevalent in older patients with Alzheimer's disease in the community with the pooled prevalence of 31.9%. The true prevalence may be much higher given that end-stage patients may not be included. This information is important for clinicians and researchers.

Background: Research studies show a positive impact of physical activities such as dancing on the improvement of cognitive reserves of people with dementia. Objective: The purpose of this study is to explore dancing efficacy on people with dementia and list the key benefits and limitations of dancing therapy for these people. Methods: The methods used in this study include a method of literature review of available Englishwritten sources with respect to the dancing therapy and dementia in the acknowledged databases Pub- Med, Web of Science, Springer, and Scopus, and a method of comparison and evaluation of their findings. Results: The findings of this mini review confirm positive efficacy of dancing therapy on cognitive, physical, emotional and social performance of people with dementia. Conclusion: More randomized controlled clinical trials should be conducted in this field, as well as other non-pharmacological therapies should be employed in order to holistically contribute to the prevention and treatment of dementia.

Background: Wearable cameras are a new type of intervention aimed at stimulating memory in Alzheimer's disease (AD). Such passive external memory aids have started to be considered as alternatives to both more active external aids (such as writing in diaries, journals, and timetables) and to internal cognitive strategies (such as spaced retrieval, errorless learning). Objective: In order to understand the benefits of these innovative devices for memory compensation, the present experiment examined the effectiveness of two memory training strategies: SenseCam, a wearable camera, a passive external memory aid and a memory training programme (MEMO+) created from tasks known to stimulate memory, in comparison with a control condition, a personal written diary. Method: Fifty-one patients with mild AD were randomly assigned to one of these three groups. Training lasted for six consecutive weeks, two sessions a week, one hour each, for all groups. Patients underwent a neuropsychological assessment at baseline, after treatment and at follow up (six months later). Results: Groups showed non-significant differences at baseline. After treatment and at follow up, the SenseCam group had a superior autobiographical memory (AM) performance, compared to the Memo+ and Diary groups. The SenseCam and the Memo+ groups both showed improved episodic and semantic memory, and somewhat improved executive function. Conclusion: Our results suggest that passive memory training with SenseCam is a promising alternative to traditional memory training programs to help AD patients with autobiographical memory performance.

Background: Mitochondrial dysfunction is called the missing link between brain aging and Alzheimer's disease (AD), the most common type of age-related dementia worldwide. Among the most advanced and promising of approaches to prevention or slowing of AD are therapeutic strategies targeting mitochondria. Objective: Mitochondria-targeted antioxidant SkQ1 can suppress the development of AD signs, but its therapeutic potential in AD at clinical stages is currently unknown. Method: Using OXYS rats that simulate key characteristics of sporadic AD, we evaluated effects of SkQ1 treatment from the age of 19 to 24 months on the locomotor and exploratory activities, signs of neurodegeneration detectable by magnetic resonance imaging (MRI), amyloid-β (Aβ) protein levels in the hippocampus and serum, and structure of the mitochondrial apparatus in hippocampal neurons. Results: Treatment with SkQ1 increased behavioral activity in OXYS and Wistar (control) rats. According to MRI, SkQ1 decreased the percentage of animals with demyelination only among Wistar rats. At the same time, the antioxidant reduced hippocampal Ц#144;β1-40 and Ц#144;β1-42 protein levels in both rat strains and did not affect serum Ц#144;β levels. The number of mitochondria was significantly lower in OXYS rats; SkQ1 had no effect on this parameter but significantly reduced the destructive changes in mitochondria of both rat strains. As a result, in OXYS rats, the proportion of severely damaged mitochondria decreased, whereas in Wistar rats, the proportion of intact mitochondria increased. Conclusion: According to our past and present results, the repair of the mitochondrial apparatus by SkQ1 is a promising strategy against AD.

