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26 Jun 2019 at 01:30
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 26 Jun 2019 at 01:30 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-06-24

Palmqvist S, Janelidze S, Stomrud E, et al (2019)

Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related β-Amyloid Status.

JAMA neurology pii:2736342 [Epub ahead of print].

Importance: Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials.

Objective: To examine the accuracy of plasma β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ.

Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study.

Main Outcome and Measures: The cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1.

Results: The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aβ42 and Aβ40 predicted Aβ status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aβ42, Aβ40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff.

Conclusions and Relevance: Plasma Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.

RevDate: 2019-06-24

O'Bryant SE (2019)

Blood Biomarkers for Use in Alzheimer Disease-Moving From "If" to "How?".

JAMA neurology pii:2736339 [Epub ahead of print].

RevDate: 2019-06-24

Campbell NL, Holden R, MA Boustani (2019)

Preventing Alzheimer Disease by Deprescribing Anticholinergic Medications.

JAMA internal medicine pii:2736349 [Epub ahead of print].

RevDate: 2019-06-24

Pyenson B, Sawhney TG, Steffens C, et al (2019)

The Real-World Medicare Costs of Alzheimer Disease: Considerations for Policy and Care.

Journal of managed care & specialty pharmacy, 25(7):800-809.

BACKGROUND: Headlines in popular media suggest that Alzheimer disease will bankrupt the Medicare program. Indeed, Alzheimer disease affects more than 5 million older Medicare beneficiaries.

OBJECTIVE: To compare total Medicare-covered (allowed) costs of patients with Alzheimer disease with the risk adjusted costs of beneficiaries without dementia over their last years of life, using claims data.

METHODS: Using the Medicare 5 Percent Limited Data Set claim files from 2006-2015, we conducted a cost impact analysis of costs for up to 8 years before the year of death. Risk adjustment was performed at a beneficiary level using Medicare's 2015 Hierarchical Condition Categories. Beneficiaries were classified into dementia categories based on their diagnoses during the last 3 years of life. Costs were trend adjusted to 2015.

RESULTS: This study found that 40% of deceased beneficiaries have Alzheimer disease or unspecified dementia diagnoses in their claims history. In their last 9 years of life, Alzheimer disease added about 11% to the average $17,000 per year Medicare cost for same-risk beneficiaries without dementia.

CONCLUSIONS: Like many diseases, Alzheimer disease and dementia are associated with aging, but unlike other diseases, families and Medicaid, rather than Medicare, bear most of the substantial cost burden. As research continues into Alzheimer treatments, it is not too early to consider how to better integrate Medicare and Medicaid to fund and improve patient outcomes, which will likely involve better diagnosis, treatment, and care coordination.

DISCLOSURES: Funding for this project was provided by the Alliance for Aging Research, which received funding from Biogen, Eli Lilly, and Janssen Pharmaceuticals. Peschin and Jenkins are employed by the Alliance for Aging Research. Scott was employed by the Alliance for Aging Research at the time of this study and also reports consulting fees from Piramal Imaging, General Electric, and Allergan, outside of this study. Scott is chair of the Board of Directors for the Alliance for Aging Research, which is a volunteer position, and is also president of Applied Policy, a health policy and reimbursement consultancy. Pyenson and Steffens are employed by Milliman, which was contracted to work on this study. Goss Sawhney and Rotter were employed by Milliman at the time this work was performed. Milliman is a consultant to thousands of organizations in the health care industry.

RevDate: 2019-06-22

Lee S, Lee H, Kim KW, et al (2019)

Magnetic resonance imaging texture predicts progression to dementia due to Alzheimer disease earlier than hippocampal volume.

Journal of psychiatry & neuroscience : JPN, 44(5):1-8 [Epub ahead of print].

Background: Early identification of people at risk of imminent progression to dementia due to Alzheimer disease is crucial for timely intervention and treatment. We investigated whether the texture of MRI brain scans could predict the progression of mild cognitive impairment (MCI) to Alzheimer disease earlier than volume.

Methods: We constructed a development data set (121 people who were cognitively normal and 145 who had mild Alzheimer disease) and a validation data set (113 patients with stable MCI who did not progress to Alzheimer disease for 3 years; 40 with early MCI who progressed to Alzheimer disease after 12–36 months; and 41 with late MCI who progressed to Alzheimer disease within 12 months) from the Alzheimer’s Disease Neuroimaging Initiative. We analyzed the texture of the hippocampus, precuneus and posterior cingulate cortex using a grey-level co-occurrence matrix. We constructed texture and volume indices from the development data set using logistic regression. Using area under the curve (AUC) of receiver operator characteristics, we compared the accuracy of hippocampal volume, hippocampal texture and the composite texture of the hippocampus, precuneus and posterior cingulate cortex in predicting conversion from MCI to Alzheimer disease in the validation data set.

Results: Compared with hippocampal volume, hippocampal texture (0.790 v. 0.739, p = 0.047) and composite texture (0.811 v. 0.739, p = 0.007) showed larger AUCs for conversion to Alzheimer disease from both early and late MCI. Hippocampal texture showed a marginally larger AUC than hippocampal volume in early MCI (0.795 v. 0.726, p = 0.060). Composite texture showed a larger AUC for conversion to Alzheimer disease than hippocampal volume in both early (0.817 v. 0.726, p = 0.027) and late MCI (0.805 v. 0.753, p = 0.019).

Limitations: This study was limited by the absence of histological data, and the pathology reflected by the texture measures remains to be validated.

Conclusion: Textures of the hippocampus, precuneus and posterior cingulate cortex predicted conversion from MCI to Alzheimer disease at an earlier time point and with higher accuracy than hippocampal volume.

RevDate: 2019-06-21

Ospina-Romero M, Abdiwahab E, Kobayashi L, et al (2019)

Rate of Memory Change Before and After Cancer Diagnosis.

JAMA network open, 2(6):e196160 pii:2736177.

Importance: Patients with a history of cancer, even nonfatal cancers, have lower subsequent Alzheimer disease incidence. An inverse biological link between carcinogenesis and neurodegeneration has been hypothesized, although survival and detection biases are possible explanations.

Objective: To compare long-term memory trajectories before and after incident cancer with memory trajectories of similarly aged individuals not diagnosed with cancer.

This population-based cohort study included 14 583 US adults born before 1949 with no cancer history from the Health and Retirement Study. Biennial assessments were performed for up to 16 years from 1998 to 2014. Data analysis was performed from January 8 to October 5, 2018.

Exposures: Self-reported physician diagnosis of any cancer (excluding nonmelanoma skin cancer) during follow-up.

Main Outcomes and Measures: A composite memory score standardized to a mean (SD) of 0 (1) at baseline was based on immediate and delayed word-list recall and proxy assessments. The rate of memory change among people diagnosed with cancer during follow-up before and after diagnosis was compared with rate of memory change in individuals who remained cancer free during follow-up using linear mixed-effect models with random intercepts and slopes.

Results: A total of 14 583 participants were included in the sample (mean [SD] age, 66.4 [10.4] years; 8453 [58.0%] female). The mean (SD) follow-up was 11.5 (5.1) years; 2250 had a cancer diagnosis during follow-up, and 12 333 had no cancer diagnosis during follow-up. The rate of memory decline in the decade before a cancer diagnosis was 10.5% (95% CI, 6.2%-14.9%), which was slower than memory decline in similarly aged cancer-free individuals. For individuals diagnosed at 75 years of age, mean memory function immediately before diagnosis was 0.096 SD units (95% CI, 0.060-0.133 SD units) higher compared with that among similarly aged cancer-free individuals. A new cancer diagnosis was associated with a short-term decline in memory of -0.058 (95% CI, -0.084 to -0.032) SD units compared with memory before diagnosis. After diagnosis, the rate of memory decline was 3.9% (95% CI, 0.9%-6.9%) slower in individuals with cancer than in those without a cancer diagnosis.

Conclusions and Relevance: In this study, older individuals who developed cancer had better memory and slower memory decline than did similarly aged individuals who remained cancer free. These findings support the possibility of a common pathologic process working in opposite directions in cancer and Alzheimer disease.

RevDate: 2019-06-21

Zsido RG, Heinrich M, Slavich GM, et al (2019)

Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults.

JAMA network open, 2(6):e196126 pii:2736176.

Importance: Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss.

Objectives: To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure.

Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 2018.

Exposures: Serum estradiol levels from fasting blood and visceral adipose tissue volume from T1-weighted magnetic resonance imaging (MRI).

Main Outcomes and Measures: Brain network covariance (individual loading on structural network derived from T1-weighted MRI) and memory performance (composite score from the Consortium to Establish a Registry for Alzheimer Disease [CERAD] verbal episodic memory test on learning [score range, 0-30], recall [score range, 0-10], and recognition [score range, 0-20]).

Results: Final analyses included data from 473 women (mean [SD] age, 50.10 [15.63] years) and 501 men (mean [SD] age, 51.24 [15.67] years). Visceral adipose tissue was associated with an exacerbation of the negative association of aging with network covariance for women (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P = .001) and men (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P < .001). Estradiol level was associated with a reduction in the negative association of VAT with network covariance in women (interaction term β = 0.63; 95% bias-corrected bootstrap CI, 0.14-1.12; P = .01), with no significant association in men. In the female midlife subgroup (age range, 35-55 years, when menopause transition occurs), low estradiol levels were associated with lower memory network covariance (Cohen d = 0.61; t80 = 2.76; P = .007) and worse memory performance (Cohen d = 0.63; t76 = 2.76; P = .007).

Conclusions and Relevance: This study reports a novel association between VAT, estradiol, and structural brain networks as a potential mechanism underlying cognitive decline in women. These findings appear to highlight the need for sex-specific strategies, including VAT and hormonal screening during midlife, to support healthy cognitive aging.

RevDate: 2019-06-21

Okereke OI, ME Meadows (2019)

More Evidence of an Inverse Association Between Cancer and Alzheimer Disease.

JAMA network open, 2(6):e196167 pii:2736171.

RevDate: 2019-06-21

Steiner H, Fukumori A, Tagami S, et al (2018)

Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase.

Cell stress, 2(11):292-310 pii:CST0178E137.

Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we review recent breakthroughs in our understanding of how the γ-secretase complex recognizes substrates, of how it binds and processes β-secretase cleaved APP into different Aβ species, as well as the progress made on a question of outstanding interest, namely how clinical AD mutations in the catalytic subunit presenilin and the γ-secretase cleavage region of APP lead to relative increases of Aβ42/43. Finally, we discuss how the knowledge emerging from these studies could be used to therapeutically target this enzyme in a safe way.

RevDate: 2019-06-21

Gouskova N, Bichsel A, Dodge H, et al (2019)

Blood-based Nutritional Risk Index for Cognition in the Nutrition and Brain Aging Study (NBAS): Emphasis on n-3 PUFA, Vitamin D and Homocysteine (P14-005-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz052.P14-005-19.

Objectives: Nutrients and their metabolites have interactive qualities that may be harnessed for prevention of cognitive decline. Simultaneous modulation of one-carbon, fatty acid and vitamin D metabolism (25-OH-D) may offer neuroprotection. We examined whether n-3 polyunsaturated fatty acids (n-3 PUFA), 25-OH-D, and homocysteine (HCy) formed into a Nutritional Risk Index (NRI) can explain cognitive performance of older non-demented adults.

Methods: The NBAS enrolled older participants from the NIA-Layton Oregon Alzheimer's Disease Center aging studies with serum samples available yielding 306 cognitively characterized older adults. Plasma fatty acids were quantified by GC-FID and 25-hydroxyvitamin D and homocysteine by LC-MS/MS. Nutritional risk defined as population nutrient biomarker tertiles with NRI calculated as the number of nutrient biomarkers meeting a sub-optimum criterion with scores ranging from 0 to 3. Global and domain specific cognitive z-scores were fit with multivariate linear regression models and NRI as the primary exposure of interest.

