Search

Sweat includes active components and metabolites, which are needed to maintain skin homeostasis. Component changes in sweat derived from atopic dermatitis (AD) have been reported. To investigate the influence of sweat components on the pathogenesis of AD, we performed a multifaceted assessment, including nuclear magnetic resonance spectroscopy-based metabolomic analysis, and linked these features to clinical features of AD. Distinctive properties of AD sweat are the quite-variation in protein, anti-microbial peptides and glucose concentrations. pH, sodium, and other salt levels in sweat of AD were comparable to that of healthy subjects. Sweat from AD patients with acute inflammation had a more prominent increase in glucose concentration than sweat from healthy individuals or those with AD with chronic inflammation. Topical glucose application delayed recovery of transepidermal water loss in barrier-disrupted mice. Furthermore, the glucose transporter GLUT2 was highly expressed in the lumen of sweat glands from AD patients. AD patients with chronic inflammation had significantly increased GLUT2 mRNA expression and near normal sweat glucose levels. Despite the small sample size in our study, we speculate that the increased glucose levels might be affected by AD severity and phenotype. We hope that this report will bring novel insight into the impact of sweat components on the clinical manifestation of AD. [ABSTRACT FROM AUTHOR]

Senile plaque accumulation and neurofibrillary tangles are primary characteristics of Alzheimer’s disease. We aimed to assess the protective functions of naringenin against β-amyloid protein fragment 25-35 (Aβ25-35)-caused nerve damage in differentiated PC12 cells, and study the potential mechanisms. We evaluated cell viability and apoptosis using the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test and flow cytometry, respectively. Moreover, we measured protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), and caspase-3 activity via western blotting and RT-PCR. We found that naringenin protected cell against Aβ25-35-caused nerve damage by increasing cell viability, promoting Akt and GSK3β activation, and inhibiting cell apoptosis and caspase-3 activity. However, treatment with the estrogen receptor (ER) antagonist ICI182, 780 or phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 suppressed the effects of naringenin. Our results suggested that naringenin could effectively suppress Aβ25-35-caused nerve damage in PC12 cells by regulating the ER and PI3K/Akt pathways. [ABSTRACT FROM AUTHOR]

Aim: Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte‐enhancer factor 2C (MEF2C) is one such candidate gene for AD. Methods: We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age‐ and sex‐matched control subjects. Results: In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = −0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects. Conclusion: MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a chronic neurodegenerative disease affecting more than 30 million people worldwide. Development of small molecule inhibitors of human β‐secretase 1 (hBACE‐1) is being the focus of pharmaceutical industry for the past 15–20 years. Here, we successfully applied multiple ligand‐based in silico modeling techniques to understand the inhibitory activities of a diverse set of small molecule hBACE‐1 inhibitors reported in the scientific literature. Strikingly, the use of only a small subset of 230 (13%) molecules allowed us to develop quality models that performed reasonably well on the validation set of 1,476 (87%) inhibitors. Varying the descriptor sets and the complexity of the modeling techniques resulted in only minor improvements to the model's performance. The current results demonstrate that predictive models can be built by choosing appropriate modeling techniques in spite of using small datasets consisting of diverse chemical classes, a scenario typical in triaging of high‐throughput screening results to identify false negatives. We hope that these encouraging results will help the community to develop more predictive models that would support research efforts for the debilitating Alzheimer's disease. Additionally, the integrated diversity of the techniques employed will stimulate scientists in the field to use in silico statistical modeling techniques like these to derive better models to help advance the drug discovery projects faster. [ABSTRACT FROM AUTHOR]

Background: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia.Objective: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia.Methods: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies.Results: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia.Conclusion: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the impact of suboptimal treatment, defined in terms of lower population coverage (percentage of total patient population receiving optimal treatment) and delay to treatment on the cost-effectiveness of pharmacological therapies approved for the treatment of different severities of Alzheimer's disease (AD) in the UK.Methods: A 5-year Markov model was used to simulate transition to full-time care, as delay and coverage were varied for AD patients with mild-to-moderate and moderate-to-severe dementia. The time-varying predictive equations, resource use, utilities, treatment effects and mortality were derived using published sources.Results: For the cohort with moderate-to-severe dementia, cost-effectiveness was optimised when delay was minimised and coverage maximised. For mild-to-moderate dementia, results were similar but varied widely depending on the inputted cost of acetylcholinesterase inhibitors.Conclusions: The average cost-effectiveness of pharmacological treatments for AD is sensitive to delays to treatment and population coverage. The results of this study can inform future healthcare policy in order to maximise cost-effectiveness of pharmacological therapies for AD. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Changes to everyday spoken language ("connected language") are evident in persons with AD dementia, yet little is known about when these changes are first detectable on the continuum of cognitive decline. The aim of this study was to determine if participants with very early, subclinical memory declines were also showing declines in connected language. We analyzed connected language samples obtained from a simple picture description task at two time points in 264 participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP). In parallel, participants were classified as either "Cognitively Healthy" or "Early Mild Cognitive Impairment" based on longitudinal neuropsychological test performance. Linear mixed effects models were used to analyze language parameters that were extracted from the connected language samples using automated feature extraction. Participants with eMCI status declined faster in features of speech fluency and semantic content than those who were cognitively stable. Measures of lexical diversity and grammatical complexity were not associated with eMCI status in this group. These findings provide novel insights about the relationship between cognitive decline and everyday language, using a quick, inexpensive, and performance-based method. [ABSTRACT FROM AUTHOR]

Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis. [ABSTRACT FROM AUTHOR]

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains. [ABSTRACT FROM AUTHOR]

Background: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention.Objective: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline.Methods: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared.Results: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01).Conclusion: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis. [ABSTRACT FROM AUTHOR]

Objective: We examined whether caregivers' employment status (i.e., retired or employed) might modify the association between the behaviours of persons with Alzheimer's disease (PwAD) and caregivers' health-related quality-of-life (HRQoL). Data came from a cross-sectional study of the primary informal caregivers of 200 persons with mild or moderate Alzheimer's disease. Caregivers completed the EQ-5D-3L to rate their HRQoL and generate health utility scores, and the Dementia Behaviour Disturbance Scale (DBDS) to assess the degree to which PwAD exhibited each of 28 behaviours. Caregivers' health utility scores were regressed on overall DBDS scores, with caregiver employment status (retired, employed) treated as an effect modifier and confounder in separate regression models. We also controlled for age, sex, income, education, caregivers' relationship to the PwAD, and whether caregivers gave up paid employment/cut down working hours to care for PwAD. Results: Effect modification by caregiver employment status is possible, with the inverse association between DBDS score and health utility score largely existing for retired versus employed caregivers. Research using larger samples and longitudinal data would further inform this area of inquiry. [ABSTRACT FROM AUTHOR]

Observations in animal models suggest that amyloid can cause network hypersynchrony in the early preclinical phase of Alzheimer's disease (AD). The aim of this study was (a) to obtain evidence of paroxysmal hypersynchrony in cognitively intact subjects (CN) with increased brain amyloid load from task-free fMRI exams using a dynamic analysis approach, (b) to investigate if and how hypersynchrony interferes with memory performance, and (c) to describe its relationship with gray and white matter connectivity. Florbetapir-F18 PET and task-free 3T functional and structural MRI were acquired in 47 CN (age = 70.6±6.6), 17 were amyloid pos (florbetapir SUVR >1.11). A parcellation scheme encompassing 382 regions of interest was used to extract regional gray matter volumes, FA-weighted fiber tracts and regional BOLD signals. Graph analysis was used to characterize the gray matter atrophy profile and the white matter connectivity of each subject. The fMRI data was processed using a combination of sliding windows, graph and hierarchical cluster analysis. Each activity cluster was characterized by identifying strength dispersion (difference between pos and neg strength) their maximal and minimal pos and neg strength rois and by investigating their distribution and association with memory performance and gray and white matter connectivity using spearman rank correlations (FDR p < 0.05). The cluster analysis identified eight different activity clusters. Cluster 8 was characterized by the largest strength dispersion indicating hypersynchrony. Its duration/subject was positively correlated with amyloid load (r = 0.42, p = 0.03) and negatively with memory performance (CVLT delayed recall r = -0.39 p = 0.04). The assessment of the regional strength distribution indicated a functional disconnection between mesial temporal structures and the rest of the brain. White matter connectivity was increased in left lateral and mesial temporal lobe and was positively correlated with strength dispersion in the cross-modality analysis suggesting that it enables widespread hypersynchrony. In contrast, precuneus, gray matter connectivity was decreased in the right fusiform gyrus and negatively correlated with high degrees of strength dispersion suggesting that progressing gray matter atrophy could prevent the generation of paroxysmal hypersynchrony in later stages of the disease. [ABSTRACT FROM AUTHOR]

Copyright of Frontiers in Aging Neuroscience is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. Main text: The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Conclusions: Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD--to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice. [ABSTRACT FROM AUTHOR]

