Current Alzheimer Research - Volume 16, Issue 2, 2019

Background: Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians. Objectives: To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnosis of dementia in memory clinics. Methods: In this prospective multicenter study, we recruited 779 patients with either subjective cognitive decline (n=252), mild cognitive impairment (n=219) or any type of dementia (n=274) and followed them for minimum 12 months. Based on all available patient baseline data (demographics, neuropsychological tests, cerebrospinal fluid biomarkers, and MRI visual and computed ratings), the PredictND tool provides a comprehensive overview and analysis of the data with a likelihood index for five diagnostic groups; Alzheimer´s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and subjective cognitive decline. At baseline, a clinician defined an etiological diagnosis and confidence in the diagnosis, first without and subsequently with the PredictND tool. The follow-up diagnosis was used as the reference diagnosis. Results: In total, 747 patients completed the follow-up visits (53% female, 69±10 years). The etiological diagnosis changed in 13% of all cases when using the PredictND tool, but the diagnostic accuracy did not change significantly. Confidence in the diagnosis, measured by a visual analogue scale (VAS, 0-100%) increased (ΔVAS=3.0%, p<0.0001), especially in correctly changed diagnoses (ΔVAS=7.2%, p=0.0011). Conclusion: Adding the PredictND tool to the diagnostic evaluation affected the diagnosis and increased clinicians’ confidence in the diagnosis indicating that CDSSs could aid clinicians in the differential diagnosis of dementia.

Background: Images of amyloid-β pathology characteristic of Alzheimer’s disease are difficult to consistently and accurately segment, due to diffuse deposit boundaries and imaging variations. Methods: We evaluated the performance of ImageSURF, our open-source ImageJ plugin, which considers a range of image derivatives to train image classifiers. We compared ImageSURF to standard image thresholding to assess its reproducibility, accuracy and generalizability when used on fluorescence images of amyloid pathology. Results: ImageSURF segments amyloid-β images significantly more faithfully, and with significantly greater generalizability, than optimized thresholding. Conclusion: In addition to its superior performance in capturing human evaluations of pathology images, ImageSURF is able to segment image sets of any size in a consistent and unbiased manner, without requiring additional blinding, and can be retrospectively applied to existing images. The training process yields a classifier file which can be shared as supplemental data, allowing fully open methods and data, and enabling more direct comparisons between different studies.

Background: Chronic pain is common among older adults and is associated with cognitive dysfunction based on cross-sectional studies. However, the longitudinal association between chronic pain and incident dementia in community-based samples is unknown. Objective: We aimed to evaluate the association of pain intensity and pain interference with incident dementia in a community-based sample of older adults. Methods: Participants were 1,114 individuals 70 years of age or older from Einstein Aging Study (EAS), a longitudinal cohort study of community-dwelling older adults in the Bronx County, NY. The primary outcome measure was incident dementia, diagnosed using DSM-IV criteria. Pain intensity and interference in the month prior to first annual visit were measured using items from the SF-36 questionnaire. Pain intensity and pain interference were assessed as predictors of time to incident dementia using Cox proportionate hazards models while controlling for potential confounders. Results: Among participants, 114 individuals developed dementia over an average 4.4 years (SD=3.1) of follow-up. Models showed that pain intensity had no significant effect on time to developing dementia, whereas higher levels of pain interference were associated with a higher risk of dementia. In the model that included both pain intensity and interference as predictors of incident dementia, pain interference had a significant effect on incident dementia, and pain intensity remained non-significant. Conclusion: As a potential remediable risk factor, the mechanisms linking pain interference to cognitive decline merit further exploration.

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer's disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

Background: Deposition of the amyloid β protein (Aβ) into neuritic plaques is the neuropathological hallmark of Alzheimer’s Disease (AD). Aβ is generated through the cleavage of the Amyloid Precursor Protein (APP) by β-secretase and γ-secretase. Currently, the evaluation of APP cleavage by β-secretase in experimental settings has largely depended on models that do not replicate the physiological conditions of this process. Objective: To establish a novel live cell-based β-secretase enzymatic assay utilizing a novel chimeric protein that incorporates the natural sequence of APP and more closely replicates its cleavage by β-secretase under physiological conditions. Methods: We have developed a chimeric protein construct, ASGβ, incorporating the β-site cleavage sequence of APP targeted by β-secretase and its intracellular trafficking signal into a Phosphatase-eGFP secreted reporter system. Upon cleavage by β-secretase, ASGβ releases a phosphatase-containing portion that can be measured in the culture medium, and an intracellular fraction that can be detected through Western Blot. Subsequently, we have generated a cell line stably expressing ASGβ that can be utilized to assay β-secretase in real time. Results: ASGβ is specifically targeted by β-secretase, being cleaved exclusively at the site responsible for the generation of Aβ. Dosage response to β-secretase inhibitors shows that β-secretase activity can be positively correlated to phosphatase activity in culture media. Conclusion: Our findings suggest this system could be a high-throughput tool to screen compounds that aim to modulate β-secretase activity and Aβ production under physiological conditions, as well as evaluating factors that regulate this cleavage.

