Current Alzheimer Research - Volume 15, Issue 8, 2018

Background: Mild cognitive deficits are more likely to occur with increasing age, and become more pronounced for people diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Conventional methods to identify cognitive declines (i.e., neuropsychological testing and clinical judgment) can lead to false positive diagnoses of cognitive impairment. Tools such as electroencephalography (EEG) offer additional measures of cognitive processing, indexing the electrophysiological changes associated with aging, MCI and AD. Objective: We reviewed the literature on EEG to determine if auditory event-related potentials (ERPs) could distinguish between healthy aging, MCI, and AD. Method: We searched two electronic databases (Medline and PyscInfo) for articles published between January 2005 and April 2017. Articles were considered for review if they included: i) participants 60 years of age or older; ii) healthy older adults or those diagnosed with MCI or AD; iii) at least one auditory elicited ERP component. Results: Our search revealed 1532 articles (800 after removing duplicates); 719 were excluded through title/abstract review, and of the 81 remaining articles, 30 satisfied inclusion criteria. All studies compared cognitive function between at least two of the three selected populations. Our findings suggest that the P300 and N200 components may distinguish between healthy cognitive aging, MCI, and AD. Conclusion: ERPs may be sensitive to progressive cognitive changes due to MCI and AD. The P300 and N200 may help identify patients who are likely to progress from MCI to AD, and could be a valuable clinical tool.

Spirochetes are suspected to be linked to the genesis of neurological diseases, including neurosyphillis or neurodegeneration (ND). Impaired iron homeostasis has been implicated in loss of function in several enzymes requiring iron as a cofactor, formation of toxic oxidative species, inflammation and elevated production of beta-amyloid proteins. This review proposes to discuss the link that may exist between the involvement of Treponema spp. in the genesis or worsening of ND, and iron dyshomeostasis. Proteins secreted by Treponema can act directly on iron metabolism, with hemin binding ability (HbpA and HbpB) and iron reductase able to reduce the central ferric iron of hemin, iron-containing proteins (rubredoxin, neelaredoxin, desulfoferrodoxin metalloproteins, bacterioferritins etc). Treponema can also interact with cellular compounds, especially plasma proteins involved in iron metabolism, contributing to the virulence of the syphilis spirochetes (e.g. treponemal motility and survival). Fibronectin, transferrin and lactoferrin were also shown to be receptors for treponemal adherence to host cells and extracellular matrix. Association between Treponema and iron binding proteins results in iron accumulation and sequestration by Treponema from host macromolecules during systemic and mucosal infections.

Objective: Evidence suggests that individuals with Alzheimer’s disease (AD) are often diagnosed in the later stages of their disease with a poor prognosis. This study is aimed to identify patterns in signs and symptoms preceding the clinical diagnosis of AD to suggest a predictive model for earlier diagnosis of the disease in the primary care. Design: A retrospective medical record review; nested case control design. Participants: Participants included one hundred and nine patients from three general practice (GP) surgeries in Milton Keynes and Luton Clinical Commissioning Groups (CCG) (37 cases with AD and 72 controls without AD). Main outcome measure: A retrospective analysis using the logistic regression of the presence of signs and symptoms before the diagnosis of AD was attained. Identification of the timing and sequence of appearance of these presentations as first reported before the clinical diagnosis was measured. Result: Episodic memory with an odds ratio of 1.85 was the most frequent presentation, documented in 1.38% of the controls and 75.6% in cases. Auditory disturbance with an odds ratio of 3.03, which has not previously been noted except in the form of auditory hallucination, could have a diagnostic value. Conclusion: Auditory disturbance, which occurred mostly in the Caucasian females, could discriminate individuals with AD from those without the disease. The symptom, which presented up to 14.5 (mean time) years prior to clinical diagnosis, was identified in Caucasians and mixed race individuals only. Strengths: The study demonstrates that auditory disturbance could allow an earlier diagnosis of AD in Caucasian females. Episodic memory was confirmed as being frequently noted in AD patients prior to a clinical diagnosis as per previous publications. This study supports the development of a scoring system for the earlier diagnosis of AD. The data used was free from the confounding effects of misinformation, as this was written at the point of collection, thereby benefitting from the use of GP data that is diversified, reliable and valid. Limitations: Limited sample size that will not allow for generalization of less frequent observations due to their low prevalence in case notes. Randomisation was not achieved; however, the best available nonrandomisation which is consecutive sampling was used. Patterns identified were in LOAD, the baseline could vary with other geographical areas.