The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate-limiting step in beta amyloid generation during Alzheimer's disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in endocytic compartments, where the acidic pH is optimal for its activity. However, mechanisms regulating the endosome-to-trans-Golgi network (TGN) retrieval of BACE1 remain unclear. Here, we show that partitioning defective 3 (Par3) facilitates BACE1 retrograde trafficking from endosomes to the TGN. Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498, which in turn promotes the interaction between BACE1 and phosphofurin acidic cluster sorting protein 1 and facilitates the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in AD pathogenesis. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1 and shed light on the mechanisms of AD pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in 2 regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the subventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD, and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified adenosine A2a receptor ( ADORA2A ) as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments ( p = 7.88 × 10 −6 ). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory. [ABSTRACT FROM AUTHOR]

Purpose: Alzheimer's disease (AD) is pathologically defined by the presence of amyloid plaques and tangles in the brain, therefore, any drug or compound with potential effect on lowering amyloid plaques, could be noticed for AD management especially in the primary phases of the disease. Ectoine constitutes a group of small molecule chaperones (SMCs). SMCs inhibit proteins and other changeable macromolecular structures misfolding from environmental stresses. Ectoine has been reported successfully prohibit insulin amyloid formation in vitro. Methods: We selected eight genes, DAXX, NFκβ, VEGF, PSEN1, MTAP2, SYP, MAPK3 and TNFα genes which had previously showed significant differential expression in Alzheimer human brain and STZ- rat model. We considered the neuroprotective efficacy by comparing the expression of candidate genes levels in the hippocampus of rat model of Sopradic Alzheimer's disease (SAD), using qPCR in compound-treated and control groups as well as therapeutic effects at learning and memory levels by using Morris Water Maze (MWM) test. Results: Our results showed significant down-regulation of Syp, Mapk3 and Tnfα and up-regulation of Vegf in rat's hippocampus after treatment with ectoine comparing to the STZ-induced group. In MWM, there was no significant change in swimming distance and time for finding the hidden platform in treated comparing to STZ-induced group. In addition, it wasn't seen significant change in compound-treated comparing to STZ-induced and control groups in memory level. Conclusion: It seems this compound may have significant effect on expression level of some AD- related genes but not on clinical levels. [ABSTRACT FROM AUTHOR]

A case study of a 39‑year‑old male presented with gradually progressive behavioral changes for 4 years, bilateral upper limb tremors for 3 years, and recurrent generalized tonic‑clonic seizures for 1 year. Topics include autosomal recessive disorder characterized by progressive presenile dementia and bone cysts caused by mutations in the genes; and non‑contrast computed tomography scan of the brain showed bilateral basal ganglia calcification.

As an extension of the brain, the spinal cord has unique properties which could allow us to gain a better understanding of CNS pathology. The brain and cord share the same cellular components, yet the latter is simpler in cytoarchitecture and connectivity. In Alzheimer’s research, virtually all focus is on brain pathology, however it has been shown that transgenic Alzheimer’s mouse models accumulate beta amyloid plaques in spinal cord, suggesting that the cord possesses the same molecular machinery and conditions for plaque formation. Here we report a spatial-temporal map of plaque load in 5xFAD mouse spinal cord. We found that plaques started to appear at 11 weeks, then exhibited a time dependent increase and differential distribution along the cord. More plaques were found in cervical than other spinal levels at all time points examined. Despite heavy plaque load at 6 months, the number of cervical motor neurons in 5xFAD mice is comparable to wild type littermates. On detailed microscopic examination, fine beta amyloid-containing and beta sheet-rich thread-like structures were found in the peri-axonal space of many axons. Importantly, these novel structures appear before any plaque deposits are visible in young mice spinal cord and they co-localize with axonal swellings at later stages, suggesting that these thread-like structures might represent the initial stages of plaque formation, and could play a role in axonal damage. Additionally, we were able to demonstrate increasing myelinopathy in aged 5xFAD mouse spinal cord using the lipid probe Nile Red with high resolution. Collectively, we found significant amyloid pathology in grey and white matter of the 5xFAD mouse spinal cord which indicates that this structure maybe a useful platform to study mechanisms of Alzheimer’s pathology and disease progression. [ABSTRACT FROM AUTHOR]