Results: Mean age was 85.8 (7.6) years, MMSE was 27.8 (2.8) and 70% were female. Sixty-five % met criteria for 'nutritional risk' (NRI ³ 1: 193/293). Participants with optimum nutritional status exhibited superior global cognitive performance (NRI-0: mean global z-score ± SE = 0.10 ± 0.097) while each addition NRI point score associated with an incremental decrease in cognitive performance (NRI-1: 0.02 ± 0.09; NRI-2: -0.23 ± 0.13; NRI-3: -0.53 ± 0.19, P for trend = 0.002). Significant and similar trends were seen in specific cognitive domains, including attention (NRI-0: mean z-score ± SE = 0.20 ± 0.11; NRI-1: 0.02 ± 0.10; NRI-2: -0.32 ± 0.13; NRI-3: -0.38 ± 0.19, P for trend < 0.001) and executive function (NRI-0: mean z-score ± SE = 0.15 ± 0.10; NRI-1: -0.09 ± 0.10; NRI-2: -0.15 ± 0.13; NRI-3: -0.55 ± 0.20, P for trend = 0.002).

Conclusions: The Nutritional Risk Index representing plasma n-3 PUFA, 25-OH-D and HCy explains significant variance in the cognitive performance of older adults, particularly attention and executive skills. These results in exceptionally healthy older adults suggest that cognitive performance is superior in those with plasma EPA + DHA wt% ≥ 2.53, 25-OH-D ≥ 25 ng/ml, and HCy < 11.57 umol/L.

Funding Sources: Nestle Institute of Health Sciences, Hinda and Arthur Marcus Institute for Aging Research, NIA-Layton Aging & Alzheimer Disease Center, Department of Veterans Affairs.

RevDate: 2019-06-21

Feng Q, Luo Y, Zhang XN, et al (2019)

MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration.

Autophagy [Epub ahead of print].

Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.

RevDate: 2019-06-21

Pohanka M (2019)

Copper and copper nanoparticles toxicity and their impact on basic functions in the body.

Bratislavske lekarske listy, 120(6):397-409.

Copper is a biogenic metal having multiple functions in basic processes in organisms and it is common in all kingdoms of life. Limited intake of copper is a problem; however, doses of copper exceeding the recommended alimentary source are problematic as well and toxicity is soon manifested. Impact of copper nanoparticles on human health is another serious issue taken into consideration in this review. Regarding to copper toxicity, neurodegenerative disorders including Alzheimer and Parkinson diseases are suspected to be linked to copper toxicity or copper can contribute to their progression. Wilson and Menke diseases are also described as examples of copper intolerance. This paper is focused on the description, literature survey and discussion of the current knowledge about copper and copper nanoparticles toxicity and their involvement in various pathological processes (Tab. 6, Fig. 2, Ref. 171). Keywords: reactive oxygen species; Alzheimer disease; acetylcholinesterase; copper; Fenton reaction; disorder; heavy metal; pollution; nanoparticle.

RevDate: 2019-06-21

Rodrigues LD, Oliveira LF, Shinoda L, et al (2019)

Cardiovascular alterations in rats with Parkinsonism induced by 6-OHDA and treated with Domperidone.

Scientific reports, 9(1):8965 pii:10.1038/s41598-019-45518-z.

After Alzheimer, Parkinson disease (PD) is the most frequently occurring progressive, degenerative neurological disease. It affects both sympathetic and parasympathetic nervous systems in a variable fashion. Cardiovascular symptoms are present in almost all stages of PD and narrower heart rate variability is the earliest sign. Administration of Levodopa to PD patients has proven to provide some degree of neurological protection. This drug, however, causes side effects including nausea and vomiting, lessened by the administration of domperidone. Autopsies in PD patients led some researchers to suggest the involvement of the ventricular arrhythmia induced by domperidone. The aim of the present study was to determine the impact of the adjusted human maximal dose of domperidone, on cardiological features of Wistar rats. domperidone was administered to both 6-hydroxydopamine Parkinsonism models and regular Wistar rats. Quantitative analysis of ranges of heart beat variation showed significant abnormal distribution in both groups receiving domperidone as compared with respective sham counterparts. However, qualitative analysis of Poincaré plots showed that 6-hydroxydopamine Parkinsonism models receiving domperidone had the narrowest full range of heart beat and the worst distribution heart beat ranges as compared with all study groups corroborating with previous suggestion that domperidone administration to PD patients is likely to play a role in sudden unexpected death in this group of patients.

RevDate: 2019-06-21

Paterson RW, Gabelle A, Lucey BP, et al (2019)

SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.

Nature reviews. Neurology pii:10.1038/s41582-019-0222-0 [Epub ahead of print].

Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics (SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.

RevDate: 2019-06-21

Salcher-Konrad M, Naci H, McDaid D, et al (2019)

Effectiveness of interventions for dementia in low- and middle-income countries: protocol for a systematic review, pairwise and network meta-analysis.

BMJ open, 9(6):e027851 pii:bmjopen-2018-027851.

INTRODUCTION: There are more people living with dementia in low- and middle-income countries (LMICs) than in high-income countries. Evidence-based interventions to improve the lives of people living with dementia and their carers are needed, but a systematic mapping of methodologically robust studies in LMICs and synthesis of the effectiveness of dementia interventions in these settings is missing.

METHODS AND ANALYSIS: A systematic review and meta-analysis will be conducted to answer the question: Which dementia interventions were shown to be effective in LMICs and how do they compare to each other? Electronic database searches (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, WHO Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit, Cochrane Database of Systematic Reviews) will be complemented by hand searching of reference lists and local knowledge of existing studies from an international network of researchers in dementia from LMICs. Studies will be eligible for inclusion if they were published between 2008 and 2018, conducted in LMICs and evaluated the effectiveness of a dementia intervention using a study design that supports causal inference of the treatment effect. We will include both randomised and non-randomised studies due to an anticipated low number of well-conducted randomised trials in LMICs and potentially greater external validity of non-randomised studies conducted in routine care settings. In addition to narrative synthesis of the interventions, feasibility of pairwise and network meta-analyses will be explored to obtain pooled effects of relative treatment effects.

ETHICS AND DISSEMINATION: Secondary analysis of published studies, therefore no ethics approval required. Planned dissemination channels include a peer-reviewed publication as well as a website, DVD and evidence summaries.


RevDate: 2019-06-21

Ahlgrim NS, Garza K, Hoffman C, et al (2019)

Prodromes and Preclinical Detection of Brain Diseases: Surveying the Ethical Landscape of Predicting Brain Health.

eNeuro pii:ENEURO.0439-18.2019 [Epub ahead of print].

The future of medicine lies in disease modification and prevention. The science of preclinical detection is young, but moving rapidly. Preclinical interventions offer the hope to decrease the severity of a disease or delay the development of a disorder substantially. With such promise, the research and practice of detecting brain disorders at a preclinical stage present unique ethical challenges, challenges that must be addressed to ensure the benefit of these technologies. Direct brain interventions have potential to impact not just what a patient has but who they are and who they could become. Further receiving an assessment for a preclinical or prodromal state has potential to impact perceptions about capacity, autonomy and personhood and could become entangled with stigma and discrimination. Discussion of the risks and benefits of the emerging technology will focus on how to ensure beneficence by presenting the limitations of preclinical detection and by contextualizing the risk associated with preclinical status. Exploring ethical issues alongside and integrated into the experimental design and research of these technologies is critical. This review will highlight ethical issues attendant to the current and near future states of preclinical detection across the life span, specifically as it relates to autism spectrum disorder (ASD), schizophrenia, and Alzheimer's disease.Significance Statement Preclinical interventions in developing brain disorders offer the strongest promise of delaying, modifying, or preventing the development of clinical disorders. Although promising, intervening at early stages in disorders inherently linked to identity and personhood presents unique ethical challenges. These challenges must be addressed before the practices are implemented. Both the treatment and the diagnosis itself have the potential to profoundly impact patients. We contextualize the risk of diagnosing preclinical states and present the limitations of preclinical interventions to guide research and policy as the field of preclinical detection rapidly expands.

RevDate: 2019-06-21

Contarini G, Franceschini D, Facci L, et al (2019)

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis.

Journal of neuroinflammation, 16(1):126 pii:10.1186/s12974-019-1514-4.

BACKGROUND: Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models.

METHODS: The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs).

RESULTS: Vehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1β, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice.

CONCLUSIONS: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors.

RevDate: 2019-06-21

Eratne D, Loi SM, Walia N, et al (2019)

A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists?.

The Australian and New Zealand journal of psychiatry [Epub ahead of print].

OBJECTIVE: Neurofilament light has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid neurofilament light in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for psychiatrists and neurologists.

METHODS: This cross-sectional retrospective pilot study assessed cerebrospinal fluid neurofilament light on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, where a neurodegenerative disorder was a differential diagnosis, who received lumbar punctures as part of a comprehensive workup. The most recent gold-standard clinical consensus diagnosis was categorised into psychiatric disorder or neurodegenerative or neurological disorder. Data from healthy controls were available for comparison. Data extraction and diagnostic categorisation was blinded to neurofilament light results.

RESULTS: A total of 129 participants were included: 77 neurodegenerative or neurological disorder (mean age 57 years, including Alzheimer's dementia, frontotemporal dementia), 31 psychiatric disorder (mean age 51 years, including schizophrenia, major depressive disorder) and 21 healthy controls (mean age 66 years). Neurofilament light was significantly higher in neurodegenerative or neurological disorder (M = 3560 pg/mL, 95% confidence intervals = [2918, 4601]) compared to psychiatric disorder (M = 949 pg/mL, 95% confidence intervals = [830, 1108]) and controls (M = 1036 pg/mL, 95% confidence intervals = [908, 1165]). Neurofilament light distinguished neurodegenerative or neurological disorder from psychiatric disorder with an area under the curve of 0.94 (95% confidence intervals = [0.89, 0.98]); a cut-off of 1332 pg/mL was associated with 87% sensitivity and 90% specificity.

CONCLUSION: Cerebrospinal fluid neurofilament light shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma neurofilament light.

RevDate: 2019-06-20

Chen C, Xia S, He J, et al (2019)

Roles of taurine in cognitive function of physiology, pathologies and toxication.

Life sciences pii:S0024-3205(19)30510-7 [Epub ahead of print].

Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.

RevDate: 2019-06-20

Gao S, Burney HN, Callahan CM, et al (2019)

Incidence of Dementia and Alzheimer Disease Over Time: A Meta-Analysis.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: Population-based incidence estimates of dementia and Alzheimer disease (AD) provide important information for public health policy and resource allocation. We conducted a meta-analysis of published studies that reported age-specific incidence rates of dementia and AD to determine whether dementia and AD incidence rates are changing over time.

DESIGN: PubMed and MEDLINE were searched for publications through June 30, 2017, using key words "dementia", "Alzheimer", and "incidence." Inclusion criteria for the meta-analysis are: (1) population-based studies using personal interviews and direct examinations of the study subjects, (2) standardized clinical diagnosis criteria, (3) reporting age-specific incidence rates, (4) published in English, and (5) sample size of 500 or greater and length of follow-up of 2 years or greater. Mixed-effects models were used to determine the association between birth year and incidence rates.

MEASUREMENTS: Age-specific dementia/AD incidence rates and their standard errors reported in each study.

RESULTS: Thirty-eight articles with 53 cohorts on dementia incidence and 31 articles with 35 cohorts on AD incidence met the inclusion criteria. There were significant associations between later birth years and decreased dementia incidence rates in all three age groups (65-74, 75-84, and 85 years and older). There were no significant associations between birth year and AD incident rates in any of the three age groups. In particular, AD incidence rates reported from Western countries stayed steady in all age groups, while studies in non-Western countries showed significantly increased AD incidence rates for the 65 to 74 years age group (odds ratio = 2.78; P = .04), but a nonsignificant association for the 75 to 84 or 85 years and older groups.

CONCLUSION: Dementia incidence declined over the past four decades, but AD incidence did not decline. Further research, especially from non-Western countries, is needed to elucidate the mechanism underlying the trends in dementia and AD incidence over time.

RevDate: 2019-06-20

Esquiva G, J Hannibal (2019)

Melanopsin-expressing retinal ganglion cells in aging and disease.

Histology and histopathology pii:HH-18-138 [Epub ahead of print].

