Current Alzheimer Research - Volume 15, Issue 9, 2018

Background: Cerebrospinal fluid (CSF) measures of tau and amyloid proteins have now been largely accepted to be a diagnostic tool to aid the clinical diagnosis of Alzheimer's disease (AD), but CSF is not routinely obtained in most clinical settings. There is a need, therefore, to uncover additional readily accessible peripheral biomarkers that will enable comprehensive detection of AD-specific proteins in blood and blood derivates. Objectives: Blood platelets contain proteins found in neuronal cell lines, including tau protein. Since tau protein is a characteristic of AD-neuropathology, platelet tau protein may be closely related to the central nervous process occurring in neurodegeneration. Method: Platelets from 25 AD and 26 control subjects were analysed for the microtubule-binding and C-terminal region, as well as two tau phosphorylation sites (Ser202/Thr205 and Thr181). Results: Tau protein measures did not discriminate between AD and control individuals. However, subjects with MMSE 24-27 had elevated C-terminal end tau protein (p=0.049) compared to those with MMSE >27, whereas older AD subjects (>80 years) showed higher t-tau protein in comparison to younger AD (<80 years; p=0.009) and control (<80 years; p=0.011) participants. Conclusions: These initial findings not only confirm that platelet tau protein can be measured, but also indicate that platelet tau measures merit further study as they may be useful in indicating early stages of cognitive impairment. Further studies on larger number of participants are needed to confirm our findings.

Background: Mild (MCI) and Subjective Cognitive Impairment (SCI) are conditions at risk of developing Alzheimer's disease (AD). Differential between normal aging at early stages can be really challenging; available biomarkers need to be combined and can be quite invasive and expensive. Objective: The aim of this pilot study is to examine possible EEG alterations in MCI and SCI compared to controls, analyzing if a cognitive task could highlight early AD hallmarks. Method: We recruited 11 MCI, 8 SCI and 7 healthy subjects as controls (CS), all matched for age and education. Neuropsychological assessment and EEG recording, at resting state and during a mental memory task, were performed. Classical spectral measures and nonlinear parameters were used to characterize EEGs. Results: During cognitive task, α-band power reduction was found predominantly in frontal regions in SCI and CS, diffused to all regions in MCI; moreover, decreased EEG complexity was found in SCI compared to controls. The α -band power attenuation restricted to frontal regions in SCI during a free recall task (involving frontal areas), suggests that MCI patients compensate for encoding deficit by activating different brain networks to perform the same task. Furthermore, EEG complexity reduction - that has been found already in SCI - could be a possible early hallmark of AD. Conclusion: This study draws attention on the importance of nonlinear approach in EEG analysis and the potential role of cognitive task in highlighting EEG alterations at very early stages of cognitive impairment; EEG could therefore have a practical impact on dementia diagnosis.

Background: There exists a need for more sensitive measures capable of detecting subtle cognitive decline due to Alzheimer's disease. Objective: To advance the literature in Alzheimer's disease by demonstrating that performance on a cued-Stroop task is impacted by preclinical Alzheimer's disease neuropathology. Method: Twenty-nine cognitively asymptomatic older adults completed a computerized, cued-Stroop task in which accuracy rates and intraindividual variability in reaction times were the outcomes of interest. Cerebrospinal fluid biomarkers of Aβ42 and tau were measured and participants were then grouped according to a published p-tau/Aβ42 cutoff reflecting risk for Alzheimer's disease (preclinical Alzheimer's disease = 14; control = 15). Results: ANOVAs indicated that accuracy rates did not differ between the groups but 4-second delay incongruent color-naming Stroop coefficient of variation reaction times were higher in the preclinical Alzheimer's disease group compared to the control group, reflecting increased within-person variability. Moreover, partial correlations showed no relationships between cerebrospinal fluid biomarkers and accuracy rates. However, increases in coefficient of variation reaction times correlated with decreased Aβ42 and increases in p-tau and the p-tau/Aβ42 ratio. Conclusion: Results supported the ability of the computerized, cued-Stroop task to detect subtle Alzheimer's disease neuropathology using a small cohort of cognitively asymptomatic older adults. The ongoing measurement of cued-Stroop coefficient of variation reaction times has both scientific and clinical utility in preclinical Alzheimer's disease.