Plant biophenols have been shown to be effective in the modulation of Alzheimer's disease (AD) pathology resulting from free radical-induced oxidative stress and imbalance of the redox chemistry of transition metal ions (e.g., iron and copper). On the basis of earlier reported pharmacological activities, olive biophenols would also be expected to have anti-Alzheimer's activity. In the present study, the antioxidant activity of individual olive biophenols (viz. caffeic acid, hydroxytyrosol, oleuropein, verbascoside, quercetin, rutin and luteolin) were evaluated using superoxide radical scavenging activity (SOR), hydrogen peroxide (H2O2) scavenging activity, and ferric reducing ability of plasma (FRAP) assays. The identification and antioxidant activities in four commercial olive extracts--Olive leaf extractTM (OLE), Olive fruit extractTM (OFE), Hydroxytyrosol ExtremeTM (HTE), and Olivenol plusTM (OLP)--were evaluated using an on-line HPLC-ABTS+ assay, and HPLC-DAD-MS analysis. Oleuropein and hydroxytyrosol were the predominant biophenols in all the extracts. Among the single compounds examined, quercetin (EC50: 93.97 μM) and verbascoside (EC50: 0.66 mM) were the most potent SOR and H2O2 scavengers respectively. However, OLE and HTE were the highest SOR (EC50: 1.89 μg/mL) and H2O2 (EC50: 115.8 μg/mL) scavengers among the biophenol extracts. The neuroprotection of the biophenols was evaluated against H2O2-induced oxidative stress and copper (Cu)-induced toxicity in neuroblastoma (SH-SY5Y) cells. The highest neuroprotection values (98% and 92%) against H2O2-induced and Cu-induced toxicities were shown by the commercial extract HTETM. These were followed by the individual biophenols, caffeic acid (77% and 64%) and verbascoside (71% and 72%). Our results suggest that olive biophenols potentially serve as agents for the prevention of neurodegenerative diseases such as AD, and other neurodegenerative ailments that are caused by oxidative stress. [ABSTRACT FROM AUTHOR]

This article reports the findings of an evaluation of a training course for care workers who care for people with dementia in the community. Twenty-four care workers participated in the training which took place in London and Surrey, United Kingdom. The training had a significant positive impact on participants’ confidence in understanding the experiences and social care needs of people with young onset dementia (YOD) and their families. Participants also perceived that the training would help them improve their working practice by furthering their understanding of practical approaches to supporting and caring for people with dementia in general. Additionally, participants reported many ways in which they perceived being able to specifically support and empower people with YOD. It was concluded that the short training course improved knowledge and confidence for care workers on dementia care, and specifically in understanding how to support people with YOD and their families. Dementia specific training should be considered by service managers as a way of potentially increasing care worker job satisfaction. [ABSTRACT FROM AUTHOR]

Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrPSc). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrPSc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt- Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound "D3", an all D-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice. [ABSTRACT FROM AUTHOR]

Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer's disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca2+-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research. [ABSTRACT FROM AUTHOR]

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice. [ABSTRACT FROM AUTHOR]

Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer's disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM. [ABSTRACT FROM AUTHOR]