Background: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. Objective: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. Method: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Results: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Conclusion: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

Background: Recent work on Alzheimer's disease (AD) diagnosis focuses on neuroimaging modalities; however, these methods are expensive, invasive, and not available to all patients. Ocular imaging of biomarkers, such as drusen in the peripheral retina, could provide an alternative method to diagnose AD. Objective: This study compares macular and peripheral drusen load in control and AD eyes. Methods: Postmortem eye tissues were obtained from donors with a neuropathological diagnosis of AD. Retina from normal donors were processed and categorized into younger (<55 years) and older (>55 years) groups. After fixation and dissection, 3-6 mm punches of RPE/choroid were taken in macular and peripheral (temporal, superior, and inferior) retinal regions. Oil red O positive drusen were counted and grouped into two size categories: small (<63 μm) and intermediate (63-125 μm). Results: There was a significant increase in the total number of macular and peripheral hard drusen in older, compared to younger, normal eyes (p<0.05). Intermediate hard drusen were more commonly found in the temporal region of AD eyes compared to older normal eyes, even after controlling for age (p<0.05). Among the brain and eye tissues from AD donors, there was a significant relationship between cerebral amyloid angiopathy (CAA) severity and number of temporal intermediate hard drusen (r=0.78, p<0.05). Conclusion: Imaging temporal drusen in the eye may have benefit for diagnosing and monitoring progression of AD. Our results on CAA severity and temporal intermediate drusen in the AD eye are novel. Future studies are needed to further understand the interactions among CAA and drusen formation.

Background: Diagnosing Alzheimer's disease (AD) in its earliest stages is important for therapeutic and support planning. Similarly, being able to predict who will convert from mild cognitive impairment (MCI) to AD would have clinical implications. Objectives: The goals of this study were to identify features from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database associated with the conversion from MCI to AD, and to characterize the temporal evolution of that conversion. Methods: We screened the publically available ADNI longitudinal database for subjects with MCI who have developed AD (cases: n=305), and subjects with MCI who have remained stable (controls: n=250). Analyses included 1,827 features from laboratory assays (n=12), quantitative MRI scans (n=1,423), PET studies (n=136), medical histories (n=72), and neuropsychological tests (n=184). Statistical longitudinal models identified features with significant differences in longitudinal behavior between cases and matched controls. A multiple-comparison adjusted log-rank test identified the capacity of the significant predictive features to predict early conversion. Results: 411 features (22.5%) were found to be statistically different between cases and controls at the time of AD diagnosis; 385 features were statistically different at least 6 months prior to diagnosis, and 28 features distinguished early from late conversion, 20 of which were obtained from neuropsychological tests. In addition, 69 features (3.7%) had statistically significant changes prior to AD diagnosis. Conclusion: Our results characterized features associated with disease progression from MCI to AD, and, in addition, the log-rank test identified features which are associated with the risk of early conversion.

Background: Emerging evidence supports the hypothesis that metabolism dysfunction is involved in pathogenesis of Alzheimer's disease (AD). One aspect of metabolic dysfunction includes dysregulation of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) metabolic axis, which is extensively present in some of the leading causes of AD such as cerebrovascular diseases, type 2 diabetes and brain ischaemic events. While the molecular basis underlying this metabolic dysregulation remains a significant challenge, mitochondrial dysfunction due to aging appears to be an essential factor to activate AMPK/mTOR signaling pathway, leading to abnormal neuronal energy metabolism and AD pathology. Methods: Using immunofluorescent imaging by Lecia confocal microscopy, we analyzed the activation of AMPK/mTOR. Concurrently, the level of mitochondrial antioxidant enzymes of superoxide dismutase 2 (SOD2) and peroxiredoxin 1 and 4 (p1 and p4) along with protein and DANA oxidation were examined to in postmortem brains of AD (n= 8) and normal (n= 7) subjects to evaluate the metabolism dysfunction role in AD pathology. Results: In spite of AMPK inhibitory control on mTOR, concurrent phosphorylation of AMPK and mTOR (p-AMPK and p-mTOR) was observed in AD brains with high colocalization with hyperphosphorylated tau. Mitochondrial antioxidant enzymes of SOD2 and p1 and p4 were substantially decreased in p-AMPK, p-mTOR and p-tau positive cells along with higher levels of DNA and protein oxidation. Conclusion: Collectively, we conclude that AMPK and mTOR metabolic axis is highly activated in AD brains. While the inhibitory link between AMPK and mTOR seems to be disrupted, we suggest oxidative stress as the underlying mechanism for concurrent activation of AMPK and mTOR in AD.

Background: Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum. Objective: To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes. Methods: Patient-level longitudinal data from the National Alzheimer's Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon. Results: Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy. Conclusion: Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.

Background: Alzheimer's disease is one of the most common mental illnesses. It is posited that more than 25% of the population is affected by some mental disease during their lifetime. Treatment of each patient draws resources from the economy concerned. Therefore, it is important to quantify the potential economic impact. Methods: Agent-based, system dynamics and numerical approaches to dynamic modeling of the population of the European Union and its patients with Alzheimer's disease are presented in this article. Simulations, their characteristics, and the results from different modeling tools are compared. Results: The results of these approaches are compared with EU population growth predictions from the statistical office of the EU by Eurostat. The methodology of a creation of the models is described and all three modeling approaches are compared. The suitability of each modeling approach for the population modeling is discussed. Conclusion: In this case study, all three approaches gave us the results corresponding with the EU population prediction. Moreover, we were able to predict the number of patients with AD and, based on the modeling method, we were also able to monitor different characteristics of the population.