Melanopsin-expressing retinal ganglion cells (mRGCs) constitute a system in the mammalian retina used for irradiance detection, regulating non-image forming functions, such as photoentrainment of circadian rhythms, control of the pupillary light reflex, masking response, light-regulated melatonin secretion, and modulation of the sleep/wake cycle. There are five subtypes of mRGCs differentiated by morphology and function. Recent years of research on mRGCs have identified a broad number of neurodegenerative diseases in the eye and the brain with altered physiologic light responses, leading to disturbances of non-image forming light response(s). In this review, we briefly summarise the melanopsin system in the normal retina and discuss its role in connection to human aging (sleep/wake problems) and retinal pathology in Alzheimer and Parkinson diseases, diabetic retinopathy, mitochondrial optic neuropathies, glaucoma, retinitis pigmentosa, and in photophobia during migraine and in seasonal affective disorder (SAD). Finally, we discuss the diagnostic tools that are being used to differentiate retinal diseases involving the melanopsin system in the rods and cones from the inner versus the outer retina.

RevDate: 2019-06-20

Goldman JS, Hahn SE, Catania JW, et al (2019)

ADDENDUM: Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.

Genetics in medicine : official journal of the American College of Medical Genetics pii:10.1038/s41436-019-0559-1 [Epub ahead of print].

RevDate: 2019-06-20

Giudici KV, Guyonnet S, Rolland Y, et al (2019)

Body Weight Variation Patterns as Predictors of Cognitive Decline over a 5 Year Follow-Up among Community-Dwelling Elderly (MAPT Study).

Nutrients, 11(6): pii:nu11061371.

This study aimed to analyze associations between weight variation patterns and changes in cognitive function and hippocampal volume among non-demented, community-dwelling elderly. Sample was formed of 1394 adults >70 years (63.9% female), all volunteers from the Multidomain Alzheimer Preventive Trial (MAPT). Weight loss was defined as ≥5% of body weight decrease in the first year of follow-up; weight gain as ≥5% of weight increase; and stability if <5% weight variation. Cognition was examined by a Z-score combining four tests. Measures were assessed at baseline, 6, 12, 24, 36, 48, and 60 months of follow-up. Hippocampal volume was evaluated with magnetic resonance imaging in 349 subjects in the first year and at 36 months. Mixed models were performed. From the 1394 participants, 5.5% (n = 76) presented weight loss, and 9.0% (n = 125) presented weight gain. Cognitive Z-score decreased among all groups after 5 years, but decline was more pronounced among those who presented weight loss (adjusted between-group mean difference vs. stable: -0.24, 95%CI: -0.41 to -0.07; p = 0.006). After 3 years, hippocampal atrophy was observed among all groups, but no between-group differences were found. In conclusion, weight loss ≥5% in the first year predicted higher cognitive decline over a 5 year follow-up among community-dwelling elderly, independently of body mass index.

RevDate: 2019-06-12

Glachet O, M El Haj (2019)

Emotional and Phenomenological Properties of Odor-Evoked Autobiographical Memories in Alzheimer's Disease.

Brain sciences, 9(6): pii:brainsci9060135.

Autobiographical memory, which contains all personal memories relative to our identity, has been found to be impaired in Alzheimer' Disease (AD). Recent research has demonstrated that odor may serve as a powerful cue for the recovery of autobiographical memories in AD. Building on this research, we investigated emotional characteristics (arousal and valence) and subjective reliving of odor-evoked autobiographical memories in AD. We also investigated the relationship between these characteristics and depression. To this end, we invited participants with mild AD and controls to retrieve autobiographical memories after odor exposure or without odor. Results showed higher arousal, subjective reliving and more positive memories after odor exposure compared with the odor-free condition, these differences being observed only in AD participants. We also found that emotion (arousal and valence) and subjective reliving triggered by odor were associated with depressive symptoms in AD. These findings demonstrate that odor may be a useful cue to trigger more detailed, vivid and positive events in AD.

RevDate: 2019-06-19

Helgadottir HT, Lundin P, Wallén Arzt E, et al (2019)

Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient.

Human molecular genetics pii:5479259 [Epub ahead of print].

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.

RevDate: 2019-06-19

Panda SS, N Jhanji (2019)

Natural Products as Potential anti-Alzheimer Agents.

Current medicinal chemistry pii:CMC-EPUB-98945 [Epub ahead of print].

Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary metabolites in one or more parts of the plant. The diverse secondary metabolites play an important role in the prevention and cure of various diseases including neurodegenerative diseases like Alzheimer's disease. Naturally occurring compounds such as flavonoids, polyphenols, alkaloids, and glycosides found in various parts of the plant and/or marine sources may potentially protect neurodegeneration as well as improve memory and cognitive function. Many natural compounds show anti-Alzheimer activity through specific pharmacological mechanisms like targeting β-amyloid, Beta-secretase 1 and Acetylcholinesterase. In this review, we have compiled more than 130 natural products with a broad diversity in the class of compounds were isolated from different sources showing anti-Alzheimer properties.

RevDate: 2019-06-19

Jiménez-Pavón D, Carbonell-Baeza A, CJ Lavie (2019)

Promoting the Assessment of Physical Activity and Cardiorespiratory Fitness in Assessing the Role of Vascular Risk on Cognitive Decline in Older Adults.

Frontiers in physiology, 10:670.

RevDate: 2019-06-19

Marquié M, Castilla-Martí M, Valero S, et al (2019)

Visual impairment in aging and cognitive decline: experience in a Memory Clinic.

Scientific reports, 9(1):8698 pii:10.1038/s41598-019-45055-9.

Visual impairment is common in people living with dementia and regular ophthalmological exams may improve their quality of life. We evaluated visual function in a cohort of elderly individuals and analyzed its association with their degree of cognitive impairment. Participants underwent neurological and neuropsychological exams, neuro-ophthalmological assessment (visual acuity, intraocular pressure, rates of past ophthalmological pathologies, use of ocular correction, treatments and surgeries) and optical coherence tomography (OCT) scan. We analyzed differences in ophthalmological characteristics among diagnostic groups. The final sample of 1746 study participants aged ≥ 50 comprised 229 individuals with Subjective Cognitive Decline (SCD), 695 with mild cognitive impairment (MCI) and 833 with Dementia (Alzheimer disease: n = 660; vascular dementia: n = 92, Lewy body dementia: n = 34; frontotemporal dementia: n = 19 and other: n = 28). Age, gender and education were used as covariates. Patients with Dementia, compared to those with SCD and MCI, presented worse visual acuity (p < 0.001), used less visual correction (p = 0.02 and p < 0.001, respectively) and fewer ophthalmological treatments (p = 0.004 and p < 0.001, respectively) and underwent fewer ocular surgeries (p = 0.009 and p < 0.001, respectively). OCT image quality worsened in parallel to cognitive decline (Dementia vs SCD: p = 0.008; Dementia vs MCI: p < 0.001). No group differences in past ophthalmological disorders or abnormal OCT findings were detected. Efforts should be made to ensure dementia patients undergo regular ophthalmological assessments to correct their visual function in order to improve their quality of life.

RevDate: 2019-06-19

Ceccariglia S, Cargnoni A, Silini AR, et al (2019)

Autophagy: a potential key contributor to the therapeutic action of mesenchymal stem cells.

Autophagy [Epub ahead of print].

Macroautophagy/autophagy occurs at basal levels in all eukaryotic cells and plays an important role in maintaining bio-energetic homeostasis through the control of molecule degradation and organelle turnover. It can be induced by environmental conditions such as starvation, and is deregulated in many diseases including autoimmune diseases, neurodegenerative disorders, and cancer. Interestingly, the modulation of autophagy in mesenchymal stem cells (MSCs) represents a possible mechanism which, affecting MSC properties, may have an impact on their regenerative, therapeutic potential. Furthermore, the ability of MSCs to modulate autophagy of cells in injured tissues/organs has been recently proposed to be involved in the regeneration of damaged tissues and organs. In particular, MSCs can affect autophagy in immune cells involved in injury-induced inflammation reducing their survival, proliferation, and function and favoring the resolution of inflammation. In addition, MSCs can affect autophagy in endogenous adult or progenitor cells, promoting their survival, proliferation and differentiation supporting the restoration of functional tissue. This review provides, for the first time, an overview of the studies which highlight a possible link between the therapeutic properties of MSCs and their ability to modulate autophagy, and it summarizes examples of disorders where these therapeutic properties have been correlated with such modulation. A better elucidation of the mechanism(s) through which MSCs can modulate the autophagy of target cells and how autophagy can affect MSCs therapeutic properties, can provide a wider perspective for the clinical application of MSCs in the treatment of many diseases. Abbreviations: 3-MA: 3-methyladenine; AD: Alzheimer disease; ATG: autophagy-related; BECN1: beclin 1; BM: bone marrow; CD: cluster of differentiation; EAE: experimental autoimmune encephalomyelitis; IL: interleukin; INF: interferon; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MSCs: mesenchymal stem cells; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson disease; PtdIns3K: class III phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; TBI: traumatic brain injury; TGF: transforming growth factor; TNF: tumor necrosis factor.

RevDate: 2019-06-18

Kim D, Yang PS, Yu HT, et al (2019)

Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a population-based cohort.

European heart journal pii:5520105 [Epub ahead of print].

AIMS: Atrial fibrillation (AF) is generally regarded as a risk factor for dementia, though longitudinal studies assessing the association between AF and dementia have shown inconsistent results. This study aimed to determine the effect of AF on the risk of developing dementia using a longitudinal, community-based, and stroke-free elderly cohort.

METHODS AND RESULTS: The association of incident AF with the development of incident dementia was assessed from 2005 to 2012 in 262 611 dementia- and stroke-free participants aged ≥60 years in the Korea National Health Insurance Service-Senior cohort. Incident AF was observed in 10 435 participants over an observational period of 1 629 903 person-years (0.64%/year). During the observational period, the incidence of dementia was 4.1 and 2.7 per 100 person-years in the incident AF and propensity score-matched AF-free groups, respectively. After adjustment, the risk of dementia was significantly increased by incident AF with a hazard ratio (HR) of 1.52 [95% confidence interval (CI) 1.43-1.63], even after censoring for stroke (1.27, 95% CI 1.18-1.37). Incident AF increased the risk of both Alzheimer (HR 1.31, 95% CI 1.20-1.43) and vascular dementia (HR 2.11, 95% CI 1.85-2.41). Among patients with incident AF, oral anticoagulant use was associated with a preventive effect on dementia development (HR 0.61, 95% CI 0.54-0.68), and an increasing CHA2DS2-VASc score was associated with a higher risk of dementia.

CONCLUSION: Incident AF was associated with an increased risk of dementia, independent of clinical stroke in an elderly population. Oral anticoagulant use was linked with a decreased incidence of dementia.

RevDate: 2019-06-18

Cheah IK, Ng LT, Ng LF, et al (2019)

Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model.

FEBS letters [Epub ahead of print].

The abnormal accumulation of β-amyloid peptide (Aβ) is recognized as a central component in the pathogenesis of Alzheimer disease. While many aspects of Aβ-mediated neurotoxicity remain elusive, Aβ has been associated with numerous underlying pathologies, including oxidative and nitrosative stress, inflammation, metal ion imbalance, mitochondrial dysfunction and even tau pathology. Ergothioneine (ET), a naturally occurring thiol/thione-derivative of histidine, has demonstrated antioxidant and neuroprotective properties against various oxidative and neurotoxic stressors. This study investigates ET's potential to counteract Aβ-toxicity in transgenic Caenorhabditis elegans overexpressing a human Aβ peptide. The accumulation of Aβ in this model leads to paralysis and premature death. We show that ET dose-dependently reduces Aβ-oligomerization and extends the lifespan and healthspan of the nematodes. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-18

Jack CR, Wiste HJ, Therneau TM, et al (2019)

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia.

JAMA, 321(23):2316-2325.

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers.

Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information.

Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018.

Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles.

Main Outcomes and Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only.

Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier.

Conclusions and Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.

RevDate: 2019-06-18

Wolk D, Salloway S, B Dickerson (2019)

Putting the New Alzheimer Disease Amyloid, Tau, Neurodegeneration (AT[N]) Diagnostic System to the Test.

JAMA, 321(23):2289-2291.