Aim of the present study is to investigate the effects of medication with donepezil (acetylcholinesterase inhibitor) on the liver and kidney function in Alzheimer's disease (AD) and to compare the effects of donepezil medication during short (one month) and long term (six years) follow-ups. We evaluated female and male patients from Cukurova [42 AD patients; short term (5 mg/day)] and Dokuz Eylul [68 AD patients; long term (10 mg/day)] University Hospital. The results compared with the geriatric population without dementia in other words who are not in medication with donepezil. For short term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; firstly, before starting treatment and then repeated one month later. For long term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; three times at the end of each two consecutive years of treatment with donepezil. AD patients' results were also compared with 79 neurologically healthy geriatric patients without dementia who were over 65 years of age and were not receiving medication with donepezil. For this task, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are used to predict possible liver damage, while the blood urea nitrogen (BUN) and creatinine (CRE) levels for kidney damage. No significant difference between the groups regarding the routine control of biochemical parameters was observed in short term drug medication. In long term patients' group; the effects of two years use of donepezil on renal and hepatic function were also evaluated and levels of AST, ALT, BUN and CRE were found to be increased significantly compared to pretreatment levels. But, they remained in the reference intervals. However, levels of AST and ALT at the end of the fourth year of therapy were similar to those measured at the end of the second year, levels of BUN and CRE continuing to increase with staying below the reference limits. Functional markers obtained at the end of the sixth year of therapy were not differing from those of the fourth year. No significant difference was found during comparisons within the results of the neurologically healthy geriatric patient group. During comparisons between the two groups, measurements obtained at all-time points were significantly high in donepezil treated AD patients. We concluded that customized dosage according to hepatic and renal functions is necessary for using acetylcholinesterase inhibitor in AD patients. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) is an important molecule that connects aging, lifespan, energy balance, glucose and lipid metabolism, and neurodegeneration. Rapamycin exerts effects in numerous biological activities via its target protein, playing a key role in energy balance, regulation of autophagy, extension of lifespan, immunosuppression, and protection against neurodegeneration. There are many similar pathophysiological processes and molecular pathways between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), and pharmacologic agents used to treat T2DM, including glucagon-like peptide-1 (GLP-1) analogs, seem to be beneficial for AD. mTOR mediates the effects of GLP-1 analogs in the treatment of T2DM; hence, I hypothesize that mTOR is a key molecule for mediating the protective effects of GLP-1 for AD. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities - such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling - in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most prevalent progressive neurodegenerative disease; to date, no AD therapy has proven effective in delaying or preventing the disease course. In the search for novel therapeutic targets in AD, it has been shown that increased chronic psychologic stress is associated with AD risk. Subsequently, biologic pathways underlying psychologic stress have been identified and shown to be able to exacerbate AD relevant pathologies. In this review, we summarize the literature relevant to the association between psychologic stress and AD, focusing on studies investigating the effects of stress paradigms on transgenic mouse models of Amyloid-β (Aβ) and tau pathologies. In recent years, a substantial amount of research has been done investigating a key stress-response mediator, corticotropin-releasing hormone (CRH) and its interactions with AD relevant processes. We highlight attempts to target the CRH signaling pathway as a therapeutic intervention in these transgenic mouse models and discuss how targeting this pathway is a promising avenue for further investigation. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that neuroinflammation comprises a major characteristic of Alzheimer's disease (AD). Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine implicated in neurodegenerative diseases including AD, and has been proposed as a potent therapeutic target for AD. Although a number of studies focusing on pharmacological or genetic manipulation of TNF-α and its receptors in AD mice have provided significant knowledge regarding the role of TNF-α signaling pathway in the pathogenesis of AD, the consequences of TNF-α genetic deletion have not been thoroughly examined. Here, we focused on the effect of TNF-α deficiency on the amyloid phenotype of 5XFAD mice. Our analysis revealed that amyloid deposition, amyloid-β (Aβ) levels, and AβPP-carboxyterminal fragments are significantly reduced in the brains of 5XFAD/TNF-α-/- mice compared to the 5XFAD/TNF-α+/+. We found decreased protein levels of β- and α-secretases in the 5XFAD/TNF-α-/- brains, suggesting for an effect of TNF-α on AβPP processing and Aβ generation. We also show for the first time that TNF-α affects PS1in vivo, as 5XFAD mice lacking TNF-α expression display reduced PS1-carboxyterminal fragments implying for diminished PS1 activity. Moreover, TNF-α deficiency decreases microglial and astrocytic activation and significantly restricts the phagocytic activity of macrophages against Aβ, supporting for reduced responsiveness of phagocytes toward Aβ. Overall, our results reveal that TNF-α genetic deletion in 5XFAD mice attenuates amyloid plaque formation by lowering Aβ generation through the reduction of functionally active PS1 and β-secretase rather than promoting Aβ clearance by phagocytic cells. Our data further suggest TNF-α inhibition as a therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) is the most widely used instrument for screening cognitive dysfunction in Alzheimer's disease. The aim of the present study was to develop an Arabic version of this scale (A-ADAS-Cog), examine its psychometric properties (reliability and validity), and provide normative data. The A-ADAS-Cog), an Arabic version of the Mini-Mental State Examination (A-MMSE), and a Standardized Clinical Dementia Rating Scale (CDR) were administered to three Tunisian groups: 124 normal controls (NC), 33 patients with non-Alzheimer dementia (N-AD), and 25 patients with Alzheimer's disease (AD). The A-ADAS-Cog scores were significantly affected by age and education. A correction table was constructed to control these effects. The results showed that the A-ADAS-Cog has good internal consistency and reliability (α= 0.82 for AD). The test-retest reliability of the A-ADAS-Cog was stable over time (r = 0.97). An evaluation of the construct validity of the A-ADAS-Cog using principal component analysis led to a solution with three factors (memory, language and praxis), which explained 72% of the variance. The concurrent validity of the A-ADAS-Cog was established using the A-MMSE score (r = -0.86), CDR Sum of Boxes score (CDR-SB; r = 0.87), and global CDR score (CDR-Global; r = 0.74). Finally, the A-ADAS-Cog has an excellent discriminating power in the diagnosis of AD (ROC area = 0.92). A cut-off score of 10 (sensitivity = 84% and specificity = 91%) is indicated for the screening of the AD. Overall, the results indicated that the A-ADAS-Cog is psychometrically reliable and valid and provides promising results for screening of dementia in Arabic speaking patients. [ABSTRACT FROM AUTHOR]