Background: Speech and Language Impairments, generally attributed to lexico-semantic deficits, have been documented in Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). This study investigates the temporal organisation of speech (reflective of speech production planning) in reading aloud in relation to cognitive impairment, particularly working memory and attention deficits in MCI and AD. The discriminative ability of temporal features extracted from a newly designed read speech task is also evaluated for the detection of MCI and AD. Method: Sixteen patients with MCI, eighteen patients with mild-to-moderate AD and thirty-six healthy controls (HC) underwent a battery of neuropsychological tests and read a set of sentences varying in cognitive load, probed by manipulating sentence length and syntactic complexity. Results: Our results show that Mild-to-Moderate AD is associated with a general slowness of speech, attributed to a higher number of speech chunks, silent pauses and dysfluences, and slower speech and articulation rates. Speech chunking in the context of high cognitive-linguistic demand appears to be an informative marker of MCI, specifically related to early deficits in working memory and attention. In addition, Linear Discriminant Analysis shows the ROC AUCs (Areas Under the Receiver Operating Characteristic Curves) of identifying MCI vs. HC, MCI vs. AD and AD vs. HC using these speech characteristics are 0.75, 0.90 and 0.94 respectively. Conclusion: The implementation of connected speech-based technologies in clinical and community settings may provide additional information for the early detection of MCI and AD.

Background: Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory. Objectives: We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI). Methods: Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions. Results: SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models. Conclusion. Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.

Background: Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Aβ leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reducing Aβ levels and inhibiting Aβ-induced neurotoxicity are feasible therapeutic strategies for AD treatment. Wolfberry has been traditionally used as a natural antioxidant and anti-aging product. However, whether wolfberry species has therapeutic potential on AD remains unknown. Method: The effects of fruitless wolfberry-sprout extract (FWE) on Aβ fibrillation and fibril disaggregation was measured by thioflavin T fluorescence and transmission electron microscope imaging; Aβ oligomer level was determined by dot-blot; Cell viability and apoptosis was assessed by MTT and TUNEL assay. The levels of Aβ40/42, oxidative stress biomarkers and inflammatory cytokines were detected by corresponding kits. 8-month-old male APP/PS1 mice and their age-matched WT littermates were treated with FWE or vehicle by oral administration (gavage) once a day for 4 weeks. Then the cognitive performance was determined using object recognition test and Y-maze test. The Aβ burden and gliosis was evaluated by immunostaining and immunoblotting, respectively. Results: FWE significantly inhibited Aβ fibrillation and disaggregated the formed Aβ fibrils, lowered Aβ oligomer level and Aβ-induced neuro-cytotoxicity, and attenuated oxidative stress in vitro. Oral administration of FWE remarkably improved cognitive function, reduced Aβ burden, decreased gliosis and inflammatory cytokines release, and ameliorated oxidative stress in the brains of APP/PS1 mice. Conclusion: These findings indicate that FWE is a promising natural agent for AD treatment.

Background: Epidemiological studies showed that dietary fat intake is associated with Alzheimer's disease (AD) and dementia risk, however, the association remain inconsistent. This metaanalysis aimed to systematically examine the association of dietary fat intake with AD and dementia risk. Methods: We have systematically searched PubMed, Embase and the Cochrane Library up to May 1st 2017. Prospective cohort studies were included if they reported on the association of dietary fat intake with AD and dementia risk. Multivariate-adjusted relative risks (RRs) for the highest versus lowest category were pooled by using a random-effects model. Results: A total of 8630 participants and 633 cases from four independent prospective cohort studies were included in the present meta-analysis. A higher dietary saturated fat intake was significantly associated with an increased risk of 39% and 105% for AD (RR: 1.39; 95% CI: 1.00, 1.94) and dementia (RR: 2.05; 95% CI: 1.06, 3.98), respectively. Dose-response analysis indicated a 4 g/day increment of saturated fat intake was related to 15% higher risk of AD (RR: 1.15; 95% CI: 1.01, 1.31). However, there was no significant association found between dietary intake of total, monounsaturated, polyunsaturated fat and AD or dementia risk. Conclusions: This meta-analysis provides significant evidence of positive association between higher saturated fat intake and AD and dementia risk.

Background: Currently, there is a significant increase in the number of older generation groups, which may result in serious economic and social issues. Therefore, there is a need to prolong the active life of these older individuals, especially by focusing on modifying lifestyle factors such as healthy nutrition. In fact, recent research has shown that, for example, nuts are an important part of people's healthy diet because they have appeared to be neuroprotective compounds which might maintain or in some cases even improve people's cognitive functions. Objective: The purpose of this review study is to explore the role of the nut nutrition in the maintenance and delay of cognitive decline among older individuals. Results: The findings indicate that the nut consumption may contribute to the delay of cognitive decline in aging. However, this nut diet is just one component of the multi-nutrient dietary intervention for health aging. Conclusion: More longitudinal controlled randomized studies have to be performed in this field to prove the efficacy of the nut nutrition for the delay of cognitive decline.

Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate's potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment’ Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.