RevDate: 2019-06-18

Casas-Herrero A, Anton-Rodrigo I, Zambom-Ferraresi F, et al (2019)

Effect of a multicomponent exercise programme (VIVIFRAIL) on functional capacity in frail community elders with cognitive decline: study protocol for a randomized multicentre control trial.

Trials, 20(1):362 pii:10.1186/s13063-019-3426-0.

BACKGROUND: The benefit of physical exercise in ageing and particularly in frailty has been the aim of recent research. Moreover, physical activity in the elderly is associated with a decreased risk of mortality, of common chronic illnesses (i.e. cardiovascular disease or osteoarthritis) and of institutionalization as well as with a delay in functional decline. Additionally, very recent research has shown that, despite its limitations, physical exercise is associated with a reduced risk of dementia, Alzheimer disease or mild cognitive decline. Nevertheless, the effect of physical exercise as a systematic, structured and repetitive type of physical activity, in the reduction of risk of cognitive decline in the elderly, is not very clear. The purpose of this study aims to examine whether an innovative multicomponent exercise programme called VIVIFRAIL has benefits for functional and cognitive status among pre-frail/frail patients with mild cognitive impairment or dementia.

METHODS/DESIGN: This study is a multicentre randomized clinical trial to be conducted in the outpatient geriatrics clinics of three tertiary hospitals in Spain. Altogether, 240 patients aged 75 years or older being capable of and willing to provide informed consent, with a Barthel Index ≥ 60 and mild cognitive impairment or mild dementia, pre-frail or frail and having someone to help to supervise them when conducting the exercises will be randomly assigned to the intervention or control group. Participants randomly assigned to the usual care group will receive normal outpatient care, including physical rehabilitation when needed. The VIVIFRAIL multicomponent exercise intervention programme consists of resistance training, gait re-training and balance training, which appear to be the best strategy for improving gait, balance and strength, as well as reducing the rate of falls in older individuals and consequently maintaining their functional capacity during ageing. The primary endpoint is the change in functional capacity, assessed with the Short Physical Performance Battery (1 point as clinically significant). Secondary endpoints are changes in cognitive and mood status, quality of life (EQ-5D), 6-m gait velocity and changes in gait parameters (i.e. gait velocity and gait variability) while performing a dual-task test (verbal and counting), handgrip, maximal strength and power of the lower limbs as well as Barthel Index of independence (5 points as clinically significant) at baseline and at the 1-month and 3-month follow-up.

DISCUSSION: Frailty and cognitive impairment are two very common geriatric syndromes in elderly patients and are frequently related and overlapped. Functional decline and disability are major adverse outcomes of these conditions. Exercise is a potential intervention for both syndromes. If our hypothesis is correct, the relevance of this project is that the results can contribute to understanding that an individualized multicomponent exercise programme (VIVIFRAIL) for frail elderly patients with cognitive impairment is more effective in reducing functional and cognitive impairment than conventional care. Moreover, our study may be able to show that an innovative individualized multicomponent exercise prescription for these high-risk populations is plausible, having at least similar therapeutic effects to other pharmacological and medical prescriptions.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03657940 . Registered on 5 September 2018.

RevDate: 2019-06-18

Lillo-Crespo M, Forner-Ruiz M, Riquelme-Galindo J, et al (2019)

Chess Practice as a Protective Factor in Dementia.

International journal of environmental research and public health, 16(12): pii:ijerph16122116.

BACKGROUND: dementia is one of the main causes of disability and dependency among the older population worldwide, producing physical, psychological, social and economic impact in those affected, caregivers, families and societies. However, little is known about dementia protective factors and their potential benefits against disease decline in the diagnosed population. Cognitive stimulating activities seem to be protective factors against dementia, though there is paucity in the scientific evidence confirming this, with most publications focusing on prevention in non-diagnosed people. A scoping review was conducted to explore whether chess practice could mitigate signs, deliver benefits, or improve cognitive capacities of individuals diagnosed with dementia through the available literature, and therefore act as a protective factor.

METHODS: twenty-one articles were selected after applying inclusion and exclusion criteria.

RESULTS: the overall findings stress that chess could lead to prevention in non-diagnosed populations, while little has been shown with respect to individuals already diagnosed. However, some authors suggest its capacity as a protective factor due to its benefits, and the evidence related to the cognitive functions associated with the game.

CONCLUSION: although chess is indirectly assumed to be a protective factor due to its cognitive benefits, more studies are required to demonstrate, with strong evidence, whether chess could be a protective factor against dementia within the diagnosed population.

RevDate: 2019-06-17

Segalas C, Amieva H, H Jacqmin-Gadda (2019)

A hypothesis testing procedure for random changepoint mixed models.

Statistics in medicine [Epub ahead of print].

In biomedical research, random changepoint mixed models are used to take into account an individual breakpoint in a biomarker trajectory. This may be observed in the cognitive decline measured by psychometric tests in the prediagnosis phase of Alzheimer's disease. The existence, intensity and duration of this accelerated decline can depend on individual characteristics. The main objective of our work is to propose inferential methods to assess the existence of this phase of accelerated decline, ie, the existence of a random changepoint. To do so, we use a mixed model with two linear phases and test the nullity of the parameter measuring the difference of slopes between the two phases. Because we face the issue of nuisance parameters being unidentifiable under the null hypothesis, the supremum of the classic score test statistic on these parameters is used. The asymptotic distribution of the supremum under the null is approached with a perturbation method based on the multiplier bootstrap. The performance of our testing procedure is assessed via simulations and the test is applied to the French cohort PAQUID of elderly subjects to study the shape of the prediagnosis decline according to educational level. The test is significant for both educational levels and the estimated trajectories confirmed that educational level is a good marker for cognitive reserve.

RevDate: 2019-06-17

Bridel C, van Wieringen WN, Zetterberg H, et al (2019)

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.

JAMA neurology pii:2735955 [Epub ahead of print].

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses.

Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

RevDate: 2019-06-17

Duong MT (2019)

The Art of Caregiving: Lessons in Alzheimer Disease.

JAMA neurology pii:2735957 [Epub ahead of print].

RevDate: 2019-06-17

Chen Y, Wang JY, Liu XY, et al (2019)

Sleep quality of spousal caregivers is associated with neuropsychiatric symptoms and living ability of patients with Alzheimer disease.

Chinese medical journal, 132(12):1490-1493.

RevDate: 2019-06-17

Chen XQ, Qiu K, Liu H, et al (2019)

Application and prospects of butylphthalide for the treatment of neurologic diseases.

Chinese medical journal, 132(12):1467-1477.

OBJECTIVE: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized.

DATA SOURCES: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis."

STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files.

RESULTS: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects.

CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.

RevDate: 2019-06-17

de Jong DLK, de Heus RAA, Rijpma A, et al (2019)

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Hypertension (Dallas, Tex. : 1979) [Epub ahead of print].

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

RevDate: 2019-06-17

Kishita N, Backhouse T, E Mioshi (2019)

Nonpharmacological Interventions to Improve Depression, Anxiety, and Quality of Life (QoL) in People With Dementia: An Overview of Systematic Reviews.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

This overview aimed to systematically synthesize evidence from existing systematic reviews to signpost practitioners to the current evidence base on nonpharmacological interventions to improve depression, anxiety, and quality of life (QoL) in people with dementia and to discuss priorities for future research. The databases MEDLINE, PsycINFO, Scopus, and Cochrane Central Register of Controlled Trials were searched in August 2017 with an updated search in January 2019. Fourteen systematic reviews of randomized controlled trials of nonpharmacological interventions were identified. Dementia stage was rated moderate or severe in the majority of the reviews and type of dementia varied. Interventions reported to be effective were cognitive stimulation (QoL: standardized mean difference [SMD] = 0.38), music-based therapeutic interventions (depression: SMD = -0.27, anxiety: SMD = -0.43, QoL: SMD = 0.32), and psychological treatments (mainly cognitive behavior therapy; depression: SMD = -0.22, anxiety: MD = -4.57). Although health-care professionals are recommended to continue using these approaches, future research needs to focus on the type and form of interventions that are most effective for different stages and types of dementia.

RevDate: 2019-06-17

Ziegler GC, Haarmann A, Daniels C, et al (2019)

The Difficult Diagnosis of Posterior Cortical Atrophy in a 62-Year-Old Woman.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

Posterior cortical atrophy (PCA) describes a rare heterogenous neurodegenerative syndrome with early visuospatial and visuoperceptual deficits due to atrophy of parieto-occipital brain regions. Here, we describe the case of a 62-year-old woman showing severe cognitive impairments as well as hemianopsia and all core symptoms of Bálint's syndrome. Years ago, the patient had complained about a "tunnel view" and concentration problems. The diagnostic results point to a case of PCA with underlying Alzheimer pathology. The disease course until diagnosis lasted for 7 years, reflecting the diagnostic difficulties with this still largely unknown syndrome. The unfamiliar symptom presentation including fluctuations in cognitive performance, affective symptoms, cerebrospinal fluid (CSF) biomarkers, which were at first inconspicuous, and a former suspected diagnosis of dissociative pseudodementia, altogether brought considerable uncertainty to the involved health-care professionals. We conclude that cases of "atypical dementia" presenting with visual symptoms, even if appearing unspecific at first, are suspect of PCA. This case report provides an ostensive overview of PCA, including imaging data, CSF-findings, original drawings and handwriting samples from the patient.

RevDate: 2019-06-16

Mittal K, Eremenko E, Berner O, et al (2019)

CD4 T Cells Induce A Subset of MHCII-Expressing Microglia that Attenuates Alzheimer Pathology.

iScience, 16:298-311 pii:S2589-0042(19)30176-2 [Epub ahead of print].

Microglia play a key role in innate immunity in Alzheimer disease (AD), but their role as antigen-presenting cells is as yet unclear. Here we found that amyloid β peptide (Aβ)-specific T helper 1 (Aβ-Th1 cells) T cells polarized to secrete interferon-γ and intracerebroventricularly (ICV) injected to the 5XFAD mouse model of AD induced the differentiation of major histocompatibility complex class II (MHCII)+ microglia with distinct morphology and enhanced plaque clearance capacity than MHCII- microglia. Notably, 5XFAD mice lacking MHCII exhibited an enhanced amyloid pathology in the brain along with exacerbated innate inflammation and reduced phagocytic capacity. Using a bone marrow chimera mouse model, we showed that infiltrating macrophages did not differentiate to MHCII+ cells following ICV injection of Aβ-Th1 cells and did not support T cell-mediated amyloid clearance. Overall, we demonstrate that CD4 T cells induce a P2ry12+ MHCII+ subset of microglia, which play a key role in T cell-mediated effector functions that abrogate AD-like pathology.

RevDate: 2019-06-16

Kurth S, Bahri MA, Collette F, et al (2019)

Alzheimer's disease patients activate attention networks in a short-term memory task.

NeuroImage. Clinical, 23:101892 pii:S2213-1582(19)30242-6 [Epub ahead of print].

Network functioning during cognitive tasks is of major interest in Alzheimer's disease (AD). Cognitive functioning in AD includes variable performance in short-term memory (STM). In most studies, the verbal STM functioning in AD patients has been interpreted within the phonological loop subsystem of Baddeley's working memory model. An alternative account considers that domain-general attentional processes explain the involvement of frontoparietal networks in verbal STM beside the functioning of modality-specific subsystems. In this study, we assessed the functional integrity of the dorsal attention network (involved in task-related attention) and the ventral attention network (involved in stimulus-driven attention) by varying attentional control demands in a STM task. Thirty-five AD patients and twenty controls in the seventies performed an fMRI STM task. Variation in load (five versus two items) allowed the dorsal (DAN) and ventral attention networks (VAN) to be studied. ANOVA revealed that performance decreased with increased load in both groups. AD patients performed slightly worse than controls, but accuracy remained above 70% in all patients. Statistical analysis of fMRI brain images revealed DAN activation for high load in both groups. There was no between-group difference or common activation for low compared to high load conditions. Psychophysiological interaction showed a negative relationship between the DAN and the VAN for high versus low load conditions in patients. In conclusion, the DAN remained activated and connected to the VAN in mild AD patients who succeeded in performing an fMRI verbal STM task. DAN was necessary for the task, but not sufficient to reach normal performance. Slightly lower performance in early AD patients compared to controls might be related to maintained bottom-up attention to distractors, to decrease in executive functions, to impaired phonological processing or to reduced capacity in serial order processing.