Background: β-Amyloid peptide (Aβ) oligomers are initial factors used to induce Alzheimer's disease (AD) development, and Aβ monomers have normal physiological function. The antibodies or vaccines against Aβ monomers have serious problems, such as side effects and low curative effects. Therefore, it is essential to specifically target Aβ oligomers rather than monomers for the treatment of AD. Methods: The mimotopes of Aβ oligomers were obtained by panning the phage-displayed random peptide libraries using oligomer-specific antibodies as targets and expressed on the surface of EBY100 Saccharomyces cerevisiae to generate yeast cell base vaccines. One vaccine (AOE1) induced antibodies specifically against Aβ oligomers and was selected for further study. The APP/PS1 mice were subcutaneously immunized with AOE1 eight times. The levels and characteristics of antibodies induced by AOE1 were determined by enzyme-linked immunosorbent assay. The effect of AOE1 on the cognitive deficits of AD mice was tested by novel object recognition (NOR) and Y-maze. Dot blot analysis, Western blot analysis, and immunohistochemistry were applied to measure the effects of AOE1 on Aβ pathologies, neuroinflammation, and microhemorrhages in the brains of AD mice. Results: Eight mimotope candidates of Aβ oligomers were selected and expressed on EBY100 S. cerevisiae. Only AOE1 vaccine containing mimotope L2 induced antibodies that specifically recognized Aβ42 oligomers rather than monomers. AOE1 immunization significantly increased the AD mice's exploration times for the novel object in the NOR test and the choices for new arms in the Y-maze test, and it reduced levels of Aβ oligomers and glial activation in the AD mouse brains. No activation of Aβ-specific T cells and microhemorrhages was observed in their brains following AOE1 vaccination. Conclusions: AOE1 is the first vaccine applying the oligomer-specific mimotope as an immunogen, which could induce antibodies with high specificity to Aβ oligomers. AOE1 immunization attenuated Aβ pathologies and cognitive deficits in AD mice, decreased the overactivation of glial cells, and did not induce microhemorrhage in the brains of AD mice. These findings suggest that AOE1 may be a safer and more effective vaccine for AD treatment. [ABSTRACT FROM AUTHOR]