Background: Alzheimer’s Disease (AD) is a chronic progressive neurodegenerative disorder in a central nervous system seen. Objective: We aimed to study the miR-107 in Alzheimer's Disease (AD) pathology through regulating SYK and NF-ΚB signaling pathway. Method: Bioinformatics analysis was performed to screen NF-ΚB signaling pathway and differentially expressed genes. The target relationship between miR-107 and SYK was verified by dual luciferase assay. QRT-PCR and western blot analysis were used to verify the expression level of miR-107, SYK and NF- ΚB signaling pathway related proteins of hippocampus primary neurons. BAY61-3606 and BAY11-7082 were purchased for functional examination. Morris water maze tests were performed to access spatial memory of AD mice with SYK and NF-ΚB signaling pathway inhibition. Fluorescence microscope dyeing experiment investigated the neurons nuclear form and apoptosis. Results: MiR-107 was lowly expressed while SYK was highly expressed in Tg19959 mouse model. Luciferase Assay confirmed the target relationship in miR-107 and SYK. With the inhibition of miR-107, SYK was up-regulated and the increase of p-p65 and the decrease of p-IΚB-α suggested that NF-ΚB signaling pathway was activated in vitro. Morris water maze test indicated that the spatial memory of Tg19959 mice was increased with the treatment. The result of DAPI staining indicated that the inhibition of SYK or NF-ΚB signaling pathway reduced the apoptosis of Tg19959 mice neuron cell. Conclusion: MiR-107 exerts its effects through suppression of the NF-ΚB signaling pathway and SYK, the inhibition of SYK and NF-ΚB signaling pathway can improve spatial memory and suppress cell apoptosis.

Background: Dementia is a common medical disorder in the elderly. Oxidative stress plays a major role in the process of cognitive decline in dementia. Perilla seed oil demonstrates its neuroprotective effects via anti-oxidative mechanisms against dementia. We investigate neuroprotective effects of perilla seed oil as an additional treatment in patients with mild to moderate dementia. Method: A double-blind, randomized-control trial (perilla seed oil versus placebo) in patients with mild to moderate dementia was conducted. Perilla seed oil or placebo was added on with standard treatment for six months. Cognitive function was compared at nine months after enrollment. Result: 182 patients, with 94 in the experimental group and 88 in the placebo group, were able to complete the study. Cognitive function is not significantly different compared between groups. However, the total cholesterol and LDL cholesterol were significantly lower in the experimental group. Perilla seed oil had no adverse effect to kidney, liver, blood components or glucose metabolism. Conclusion: Perilla seed oil as additional neuroprotective therapy in patients with mild to moderate dementia does not improve cognitive function. Perilla seed oil significantly reduced total cholesterol and LDL cholesterol. A clinical trial is needed to prove the benefit of cholesterol-lowering effects with perilla seed oil in human.

Background & Objective: The purpose of this study is to identify the risk factors associated with the conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s Disease (AD) dementia for the early detection of AD. Methods: The study comprised a prospective cohort study that included 400 MCI subjects with annual follow-ups for 3 years. Results: During the first 12 months' follow-up, 42 subjects converted to Alzheimer’s dementia (21 probable AD and 21 possible AD), two subjects converted to other types of dementia and 56 subjects lost follow. The factors associated with a greater risk of conversion from MCI to AD included gender, whole brain volume, and right hippocampal volume (rt. HV), as well as scores on the Revised Chinese version of the Alzheimer's Disease Assessment Scale-Cognitive subscale 13 (ADAS-Cog-C), Clock Drawing Test (CDT), Symbol Digit Modalities Test (SDMT), and Rey-Osterrieth Complex Figure Test (ROCFT). The risk classification of the combined ADAS-Cog-C and Alzheimer Cognitive Composite (ACC) score with the rt. HV and left Entorhinal Cortex Volume (lt. ECV) showed a conversion difference among the groups. Conclusion: Early detection of AD and potential selection for clinical trial design should utilize the rt. HV, as well as neuropsychological test scores, including those of the ADAS-Cog-C and ACC.

Background: There are a few risk factors which definitely have an impact on the development of Alzheimer's disease (AD). Those include genetics, gender, age, diabetes, head injuries, and lifestyle. Physical activity together with a healthy diet is part of people's lifestyle. At present, there exist several research studies showing that the physical activities can be a good intervention tool in the delay of cognitive decline in AD. Objective: The aim of this study is to discuss a relationship between the physical activities and the delay and/or maintenance of cognitive decline in AD and the types of physical activities which are especially suitable for this delay. Methods: The method of this review study consists of a method of literature review analysing the data contained in the world’s prestigious scientific databases: PubMed, Springer, Web of Science and Scopus in the period of 2010 - 2015. In addition, a method of comparison of different research studies discussing various aspects and factors of the correlation of physical activities and AD is used. Results: The findings of this review confirm that in most cases, physical activities have a positive effect on the improvement of cognitive decline in AD. Conclusion: Although physical activities seem to be beneficial for people with AD, more convincing results, particularly in the area of specific types of exercises and their impact on slowing down the cognitive decline, respectively AD, are needed.

Transgenic mice have been extensively used to study the Alzheimer pathology. In order to reduce, refine and replace (3Rs) the number of animals, ex vivo cultures are used and optimized. Organotypic brain slices are the most potent ex vivo slice culture models, keeping the 3-dimensional structure of the brain and being closest to the in vivo situation. Organotypic brain slice cultures have been used for many decades but were mainly prepared from postnatal (day 8-10) old rats or mice. More recent work (including our lab) now aims to culture organotypic brain slices from adult mice including transgenic mice. Especially in Alzheimer´s disease research, brain slices from adult transgenic mice will be useful to study beta-amyloid plaques, tau pathology and glial activation. This review will summarize the studies using organotypic brain slice cultures from adult mice to mimic Alzheimer's disease and will highlight advantages and also pitfalls using this technique.