RevDate: 2019-06-15

Chiaravalloti A, Barbagallo G, Martorana A, et al (2019)

Brain metabolic patterns in patients with suspected non-Alzheimer's pathophysiology (SNAP) and Alzheimer's disease (AD): is [18F] FDG a specific biomarker in these patients?.

European journal of nuclear medicine and molecular imaging pii:10.1007/s00259-019-04379-4 [Epub ahead of print].

PURPOSE: The present study was conducted to compare the pattern of brain [18F] FDG uptake in suspected non-Alzheimer's pathophysiology (SNAP), AD, and healthy controls using 2-deoxy-2-[18F]fluoroglucose ([18F] FDG) positron emission tomography imaging. Cerebrospinal fluid (CSF) biomarkers amyloid-β1-42 peptide (Aβ1-42) and tau were used in order to differentiate AD from SNAP.

METHODS: The study included 43 newly diagnosed AD patients (female = 23; male = 20) according to the NINCDS-ADRDA criteria, 15 SNAP patients (female = 12; male =3), and a group of 34 healthy subjects that served as the control group (CG), who were found to be normal at neurological evaluation (male = 20; female = 14). A battery of neuropsychological tests was administrated in AD and SNAP subjects; cerebrospinal fluid assay was conducted in both AD and SNAP as well. Brain PET/CT acquisition was started 30 ± 5 min after [18F] FDG injection in all subjects. SPM12 [statistical parametric mapping] implemented in MATLAB 2018a was used for the analysis of PET scans in this study.

RESULTS: As compared to SNAP, AD subjects showed significant hypometabolism in a wide cortical area involving the right frontal, parietal, and temporal lobes. As compared to CG, AD subjects showed a significant reduction in [18F] FDG uptake in the parietal, limbic, and frontal cortex, while a more limited reduction in [18F] FDG uptake in the same areas was found when comparing SNAP to CG.

CONCLUSIONS: SNAP subjects show milder impairment of brain [18F] FDG uptake as compared to AD. The partial overlap of the metabolic pattern between SNAP and AD limits the use of [18F] FDG PET/CT in effectively discriminating these clinical entities.

RevDate: 2019-06-15

Vedel I, Sourial N, Arsenault-Lapierre G, et al (2019)

Impact of the Quebec Alzheimer Plan on the detection and management of Alzheimer disease and other neurocognitive disorders in primary health care: a retrospective study.

CMAJ open, 7(2):E391-E398 pii:7/2/E391.

BACKGROUND: The Quebec Alzheimer Plan aims to improve care provided to patients with neurocognitive disorders in Family Medicine Groups (FMGs) (multidisciplinary team-based primary care practices). The objective of this study was to determine changes in the detection and management of neurocognitive disorders following implementation of the plan, in 2014.

METHODS: This was a retrospective chart review before and after implementation of the Quebec Alzheimer Plan in 13 FMGs. We reviewed 1919 randomly selected charts of patients aged 75 years or more and 945 randomly selected charts of patients in this age group with neurocognitive disorders. In the first group, selected outcomes were proportion of patients with documentation of cognitive status, documented diagnosis of neurocognitive disorder, documented cognitive testing and referral to a memory clinic. In patients with neurocognitive disorders, the outcomes were number of contacts with an FMG, quality of follow-up score (documented assessments in 10 domains: cognitive testing, functional status, behavioural and psychological symptoms of dementia, weight, caregiver needs, driving status, home care needs, community service needs, absence of anticholinergic medication and management of dementia medications) and proportion referred to a memory clinic.

RESULTS: Significantly more patients aged 75 or more had documentation of cognitive status in their chart after plan implementation than before implementation (440 [45.1%] v. 351 [37.2%]) (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.18-1.81). No significant changes were found in documented diagnosis of neurocognitive disorders, cognitive testing or referral to a memory clinic. Among patients with neurocognitive disorders, the number of contacts with an FMG (adjusted mean difference 1.6, 95% CI 0.3-2.8) and quality of follow-up score (adjusted mean difference 6.6, 95% CI 3.9-9.2) increased significantly, without significant changes in the number of referrals to a memory clinic.

INTERPRETATION: The results suggest that the Quebec Alzheimer Plan is feasible and beneficial in terms of detection and management of neurocognitive disorders, without an increase in referral to specialists. The findings will be used to scale up the Quebec Alzheimer Plan and to develop the Canadian federal dementia strategy.

RevDate: 2019-06-14

Wolfe MS (2019)

Structure and Function of the γ-Secretase Complex.

Biochemistry [Epub ahead of print].

γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With over 90 known substrates, the γ-secretase complex is considered "the proteasome of the membrane", with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of substrate multiple times before releasing secreted products. For many years, elucidation of γ-secretase structure and function largely relied on small molecule probes and mutagenesis. Recently however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of γ-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer drug discovery.

RevDate: 2019-06-14

Allison SL, Rodebaugh TL, Johnston C, et al (2019)

Developing a Spatial Navigation Screening Tool Sensitive to the Preclinical Alzheimer Disease Continuum.

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists pii:5518889 [Epub ahead of print].

OBJECTIVE: There remains a need for a non-invasive and cost-effective screening measure that could be administered prior to the provision of a lumbar puncture or positron emission tomography scan for the detection of preclinical Alzheimer disease (AD). Previous findings suggest that a hippocampally-based spatial navigation task may be effective for screening individuals for the preclinical AD continuum (i.e., low cerebrospinal fluid (CSF) Aβ42). Unfortunately, this task took 1.5-2 hours to administer, which would be time-prohibitive in a clinical setting. Therefore, the goal of this study was to compare psychometric properties of six spatial navigation-related tasks in order to take the next steps in developing a clinically appropriate screening measure.

METHODS: Psychometric properties (i.e., reliability, diagnostic accuracy, validity) of a modified version of the cognitive mapping task, two binding tasks, a visual perspective taking task, and self- and informant report versions of a questionnaire were examined in a sample of 91 clinically normal (CN) individuals. CSF Aβ42 and ptau181 were available for 30 individuals.

RESULTS: The learning phase of the cognitive mapping task and the self-report questionnaire were sensitive to identifying individuals in the preclinical AD continuum (93% and 87% sensitivity, 60% and 67% specificity, respectively). These two measures also demonstrated good test-retest stability (intraclass correlation coefficients = .719 and .838, respectively) and internal consistency (Cronbach's αs = .825 and .965, respectively).

CONCLUSIONS: These findings suggest that a self-report questionnaire and aspects of a cognitive mapping task may be particularly appropriate for development as screening tools for identifying individuals in the preclinical AD continuum.

RevDate: 2019-06-14

Lin CH, Fann JC, Chen SL, et al (2019)

Heterogeneity in cost-effectiveness analysis of vaccination for mild and moderate Alzheimer's disease.

Current Alzheimer research pii:CAR-EPUB-98776 [Epub ahead of print].

BACKGROUND: Immunotherapy for Alzheimer's disease(AD) has gained momentum in recent years. One of concerns over its application is pertaining to cost-effectiveness analysis(CEA) from population average and specific subgroup differences for such a therapy is imperative for health decision-maker to allocate limited resources. However, this sort of CEA model considering heterogeneous population with risk factors adjustment has been rarely addressed.

OBJECTIVES: We aimed to show the heterogeneity of CEA in immunotherapy for AD in comparison with the comparator without intervention. Economic evaluation was performed via incremental cost-effectiveness ratio(ICER) and cost-effectiveness acceptability curve(CEAC) in terms of the quality-adjusted life years(QALY). First, population-average CEA was performed with and without adjustment for age and gender. Secondly, sub-group CEA was performed with the stratification of gender and age based on Markov process.

RESULTS: Given the threshold of $20,000 of willingness to pay, the results of ICER without and with adjustment for age and sex revealed similar results ($14,691/QALY and $17,604/QALY). The sub-group ICER results by different age groups and sex showed substantial differences. The CEAC showed the probability of being cost-effective was only 48.8%-53.3% in terms of QALY at population level but varied from 83.5% in women aged 50-64 years, following women aged 65-74 years and decreased to 0.2% in men≥ 75 years.

CONCLUSION: There were considerable heterogeneities observed in the CEA of vaccination for AD. As with the development of personalized medicine, the CEA results assessed by health decision-maker should not only be considered by population-average level but also specific sub-group levels.

RevDate: 2019-06-14

Lazzari C, Kotera Y, H Thomas (2019)

Social Network Analysis of Dementia Wards in Psychiatric Hospitals to Explore the Advancement of Personhood in Patients with Alzheimer's Disease.

Current Alzheimer research pii:CAR-EPUB-98775 [Epub ahead of print].

BACKGROUND: Little is known on investigating how healthcare teams in dementia wards act for promoting personhood in persons with Alzheimer's disease (PWA).

OBJECTIVE: The current research aimed to identify the social networks of dementia health carers promoting the personhood of PWA in acute or long-term dementia wards in public and private psychiatric hospitals.

METHOD: We used a mixed-method research approach. Ethnographic observations and two-mode Social Network Analysis (SNA) captured the role and social networks of healthcare professionals promoting PWA personhood, using SocNetv version 2.4. The social network graphs illustrated how professionals participated in PWA care by computing the degree of centrality (%DC) for each professional; higher values indicated more statistical significance of a professional role compared to others in the provision of personhood care. The categories of personhood were biological, individual, and sociologic. Nurses, doctors, ward managers, hospital managers, clinical psychologists, occupational therapists, care coordinators, physiotherapists, healthcare assistants, and family members were observed if they were promoting PWA personhood.

RESULTS: The highest %DC in SNA in biological personhood was held by the ward nurses (36%), followed by the ward doctors (20%) and ward managers (20%). All professional roles were involved in 16% of cases in the promotion of individual personhood, while the hospital managers had the highest %DC (33%) followed by the ward managers and nurses (27%) in the sociologic personhood.

CONCLUSION: All professional roles were deemed to promote PWA personhood in dementia wards, although some limitation exists according to the context of the assessment.

RevDate: 2019-06-13

Subaraja M, AJ Vanisree (2019)

Counter effects of Asiaticosids-D through putative neurotransmission on rotenone induced cerebral ganglionic injury in Lumbricus terrestris.

IBRO reports, 6:160-175 pii:S2451-8301(18)30096-7.

Asiaticoside-D (AD) was shown to efficacy of ganglionic degenerated Lumbricus terrestris as a pioneering observation in our earlier research. Though, extract molecular mechanisms of AD for degenerative diseases (DDs) remains largely unknown. We investigated the neuroprotective effects of AD against ROT in cerebral ganglions (CGs) of degenerative L. terrestris. Worms were exposed to 0.4 ppm ROT for 7 days were subjected to co- treatment with 15 ppm of AD. After, CGs was removed. The levels oxidant, non-antioxidant, antioxidant status, ganglioside, ceramide and ceramide glycanase (CGase) were estimated. The m-RNA levels of dopamine transporter (DAT), octopamine transporter (OAT), innexins-9 (inx-9), ionotropic glutamate receptor 3 (iGlu3), heat shock proteins (hsp70), XPRLamide neuropeptide precursor, tyramine beta-hydroxylase (tbh-1) and β- adrenergic receptor kinase-2 (β-ARK2-3) by semi-qRT- PCR. The expression pattern of tyramine beta hydroxylase (TBH), glutamate receptor (iGluR), serotonin transporter (SERT), dopamine transporters (DAT), nerve growth factors (NGF), cytochrome C oxidase (COC), NADH dehydogenase subunit-1 (ND-1), neurotrophin receptor p75 (p75NTR), neuronal nitric oxiside synthase (nNOs) interleukin 1- beta (IL1-β) and tumor necrosis factor alpha (TNF-α) by western blotting. Glutaminergic, serotogenic and dopaminergic toxicity variations were also performed. The levels of oxidant, non-antioxidant, antioxidant status, lipids, proteins and m-RNAs were significantly altered (p < 0.001) on ROT-induced (group II) and their levels were significantly changes (p < 0.05) by ROT+AD in CGs. The sensitive study plan concluded the neuroprotective effects of AD against ROT induced degeneration in worms and suggest that the AD deserves future studies for its use as an effective alternative medicine that could minimize the morbidity of ganglionic degenerative diseases patients.