Object-location memory is particularly fragile and specifically impaired in Alzheimer's disease (AD) patients. Electroencephalogram (EEG) was utilized to objectively measure memory impairment for memory formation correlates of EEG oscillatory activities. We aimed to construct an object-location memory paradigm and explore EEG signs of it. Two groups of 20 probable mild AD patients and 19 healthy older adults were included in a cross-sectional analysis. All subjects took an object-location memory task. EEG recordings performed during object-location memory tasks were compared between the two groups in the two EEG parameters (spectral parameters and phase synchronization). The memory performance of AD patients was worse than that of healthy elderly adults The power of object-location memory of the AD group was significantly higher than the NC group (healthy elderly adults) in the alpha band in the encoding session, and alpha and theta bands in the retrieval session. The channels-pairs the phase lag index value of object-location memory in the AD group was clearly higher than the NC group in the delta, theta, and alpha bands in encoding sessions and delta and theta bands in retrieval sessions. The results provide support for the hypothesis that the AD patients may use compensation mechanisms to remember the items and episode. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive complaints (SCCs) may be an early marker of prodromal Alzheimer's disease.Objectives: Using a 10-item yes/no SCCs questionnaire (Le Questionnaire de Plainte Cognitive [QPC]), we evaluated the prevalence and distribution of SCCs in cognitively healthy Czech older adults and examined total score and specific QPC items in relation to depressive symptomology and cognitive performance.Methods: A sample of 340 cognitively healthy older community-dwelling volunteers aged 60 or older from the third wave of the longitudinal project National Normative Study of Cognitive Determinants of Healthy Aging, who underwent a comprehensive neuropsychological assessment and completed the QPC and the 15-item Geriatric Depression Scale (GDS-15). Regression analysis was controlled for age when GDS-15 was the outcome and for age and GDS-15 with cognitive domains as the outcome.Results: 71% reported 1 + SCCs, with prevalence of individual complaints ranging from 4% to 40%. The number of SCCs was associated with GDS-15 (p < 0.001). Personality change (p < 0.001) and Limitation in daily activities (p = 0.002) were significantly associated with higher GDS-15 score and Spatial orientation difficulties (p = 0.019) and Impression of worse memory in comparison to peers (p = 0.012) were significantly associated with lower memory performance.Conclusions: We identified some cognitive complaints that were very common in our sample. Overall, a higher number of SCCs in well cognitively functioning individuals was most closely related to depressive symptomatology, while some specific complaints reflected lower memory performance and should be considered when screening for people at risk of cognitive decline. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (Alzheimer's), an ultimately fatal form of dementia, is the sixth leading cause of death in the United States, accounting for 3.6% of all deaths in 2014 (1,2). Alzheimer's deaths can be an indicator of paid and unpaid caregiver burden because nearly everyone in the final stages of Alzheimer's needs constant care, regardless of the setting, as the result of functional and cognitive declines (2). To examine deaths with Alzheimer's as the underlying cause, state-level and county-level death certificate data from the National Vital Statistics System for the period 1999-2014 were analyzed. A total of 93,541 Alzheimer's deaths occurred in the United States in 2014 at an age-adjusted (to the 2000 standard population) rate of 25.4 deaths per 100,000 population, a 54.5% increase compared with the 1999 rate of 16.5 deaths per 100,000. Most deaths occurred in a nursing home or long-term care facility. The percentage of Alzheimer's decedents who died in a medical facility (e.g., hospital) declined from 14.7% in 1999 to 6.6% in 2014, whereas the percentage who died at home increased from 13.9% in 1999 to 24.9% in 2014. Significant increases in Alzheimer's deaths coupled with an increase in the number of persons with Alzheimer's dying at home have likely added to the burden on family members or other unpaid caregivers. Caregivers might benefit from interventions such as education, respite care, and case management that can lessen the potential burden of caregiving and can improve the care received by persons with Alzheimer's. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease is a neurodegenerative syndrome characterized by multiple dimensions including cognitive decline, decreased daily functioning and psychiatric symptoms. This systematic review aims to investigate the relation between somatic comorbidity burden and progression in late-onset Alzheimer’s disease (LOAD). Methods: We searched four databases for observational studies that examined cross-sectional or longitudinal associations of cognitive or functional or neuropsychiatric outcomes with comorbidity in individuals with LOAD. From the 7966 articles identified originally, 11 studies were included in this review. The Newcastle-Ottawa quality assessment was used. The large variation in progression measures, comorbidity indexes and study designs hampered the ability to perform a meta-analysis. This review was registered with PROSPERO under DIO: 10.15124/CRD42015027046. Results: Nine studies indicated that comorbidity burden was associated with deterioration in at least one of the three dimensions of LOAD examined. Seven out of ten studies investigating cognition found comorbidities to be related to decreased cognitive performance. Five out of the seven studies investigating daily functioning showed an association between comorbidity burden and decreased daily functioning. Neuropsychiatric symptoms (NPS) increased with increasing comorbidity burden in two out of three studies investigating NPS. Associations were predominantly found in studies analyzing the association cross-sectionally, in a time-varying manner or across short follow-up (≤2 years). Rarely baseline comorbidity burden appeared to be associated with outcomes in studies analyzing progression over longer follow-up periods (>2 years). Conclusion: This review provides evidence of an association between somatic comorbidities and multifaceted LOAD progression. Given that time-varying comorbidity burden, but much less so baseline comorbidity burden, was associated with the three dimensions prospectively, this relationship cannot be reduced to a simple cause-effect relation and is more likely to be dynamic. Therefore, both future studies and clinical practice may benefit from regarding comorbidity as a modifiable factor with a possibly fluctuating influence on LOAD. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the inter-rater variability of the visual interpretation of C-PiB PET images regarding the positivity/negativity of amyloid deposition that were obtained in a multicenter clinical research project, Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI). The results of visual interpretation were also compared with a semi-automatic quantitative analysis using mean cortical standardized uptake value ratio to the cerebellar cortex (mcSUVR). Methods: A total of 162 C-PiB PET scans, including 45 mild Alzheimer's disease, 60 mild cognitive impairment, and 57 normal cognitive control cases that had been acquired as J-ADNI baseline scans were analyzed. Based on visual interpretation by three independent raters followed by consensus read, each case was classified into positive, equivocal, and negative deposition (ternary criteria) and further dichotomized by merging the former two (binary criteria). Results: Complete agreement of visual interpretation by the three raters was observed for 91.3% of the cases (Cohen κ = 0.88 on average) in ternary criteria and for 92.3% ( κ = 0.89) in binary criteria. Cases that were interpreted as visually positive in the consensus read showed significantly higher mcSUVR than those visually negative (2.21 ± 0.37 vs. 1.27 ± 0.09, p < 0.001), and positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. Significant positive/negative associations were observed between mcSUVR and the number of raters who evaluated as positive ( ρ = 0.87, p < 0.0001) and negative ( ρ = −0.85, p < 0.0001) interpretation. Cases of disagreement among raters showed generally low mcSUVR. Conclusions: Inter-rater agreement was almost perfect in C-PiB PET scans. Positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. As some cases of disagreement among raters tended to show low mcSUVR, referring to quantitative method may facilitate correct diagnosis when evaluating images of low amyloid deposition. [ABSTRACT FROM AUTHOR]