Background: Alzheimer's disease (AD), a common protein misfolding progressive neurodegenerative disorder, is one of the most common forms of dementia. Amyloid precursor protein (APP) derived amyloid-β (Aβ) protein accumulate into interneuronal spaces and plays a crucial role in the disease progression and its pathology. The aggregated Aβ exerts its neurotoxic effects by inducing apoptosis and oxidative damage in neuronal cells. Objectives: We have investigated the effects of a synthesized Pro-Drug peptide (PDp) on Aβ1-40 induced cytotoxicity in human neuroblastoma SH-SY5Y cells, represents one of the most effective strategies in combating human AD. Methods: Cells were treated with Aβ1-40 to induce cytotoxicity in the experimental model of AD to screen the inhibitory effect of PDp. Assays for cell viability, reactive oxygen species (ROS) generation, levels of intracellular free Ca2+ and expression of key apoptotic proteins were assessed by Western Blotting. Results: Our results showed that Aβ1-40 induces for 24h caused reduce cell viability, imbalance in Ca2+ homeostasis and increase in neuronal apoptosis in vitro. Treatment with PDp could effectively ameliorated Aβ1-40 induced neurotoxicity and attenuates ROS generation that mediates apoptotic signaling through Bcl-2, Bax, Caspase-3 activity and cytochrome c in the cells. Conclusion: These findings suggested that PDp has potential role as a neuroprotective and therapeutic agent for combating human AD.

Background: miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and Alzheimer's disease (AD). Methods: The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice. Conclusion: These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation.

Background: Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in serum is higher in a percentage of Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype. Objective: In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off. Method: We assessed levels of copper, ceruloplasmin, non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and β-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in 128;Normal128;™ and 128;High128;™ non-Cp Cu groups. Results: The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parietooccipital and temporal white matter hyperintensities), infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042). Conclusion: This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; non-Cp Cu appears a good marker of this copper AD.

Background: It is well established that mitochondrial damage plays a role in the pathophysiology of Alzheimer's disease (AD). However, studies carried out in humans barely contemplate regional differences with disease progression. Objective: To study the expression of selected nuclear genes encoding subunits of the mitochondrial complexes and the activity of mitochondrial complexes in AD, in two regions: the entorhinal cortex (EC) and frontal cortex area 8 (FC). Methods: Frozen samples from 148 cases processed for gene expression by qRT-PCR and determination of individual activities of mitochondrial complexes I, II, IV and V using commercial kits and home-made assays. Results: Decreased expression of NDUFA2, NDUFB3, UQCR11, COX7C, ATPD, ATP5L and ATP50, covering subunits of complex I, II, IV and V, occurs in total homogenates of the EC in AD stages V-VI when compared with stages I-II. However reduced activity of complexes I, II and V of isolated mitochondria occurs as early as stages I-II when compared with middle-aged individuals in the EC. In contrast, no alterations in the expression of the same genes and no alterations in the activity of mitochondrial complexes are found in the FC in the same series. Conclusion: Different mechanisms of impaired energy metabolism may occur in AD, one of them, represented by the EC, is the result of primary and early alteration of mitochondria; the other one is probably the result, at least in part, of decreased functional input and is represented by hypometabolism in the FC in AD patients aged 86 or younger.

Background: Alzheimer's disease (AD) as a disconnection syndrome which disrupts both brain information sharing and memory binding functions. The extent to which these two phenotypic expressions share pathophysiological mechanisms remains unknown. Objective: To unveil the electrophysiological correlates of integrative memory impairments in AD towards new memory biomarkers for its prodromal stages. Methods: Patients with 100% risk of familial AD (FAD) and healthy controls underwent assessment with the Visual Short-Term Memory binding test (VSTMBT) while we recorded their EEG. We applied a novel brain connectivity method (Weighted Symbolic Mutual Information) to EEG data. Results: Patients showed significant deficits during the VSTMBT. A reduction of brain connectivity was observed during resting as well as during correct VSTM binding, particularly over frontal and posterior regions. An increase of connectivity was found during VSTM binding performance over central regions. While decreased connectivity was found in cases in more advanced stages of FAD, increased brain connectivity appeared in cases in earlier stages. Such altered patterns of task-related connectivity were found in 89% of the assessed patients. Conclusions: VSTM binding in the prodromal stages of FAD are associated to altered patterns of brain connectivity thus confirming the link between integrative memory deficits and impaired brain information sharing in prodromal FAD. While significant loss of brain connectivity seems to be a feature of the advanced stages of FAD increased brain connectivity characterizes its earlier stages. These findings are discussed in the light of recent proposals about the earliest pathophysiological mechanisms of AD and their clinical expression.