RevDate: 2019-06-13

Gleerup HS, Hasselbalch SG, AH Simonsen (2019)

Biomarkers for Alzheimer's Disease in Saliva: A Systematic Review.

Disease markers, 2019:4761054.

Background: The histopathological changes of Alzheimer's disease (AD) are detectable decades prior to its clinical expression. However, there is a need for an early, inexpensive, noninvasive diagnostic biomarker to detect specific Alzheimer pathology. Recently developed neuroimaging biomarkers show promising results, but these methods are expensive and cause radiation. Furthermore, the analysis of cerebrospinal fluid (CSF) biomarkers requires an invasive lumbar puncture. Saliva is an easily obtained body fluid, and a stable saliva biomarker would therefore be a promising candidate for a future method for diagnosing AD. The purpose of this systematic review was to investigate studies of biomarkers in saliva samples for the diagnosis of AD.

Methods: The included articles were identified through a literature search in PubMed and Google Scholar for all articles until November 1st, 2018, and furthermore, all reference lists of included articles were reviewed by hand. We included articles written in English investigating saliva from patients with AD and a control group.

Results: A total of 65 studies were identified, whereof 16 studies met the inclusion criteria and were included in the systematic review. A plethora of different biomarkers were investigated, and ten out of the sixteen studies showed a statistical significance in biomarkers between patients with AD and healthy, elderly controls, among these biomarkers for specific AD pathology (amyloid beta 1-42 (Aβ42) and tau).

Conclusion: Aβ42 and tau seem to be worthy candidates for future salivary biomarkers for AD, but other biomarkers such as lactoferrin and selected metabolites also have potential. More studies must be carried out with larger sample sizes and a standardization of the sampling and processing method. Factors such as diurnal variation, AD patients' decreased ability of oral self-care, and salivary flowrates must be taken into consideration.

RevDate: 2019-06-13

Goltermann J, Redlich R, Dohm K, et al (2019)

Apolipoprotein E Homozygous ε4 Allele Status: A Deteriorating Effect on Visuospatial Working Memory and Global Brain Structure.

Frontiers in neurology, 10:552.

Theoretical background: The Apolipoprotein E (APOE) ε4 genotype is known to be one of the strongest single-gene predictors for Alzheimer disease, which is characterized by widespread brain structural degeneration progressing along with cognitive impairment. The ε4 allele status has been associated with brain structural alterations and lower cognitive ability in non-demented subjects. However, it remains unclear to what extent the visuospatial cognitive domain is affected, from what age onward changes are detectable and if alterations may interact with cognitive deficits in major depressive disorder (MDD). The current work investigated the effect of APOE ε4 homozygosity on visuospatial working memory (vWM) capacity, and on hippocampal morphometry. Furthermore, potential moderating roles of age and MDD were assessed. Methods: A sample of n = 31 homozygous ε4 carriers was contrasted with n = 31 non-ε4 carriers in a cross-sectional design. The sample consisted of non-demented, young to mid-age participants (mean age = 34.47; SD = 13.48; 51.6% female). Among them were n = 12 homozygous ε4 carriers and n = 12 non-ε4 carriers suffering from MDD (39%). VWM was assessed using the Corsi block-tapping task. Region of interest analyses of hippocampal gray matter density and volume were conducted using voxel-based morphometry (CAT12), and Freesurfer, respectively. Results: Homozygous ε4 carriers showed significantly lower Corsi span capacity than non-ε4 carriers did, and Corsi span capacity was associated with higher gray matter density of the hippocampus. APOE group differences in hippocampal volume could be detected but were no longer present when controlling for total intracranial volume. Hippocampal gray matter density did not differ between APOE groups. We did not find any interaction effects of age and MDD diagnosis on hippocampal morphometry. Conclusion: Our results point toward a negative association of homozygous ε4 allele status with vWM capacity already during mid-adulthood, which emerges independently of MDD diagnosis and age. APOE genotype seems to be associated with global brain structural rather than hippocampus specific alterations in young- to mid-age participants.

RevDate: 2019-06-13

Hernández F, Cuadros R, Ollá I, et al (2019)

Differences in structure and function between human and murine tau.

Biochimica et biophysica acta. Molecular basis of disease, 1865(8):2024-2030.

The main difference between the primary structures of human and mouse tau can be found at the N-terminal end of the protein. Residues 17 to 28 in human tau are not present in the mouse form of the molecule. Here we tested the capacity of these human tau residues to bind to specific proteins. Several proteins were observed to bind to these residues. Among those that showed the greatest binding were three related to energetic processes: enolase, glyceraldehyde 3 phosphate dehydrogenase and creatine kinase B. The latter did not bind to tau from brain extracts taken from patients with Alzheimer's disease (AD). This lack of binding could be due to the modification of CKB by oxidation in AD.

RevDate: 2019-06-12

König A, Francis LE, Joshi J, et al (2017)

Qualitative study of affective identities in dementia patients for the design of cognitive assistive technologies.

Journal of rehabilitation and assistive technologies engineering, 4:2055668316685038 pii:10.1177_2055668316685038.

Our overall aim is to develop an emotionally intelligent cognitive assistant (ICA) to help older adults with Alzheimer's disease (AD) to complete activities of daily living more independently. For improved adoption, such a system should take into account how individuals feel about who they are. This paper investigates different affective identities found in older care home residents with AD, leading to a computational characterization of these aspects and, thus, tailored prompts to each specific individual's identity in a way that potentially ensures smoother and more effective uptake and response. We report on a set of qualitative interviews with 12 older adult care home residents and caregivers. The interview covered life domains (family, origin, occupation, etc.), and feelings related to the ICA. All interviews were transcribed and analyzed to extract a set of affective identities, coded according to the social-psychological principles of affect control theory (ACT). Preliminary results show that a set of identities can be extracted for each participant (e.g. father, husband). Furthermore, our results provide support for the proposition that, while identities grounded in memories fade as a person loses their memory, habitual aspects of identity that reflect the overall "persona" may persist longer, even without situational context.

RevDate: 2019-06-12

Villar-Alvarez E, Leal BH, Cambón A, et al (2019)

Triggered RNAi therapy using metal inorganic nanovectors.

Molecular pharmaceutics [Epub ahead of print].

Small interfering RNA (siRNA) is as a very interesting therapeutic alternative to treat genetic diseases such Alzheimer´s or some types of cancer, but its effective delivery still remains a challenge. Herein, Au nanorods (GNRs)-based platforms functionalised with polyelectrolyte (PE) layers were developed and analysed as potential siRNA nanocarriers. The polymeric layers were successfully assembled on the particle surfaces by means of the layer-by-layer (LbL) technique through the alternating deposition of oppositely charged poly(styrene) sulfonate, PSS, poly(lysine), PLL, and siRNA biopolymers, with a final hyaluronic acid (HA) layer in order to provide the nanoconstructs with a potential targeting ability as well as colloidal stability in physiological medium. Once the hybrid nanocarriers were obtained, their release, colloidal stability, cytotoxicity, cellular uptake and gene silencing potential were studied. In this regard, these hybrid particles release the genetic material inside cells by means of a protease-assisted and/or a light-triggered release mechanism in order to control the delivery of the oligonucleotides on demand. In addition, the hybrid nanovectors were observed to be non-toxic to cells and could efficiently deliver the genetic material in the cell cytoplasms. The GNR-based nanocarriers here proposed can provide a suitable environment to load and protect sufficient amount of the genetic material to allow an efficient and sustained knockdown gene expression for a prolonged period of time (up to 93% for 72 h) thanks to the slow degradation of PLL, and without the observation of adverse side toxic effects. It was also found that the knockdown activity correlated with the number of siRNA layers assembled in the nanoplatforms.

RevDate: 2019-06-11

Cao Y, Xu H, Zhu Y, et al (2019)

ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.

PLoS biology, 17(6):e3000313 pii:PBIOLOGY-D-18-00021 [Epub ahead of print].

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aβ, reductions in Aβ brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.

RevDate: 2019-06-10

Ma Y, Jun GR, Zhang X, et al (2019)

Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.

JAMA neurology pii:2735123 [Epub ahead of print].

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles.

Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing.

The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018.

Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis.

Results: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women).

Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.

RevDate: 2019-06-10

Bayart JL, Hanseeuw B, Ivanoiu A, et al (2019)

Analytical and clinical performances of the automated Lumipulse cerebrospinal fluid Aβ42 and T-Tau assays for Alzheimer's disease diagnosis.

Journal of neurology pii:10.1007/s00415-019-09418-6 [Epub ahead of print].

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer's disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls.

METHODS: CSF samples of 156 patients were used to quantify Amyloïd Aβ1-42 peptide (Aβ1-42) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aβ1-42). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aβ1-42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays.

RESULTS: Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aβ1-42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects.

CONCLUSIONS: Our results demonstrate that the Lumipulse Aβ1-42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability.

RevDate: 2019-06-10

Adorni MP, Ruscica M, Ferri N, et al (2019)

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer's Disease.

Frontiers in aging neuroscience, 11:120.

Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.

RevDate: 2019-06-10

Tian Y, Wang JL, Huang W, et al (2019)

Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders.

American journal of human genetics pii:S0002-9297(19)30200-9 [Epub ahead of print].

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

RevDate: 2019-06-09

Zakirova EY, Chastukhina IB, Valeeva LR, et al (2019)

Stable Co-Cultivation of the Moss Physcomitrella Patens with Human Cells in vitro as a New Approach to Support Metabolism of Diseased Alzheimer Cells.

Journal of Alzheimer's disease : JAD pii:JAD190333 [Epub ahead of print].

Alzheimer's disease (AD) is a devastating slowly progressive neurodegenerative disorder with no cure. While there are many hypotheses, the exact mechanism causing this pathology is still unknown. Among many other features, AD is characterized by brain hypometabolism and decreased sugar availability, to which neurons eventually succumb. In light of this aspect of the disease, we hypothesized that boosting fuel supply to neurons may help them survive or at least alleviate some of the symptoms. Here we demonstrate that live moss Physcomitrella patens cells can be safely co-cultured with human fibroblasts in vitro and thus have a potential for providing human cells with energy and other vital biomolecules. These data may form the foundation for the development of novel approaches to metabolic bioengineering and treatment of diseased cells based on live plants. In addition, by providing alternative energy sources to human tissues, the biotechnological potential of this interkingdom setup could also serve as a springboard to foster innovative dietary processes addressing current challenges of mankind such as famine or supporting long-haul space flight.

RevDate: 2019-06-09

Kawarabayashi T, Terakawa T, Takahashi A, et al (2019)

Oral Immunization with Soybean Storage Protein Containing Amyloid-β 4-10 Prevents Spatial Learning Decline.

Journal of Alzheimer's disease : JAD pii:JAD190023 [Epub ahead of print].

Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aβ4-10, named Aβ+, for oral Aβ immunization. One mg of Aβ+ or control protein (Aβ-) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aβ+ immunization raised both anti-Aβ antibodies and cellular immune responses. Spatial learning decline was prevented in the Aβ+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-β protein precursor was not different between Aβ+ and Aβ- groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aβ+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

RevDate: 2019-06-09

Nam GE, Park YG, Han K, et al (2019)

BMI, Weight Change, and Dementia Risk in Patients With New-Onset Type 2 Diabetes: A Nationwide Cohort Study.

Diabetes care pii:dc18-1667 [Epub ahead of print].

OBJECTIVE: This study examined the association between baseline BMI, percentage weight change, and the risk of dementia in patients newly diagnosed with type 2 diabetes.

RESEARCH DESIGN AND METHODS: Using the South Korean National Health Insurance Service-National Health Screening Cohort database, we identified 167,876 subjects aged ≥40 years diagnosed with new-onset type 2 diabetes between 2007 and 2012. Their weight changes were monitored for ∼2 years after diagnosis, with follow-up assessments occurring for an average of 3.5 years. The hazard ratios (HRs) and Bonferroni-adjusted 95% CIs of all-cause dementia, Alzheimer disease (AD), and vascular dementia were estimated using multivariable Cox proportional hazards regression models.