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology. [ABSTRACT FROM AUTHOR]

Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene ( CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. [ABSTRACT FROM AUTHOR]

Background: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion.Objective: To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls.Methods: Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9).Results: von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion.Conclusion: The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion. [ABSTRACT FROM AUTHOR]

Objective: Impairment of visual perception frequently occurs in Alzheimer's disease (AD) and can cause severe constraints in daily activities. The nonverbal Raven's Colored Progressive Matrices (RCPM) test consists of sets A, AB, and B and is easily performed in a short time to evaluate both visual perception and reasoning ability. The purpose of this study was to evaluate the neural basis of visual perception and reasoning ability in patients with AD using RCPM and single-photon emission computed tomography (SPECT).Methods: Fifty patients who fulfilled the National Institute on Aging/Alzheimer's Association criteria for probable AD dementia were examined with RCPM and SPECT. All SPECTs were performed using N-isopropyl-p-[123 I]-iodoamphetamine. A multiple regression model was used to perform multivariate analyses of the relationships between regional cerebral blood flow (rCBF) and RCPM scores.Results: There was a significant positive correlation between RCPM total score and rCBF in the inferior parietal lobes bilaterally, the right inferior temporal gyrus, and the right middle frontal gyrus. Set A was positively correlated with rCBF in the right temporal and right parietal lobes. Set AB was positively correlated with rCBF in the right temporal, right parietal, and right frontal lobes. Set B was positively correlated with rCBF in the right parietal and right frontal lobes.Conclusion: Our findings suggest that deteriorations of specific brain regions are associated with dysfunction of visual perception and reasoning ability in AD. RCPM is another informative assessment scale of cognition for use in patients with AD. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We investigated the protective effects and mechanism of TPX2 on apoptosis of rat neurocytes. A total of 90 SD rats were randomly divided into the drug group, the control group and the blank group, with 30 rats in each group. The rats in the drug group and in the blank group were anesthetized with 10% chloral hydrate (at the dose of 0.5 ml/100 g) and Aβ1‑42, with the concentration of 5 μl (1 μg/μl), was injected in the exact position of bilateral hippocampal areas of rats to establish the model. The configured TPX2 inhibitors and edible benne oil were mixed and made into a suspension. After model establishment, the rats were given different treatment methods; the rats in the drug group were given gavage administration in the proportion of 75 mg/kg once a day. The rats in the control group were given intragastric administration with the same proportion of physiological saline once a day. The blank group was the normal healthy group and the rats in this group did not undergo any surgery or drug treatment. Brain tissue in rats were divided into two parts, one part was fixed, dehydrated, paraffin-embedded and made into slices of approximately 5 μm. TUNEL staining was used to examine the apoptosis of brain tissue, H&E staining was used to observe the brain tissue cells of each group, and western blotting for detecting the MAPK, Erk and expression levels of p38 and RT‑polymerase chain reaction method was employed to examine mRNA expression levels of MAPK, Erk and p21. After one week, TUNEL staining showed that apoptosis of brain tissue in the drug group was significantly greater than those of the control and blank groups. The protein expression levels of MAPK, Erk and p38 were significantly higher than those of the control group and the normal healthy group; the differences were statistically significant (P<0.05). Western blotting showed that the protein expression levels of MAPK, Erk and p38 of the drug group were significantly lower than those of the control group but higher than those of the normal healthy group; the differences were statistically significant (P<0.05). TPX2 has a protective effect on the apoptosis of brain tissue processed by Aβ1‑42, which plays its role through the inhibition of the protein expression levels of MAPK, Erk and p38. [ABSTRACT FROM AUTHOR]

Background: Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer's disease (AD). Aβ generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet. Methods: In this study, human brain tissue and APP/PS1 mouse brain tissue were used to check the disease relevance of SNX4. To investigate the role of SNX4 in AD pathogenesis, several experiments were done, such as coimmunoprecipitation, Western blotting, immunohistochemistry, and gradient fractionation. Results: We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. Overexpression of SNX4 significantly increased the levels of BACE1 and Aβ. Downregulation of SNX4 had the opposite effect. SNX4 interacts with BACE1 and prevents BACE1 trafficking to the lysosomal degradation system, resulting in an increased half-life of BACE1 and increased production of Aβ. Conclusions: We show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated β-processing of APP and subsequent Aβ generation. [ABSTRACT FROM AUTHOR]