RESULTS: We identified 2,563 incident dementia cases during follow-up. Baseline BMI among patients with new-onset type 2 diabetes was inversely associated with the risk of all-cause dementia and AD, independent of confounding variables (P for trend <0.001). The percentage weight change during the 2 years after a diagnosis of type 2 diabetes showed significant U-shaped associations with the risk of all-cause dementia development (P < 0.001); the HRs of the disease increased significantly when weight loss or gain was >10% (1.34 [95% CI 1.11-1.63] and 1.38 [1.08-1.76], respectively). Additionally, weight loss >10% was associated with an increased risk of AD (HR 1.26 [95% CI 1.01-1.59]).

CONCLUSIONS: A lower baseline BMI was associated with increased risks of all-cause dementia and AD in patients with new-onset type 2 diabetes. Weight loss or weight gain after the diagnosis of diabetes was associated with an increased risk of all-cause dementia. Weight loss was associated with an increased risk of AD.

RevDate: 2019-06-10

Hong Y, Liu Y, Yu D, et al (2019)

The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes.

International immunopharmacology, 74:105669 pii:S1567-5769(19)30442-4 [Epub ahead of print].

Neuroinflammation and autophagy dysfunction are known to be involved in the pathological procession of Alzheimer's disease (AD). Progesterone (PG), neuroactive steroids, exerts a characteristic neuroprotective function in improving AD syndrome. The NOD-like receptor pyrin 3 (NLRP3)-Caspase-1 inflammasome has specific relevance to AD pathological procession. However, the exact role of PG in regulating NLRP3-Caspase-1 inflammasome remains to be elucidated. We demonstrated Aβ up-regulated IL-1β expression in astrocytes by activating NLRP3-Caspase-1 inflammasome. However, pharmacological activation of autophagy by Rapamycin (RAPA) efficiently suppressed Aβ-, lipopolysaccharides (LPS)-induced IL-1β expression via regulating NLRP3-Caspase-1 inflammasome in astrocytes. Remarkably, PG significantly inhibited Aβ-induced NLRP3-Caspase-1 inflammasome activation. Autophagy inhibitor 3-MA blocked the protective effects of PG in mediating NLRP3 inflammasome and IL-1β processing. Taken together, our observations suggest that autophagy-lysosome pathway is one specific molecular mechanism in regulating Aβ-induced NLRP3-Caspase-1 inflammasome activation in astrocytes, particularly uncover the potential neuroprotection of PG in regulating upstream signaling leading to the sequence events of neuroinflammation. That neuroprotective mechanism of PG in regulating NLRP3-Caspase-1 inflammasome can be a potential therapeutic target for ameliorating the pathological procession of AD.

RevDate: 2019-06-08

Goldschmidt-Clermont PJ, Volinsky FG, LaRosa SP, et al (2019)

Time for Well-Powered Controlled Prospective Studies to test a Causal Role for Herpes Viruses in Alzheimer Using Anti-Herpes Drugs.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5512977 [Epub ahead of print].

Twenty-six phase III studies on Alzheimer's Disease (AD) are ongoing or have been completed in 2018. Most of these studies are targeting amyloid-beta, its production, polymerization, and/or multiple interactions. None of the amyloid-beta studies seem to impact positively the clinical outcome of AD patients thus far, no matter the advancement of disease. It is time to consider other hypotheses for the pathogenesis of AD, including the potential role of human herpes viruses (HHV), and especially HHV1 (herpes simplex virus type 1), HHV3 (varicella zoster virus), HHV6A and HHV7. With this Perspective, we review the scientific evidence, and make the case for appropriately powered, prospective, randomized and controlled studies using an anti-HHV drug, to establish a causal role for HHV in AD.

RevDate: 2019-06-08

Vatanabe IP, Manzine PR, MR Cominetti (2019)

Historic concepts of dementia and Alzheimer's disease: From ancient times to the present.

Revue neurologique pii:S0035-3787(18)30950-0 [Epub ahead of print].

The aim of this work is to describe the history of dementia and Alzheimer's disease (AD) concepts, from early descriptions in antiquity, through studies and authors from different historical periods throughout the centuries, to the latest updates of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). The article also presents the inclusion of the biomarkers from the cerebrospinal fluid, such as Tau and phosphorylated Tau proteins and beta-amyloid peptide in the most recent diagnostic criteria. A literature search was carried out in order to construct a reflexive narrative review of studies dated up to 2015 in the LILACS and Medline databases and with the inclusion of bibliographical references of the area. The different terms used throughout the history of the dementia and Alzheimer's disease concepts were contextualized according to the scientific perspective of a given epoch and its way of producing and reproducing knowledge. The concepts of dementia and AD continue to evolve, largely due to their complexity. Considering the importance and the growth of AD cases in the last and the next decades, this review may contribute in practice with the historical knowledge of the concepts related to dementia and AD.

RevDate: 2019-06-07

Isik AT, Kocyigit SE, Smith L, et al (2019)

A comparison of the prevalence of orthostatic hypotension between older patients with Alzheimer's Disease, Lewy body dementia, and without dementia.

Experimental gerontology pii:S0531-5565(19)30202-5 [Epub ahead of print].

Orthostatic hypotension (OH) is reported to be more prevalent particularly in patients with Dementia with Lewy bodies (DLB) because of the autonomic dysfunction, but prevalence of OH is not known in patients with Alzheimer Disease (AD). The aim of the present study was to determine whether OH can be used to distinguish DLB from AD. 38 patients with DLB, 88 patients with AD and 521 patients without dementia, underwent Comprehensive Geriatric Assessment. OH were evaluated for the 1st (OH1) and 3rd (OH3) minutes, taking the data in supine position as the basis, by Head-Up-Tilt Test. Prevalence of OH1 was 43.2% in AD, 44.7% in DLB and 17.9% in patients without dementia, and OH3 was 44.3% in AD, 47.4% in DLB and 17.9% in non-dementia group. The frequency of OH1 and OH3 was higher in the AD and DLB groups than in the patients without dementia (p < 0.001), but there was no significant difference between DLB and AD in terms of OH (p > 0.05). The percentage of asymptomatic patients with OH was 87.2% and 89.6% during 1st and 3rd minutes, respectively, and this percentage was similar in three groups (p > 0.05, for each). There was no significant difference between the two dementia groups in terms of comorbidities, drugs and laboratory values (p > 0.05). OH is more prevalent in patients with AD than controls and similar levels are observed in those with DLB. The prevalence of OH equally is greater with DLB or AD disease progression. Clinicians should be aware of OH and its related consequences in the management of the AD in older adults.

RevDate: 2019-06-07

Quintela-López T, Ortiz-Sanz C, Serrano-Regal MP, et al (2019)

Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling.

Cell death & disease, 10(6):445 pii:10.1038/s41419-019-1636-8.

Alzheimer´s disease (AD) is characterized by a progressive cognitive decline that correlates with the levels of amyloid β-peptide (Aβ) oligomers. Strong evidences connect changes of oligodendrocyte function with the onset of neurodegeneration in AD. However, the mechanisms controlling oligodendrocyte responses to Aβ are still elusive. Here, we tested the role of Aβ in oligodendrocyte differentiation, maturation, and survival in isolated oligodendrocytes and in organotypic cerebellar slices. We found that Aβ peptides specifically induced local translation of 18.5-kDa myelin basic protein (MBP) isoform in distal cell processes concomitant with an increase of process complexity of MBP-expressing oligodendrocytes. Aβ oligomers required integrin β1 receptor, Src-family kinase Fyn and Ca2+/CaMKII as effectors to modulate MBP protein expression. The pharmacological inhibition of Fyn kinase also attenuated oligodendrocyte differentiation and survival induced by Aβ oligomers. Similarly, using ex vivo organotypic cerebellar slices Aβ promoted MBP upregulation through Fyn kinase, and modulated oligodendrocyte population dynamics by inducing cell proliferation and differentiation. Importantly, application of Aβ to cerebellar organotypic slices enhanced remyelination and oligodendrocyte lineage recovery in lysolecithin (LPC)-induced demyelination. These data reveal an important role of Aβ in oligodendrocyte lineage function and maturation, which may be relevant to AD pathogenesis.

RevDate: 2019-06-07

Sharma G, Huo A, Kimura T, et al (2019)

Tau isoform expression and phosphorylation in marmoset brains.

The Journal of biological chemistry pii:RA119.008415 [Epub ahead of print].

Tau is a microtubule-associated protein expressed in neuronal axons. Hyperphosphorylated tau is a major component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease (AD). Hyperphosphorylated tau aggregates are also found in many neurodegenerative diseases, collectively referred to as "tauopathies," and tau mutations are associated with familiar frontotemporal lobar degeneration (FTLD). Previous studies have generated transgenic mice with mutant tau as tauopathy models, but non-human primates, which are more similar to humans, may be a better model to study tauopathies. For example, the common marmoset is poised as a nonhuman primate model for investigating the etiology of age-related neurodegenerative diseases. However, no biochemical studies of tau have been conducted in marmoset brains. Here, we investigated several important aspects of tau, including expression of different tau isoforms and its phosphorylation status, in the marmoset brain. We found that marmoset tau does not possess the "primate unique motif" in its N-terminal domain. We also discovered that the tau isoform expression pattern in marmosets is more similar to that of mice than of humans, with adult marmoset brains expressing only four-repeat tau isoforms as in adult mice but unlike in adult human brains. Of note, tau in brains of marmoset newborns was phosphorylated at several sites associated with AD pathology. However, in adult marmoset brains, much of this phosphorylation was lost, except for Ser-202 and Ser-404 phosphorylation. These results reveal key features of tau expression and phosphorylation in the marmoset brain, a potentially useful non-human primate model of neurodegenerative diseases.

RevDate: 2019-06-07

Borges LG, Rademaker AW, Bigio EH, et al (2019)

Apathy and Disinhibition Related to Neuropathology in Amnestic Versus Behavioral Dementias.

American journal of Alzheimer's disease and other dementias [Epub ahead of print].

OBJECTIVES: Investigating the frequency of apathy and disinhibition in patients clinically diagnosed with dementia of the Alzheimer type (DAT) or behavioral variant frontotemporal dementia (bvFTD) with neuropathology of either Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD).

METHODS: Retrospective data from 887 cases were analyzed, and the frequencies of apathy and disinhibition were compared at baseline and longitudinally in 4 groups: DAT/AD, DAT/FTLD, bvFTD/FTLD, and bvFTD/AD.

RESULTS: Apathy alone was more common in AD (33%) than FTLD (25%), and the combination of apathy and disinhibition was more common in FTLD (43%) than AD (14%; P < .0001). Over time, apathy became more frequent in AD with increasing dementia severity (33%-41%; P < .006).

CONCLUSIONS: Alzheimer disease neuropathology had the closest association with the neuropsychiatric symptom of apathy, while FTLD was most associated with the combination of apathy and disinhibition. Over time, the frequency of those with apathy increased in both AD and FTLD neuropathology.

RevDate: 2019-06-06

Guerville F, de Souto Barreto P, Giudici KV, et al (2019)

Association of 3-Year Multidomain Intervention and Omega-3 Supplementation with Frailty Incidence.

Journal of the American Geriatrics Society [Epub ahead of print].

OBJECTIVES: To assess the associations of long-term lifestyle multidomain intervention (MI) and omega-3 supplementation with frailty level evolution and frailty incidence in community-dwelling older persons.

DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial.

SETTING: Thirteen memory centers in France and Monaco between 2008 and 2011.

PARTICIPANTS: A total of 1588 community-dwelling persons aged 70 years or older with memory complaints (without dementia), slow gait speed, or limitation in one instrumental activity of daily living.

INTERVENTION: A 3-year MI (43 group sessions including cognitive training, physical activity, and nutrition advice and three preventive consultations) plus daily omega-3 fatty acids, MI plus placebo, omega-3 alone, or placebo alone.

MEASUREMENTS: The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength: 0 to 5 score, higher is worse; a score of 3 or higher defines frailty) was assessed at baseline, 6, 12, 24, and 36 months. We used mixed-effect models for frailty level (0-5 score as an ordinal variable) and Cox models for frailty incidence.

RESULTS: No differences were found between the intervention groups and placebo on the 3-year evolution of frailty level. Among 1394 non-frail participants at baseline, frailty incidence occurred in 134 (9.6%) persons: 26 (7.6%) in the MI plus omega-3 group, 34 (10%) in the omega-3 alone group, 31 (8.5%) in the MI plus placebo group, and 43 (12.3%) in the placebo-alone group). No differences regarding frailty incidence were found between intervention groups and placebo. After exclusion of 53 participants with incident frailty during the first year of follow-up, MI plus omega-3 was associated with a lower frailty incidence compared with placebo (hazard ratio = .43; 95% confidence interval = .22-.81).

CONCLUSION: In community-dwelling older persons, the combination of a long-term lifestyle MI and omega-3 supplementation did not reduce frailty level or incidence. The reduction of frailty incidence associated with the combined intervention in a sensitivity analysis needs to be further confirmed.

RevDate: 2019-06-06

Huang Q, Cao X, Chai X, et al (2019)

Three-dimensional pseudocontinuous arterial spin labeling and susceptibility-weighted imaging associated with clinical progression in amnestic mild cognitive impairment and Alzheimer's disease.

Medicine, 98(23):e15972.

BACKGROUND: This study aimed to evaluate the value of 3-dimensional pseudocontinuous arterial spin labeling (3D-pcASL) and susceptibility-weighted imaging (SWI) for the early disease-sensitive markers of conversion from amnestic MCI (aMCI) to Alzheimer disease (AD) in this process.

METHODS: Forty patients with aMCI and AD respectively were recruited in the study, and 40 healthy subjects were taken as controls. Data were recorded using 3T MR scanner. We assessed the cerebral blood flow (CBF) in 11 different regions of interest, and counted number of microhemorrhages (MB) in 3 regions of brain lobes, bilateral basal ganglia/thalamus, and brain stem/cerebellum, and then investigated correlations between Montreal Cognitive Assessment (MoCA) scores, CBF, and susceptibility-weighted imaging (SWI) features in these 3 groups.

RESULTS: The results revealed that for AD patients, the MoCA scores and CBF values in frontal gray matter (FGM), occipital gray matter (OGM), temporal gray matter (TGM), parietal gray matter (PGM), hippocampus, anterior cingulate cortex (ACC), precuneus, posterior cingulate cortex (PCC), precuneus, basal ganglia and thalamus decreased compared with aMCI patients and control group, and significant difference was revealed among the 3 groups. While in cerebellum, statistical significance was only found between AD patients and control group. On SWI, the average numbers of hemorrhage in regions of lobes for AD patients were significantly higher than aMCI patients and control group. The same results occurred in the bilateral basal ganglia/thalamus. We further found the MoCA score was positively correlated with CBF, but negatively correlated with hypointense signal on SWI.

CONCLUSION: 3D-pCASL and SWI have promising potential to be biomarkers for conversion from aMCI to AD in this process.

RevDate: 2019-06-06

Yang T, Dang Y, Ostaszewski B, et al (2019)

Target Engagement in an Alzheimer Trial: Crenezumab Lowers Aβ Oligomers in CSF.

Annals of neurology [Epub ahead of print].

OBJECTIVE: Oligomeric forms of amyloid β-protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer's disease, but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans.

METHODS: We developed an ultrasensitive immunoassay and used it to measure oAβ in CSF from 104 AD subjects participating in the ABBY and BLAZE Phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every two weeks or else intravenous (IV) crenezumab (15mg/kg) or placebo every four weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (N=28), SC (N=35) and IV (N=35) treated patients.

RESULTS: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p=0.0035 for SC and p=0.01 for IV crenezumab vs. placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change.

INTERPRETATION: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-06

Bischof GN, HIL Jacobs (2019)

Subthreshold amyloid and its biological and clinical meaning: Long way ahead.

Neurology pii:WNL.0000000000007747 [Epub ahead of print].

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), β-amyloid (Aβ), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of Aβ deposition below a threshold indicative of Aβ positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of Aβ and its convergence and divergence with in vivo Aβ imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into Aβ accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of Aβ, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions.

RevDate: 2019-06-06

Marchi C, Adorni MP, Caffarra P, et al (2019)

ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease.

Journal of lipid research pii:jlr.P091033 [Epub ahead of print].

HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes towards the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer disease (AD), by analyzing AD (n = 37), non-AD dementia patients (non-AD DEM, n = 16) and control subjects (n = 39). As expected, AD patients showed reduced CSF Aβ 1-42, increased total- and phospho-Tau and higher frequency of apo Ɛ4 genotype. ABCA1- and ABCG1-mediated CSF-CEC was markedly reduced in AD (-73% and -33%, respectively) but not in non-AD DEM, in which a reduced passive diffusion CEC (-40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (-24%) compared to controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apo Ɛ4 status. ABCG1 CSF-CEC positively correlated with Aβ 1-42 (r = 0.305, p = 0.025) while ABCA1 CSF-CEC inversely correlated with total- and phospho-Tau (r = -0.348, p = 0.018 and r = -0.294, p = 0.048 respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.

RevDate: 2019-06-06

Butterfield DA (2018)

Phosphoproteomics of Alzheimer disease brain: Insights into altered brain protein regulation of critical neuronal functions and their contributions to subsequent cognitive loss.

Biochimica et biophysica acta. Molecular basis of disease pii:S0925-4439(18)30328-4 [Epub ahead of print].

Alzheimer disease (AD) is the major locus of dementia worldwide. In the USA there are nearly 6 million persons with this disorder, and estimates of 13-20 million AD cases in the next three decades. The molecular bases for AD remain unknown, though processes involving amyloid beta-peptide as small oligomeric forms are gaining attention as known agents to both lead to oxidative stress and synaptic dysfunction associated with cognitive dysfunction in AD and its earlier forms, including amnestic mild cognitive impairment (MCI) and possibly preclinical Alzheimer disease (PCAD). Altered brain protein phosphorylation is a hallmark of AD, and phosphoproteomics offers an opportunity to identify these altered phosphoproteins in order to gain more insights into molecular mechanisms of neuronal dysfunction and death that lead to cognitive loss. This paper reviews what, to this author, are believed to be the known phosphoproteomics studies related to in vitro and in vivo models of AD as well as phosphoproteomics studies of brains from subjects with AD, and in at least one case in MCI and PCAD as well. The results of this review are discussed with relevance to new insights into AD brain protein dysregulation in critical neuronal functions and to potential therapeutic targets to slow, or in favorable cases, halt progression of this dementing disorder that affects millions of persons and their families worldwide.

RevDate: 2019-06-10

Orth J, Li Y, Simning A, et al (2019)

Providing Behavioral Health Services in Nursing Homes Is Difficult: Findings From a National Survey.

Journal of the American Geriatrics Society [Epub ahead of print].

OBJECTIVES: Behavioral health (BH) disorders affect 65% to 90% of nursing home (NH) residents. Access to BH services in NHs has been generally considered inadequate, but the empirical evidence is sparse. We examined the availability of BH services and identified facility-level factors associated with the difficulty of providing BH services in NHs.

DESIGN: A national random sample of 3996 NHs was identified. Two structured surveys with questions about BH service availability, quality, satisfaction, staffing, staff education, turnover, and service barriers were mailed to administrators and directors of nursing in each NH between July and December 2017.

SETTING/PARTICIPANTS: Completed surveys were obtained from 1079 NHs (27% response rate). Descriptive statistics and multivariable logistic regressions were employed.

MEASUREMENTS: Four outcome measures were based on five-point Likert scales: (1) adequacy of BH staff education; (2) ability to meet resident BH service needs; (3) adequacy of coordination/collaboration between NH/community providers; and (4) availability of necessary facility infrastructure.

RESULTS: BH service needs were unmet in one third of NHs; almost half lacked appropriate staff BH education. Over 30% reported having inadequate coordination of care between NH and community providers, and 26.2% had inadequate infrastructure for residents' referrals/transport. Staff BH education was less problematic in NHs with Alzheimer disease units (odds ratio [OR] = 0.6; P < .05), lower registered nurse (RN) turnover (OR = 0.7; P < .05), and more psychiatrically trained RNs (OR = 0.5; P < .001) and social workers (OR = 0.6; P < .05). Lower RN turnover (OR = 0.7; P < .05) and more psychiatrically trained RNs (OR = 0.6; P < .05) were associated with fewer NHs reporting being unable to meet BH service needs. Having more psychiatrically trained RNs (OR = 0.6; P < .05) was associated with fewer NHs reporting inadequate coordination with community providers.

CONCLUSION: Inadequate BH education and psychiatric training among NH staff were associated with subpar provision of BH services in this care setting. New initiatives that increase access to BH providers and services and improve staff education are urgently needed in NHs.

RevDate: 2019-06-05

Gondim DD, Oblak A, Murrell JR, et al (2019)

Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation.

Journal of neuropathology and experimental neurology pii:5511542 [Epub ahead of print].

In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.

RevDate: 2019-06-05

Maia PD, Raj A, JN Kutz (2019)

Slow-gamma frequencies are optimally guarded against effects of neurodegenerative diseases and traumatic brain injuries.

Journal of computational neuroscience pii:10.1007/s10827-019-00714-8 [Epub ahead of print].

We introduce a computational model for the cellular level effects of firing rate filtering due to the major forms of neuronal injury, including demyelination and axonal swellings. Based upon experimental and computational observations, we posit simple phenomenological input/output rules describing spike train distortions and demonstrate that slow-gamma frequencies in the 38-41 Hz range emerge as the most robust to injury. Our signal-processing model allows us to derive firing rate filters at the cellular level for impaired neural activity with minimal assumptions. Specifically, we model eight experimentally observed spike train transformations by discrete-time filters, including those associated with increasing refractoriness and intermittent blockage. Continuous counterparts for the filters are also obtained by approximating neuronal firing rates from spike trains convolved with causal and Gaussian kernels. The proposed signal processing framework, which is robust to model parameter calibration, is an abstraction of the major cellular-level pathologies associated with neurodegenerative diseases and traumatic brain injuries that affect spike train propagation and impair neuronal network functionality. Our filters are well aligned with the spectrum of dynamic memory fields including working memory, visual consciousness, and other higher cognitive functions that operate in a frequency band that is - at a single cell level - optimally guarded against common types of pathological effects. In contrast, higher-frequency neural encoding, such as is observed with short-term memory, are susceptible to neurodegeneration and injury.

RevDate: 2019-06-05

Pulst SM (2019)

[Antisense therapies for neurological diseases].

Der Nervenarzt pii:10.1007/s00115-019-0724-4 [Epub ahead of print].

Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.

RevDate: 2019-06-04

Bakly WE, Wagdy O, Sobhy A, et al (2019)

The Efficacy and Underlying Mechanism of Phosphodiesterase- 5 inhibitors in Preventing Cognitive Impairment and Alzheimer Pathology: A Systematic Review of Animal Studies.

Behavioural brain research pii:S0166-4328(18)31698-X [Epub ahead of print].

BACKGROUND: Alzheimer disease (AD) initially presents with cognitive decline that affects the affected individual's daily activities. Cognitive decline reversal represents an important medical need, where Phosphodiesterase-5 inhibitors (PDE-5Is) might play a role.

AIM: This systematic review was performed to verify the efficacy of PDE-5Is in preventing cognitive impairment and to elucidate the underlying mechanism.

METHODS: Preclinical animal studies assessing the efficacy of PDE-5Is in preventing cognitive impairment and pathological changes by measuring Aβ-42 β42 and p-Tau were included in the analysis. CAMARADES Checklist was used to assess study quality. Further, various signaling pathways in different studies were examined.

RESULTS AND OUTCOMES: Data of behavioral tests were extracted and a meta-analysis was conducted. Fifteen animal trials met the inclusion criteria, and all reported the prevention of cognitive deficits by PDE-5Is in Alzheimer's disease. A significant effect of PDE-5Is in increasing the time spent in the target quadrant was reported in four of seven studies using the water maze. Four studies showed significant improvement in contextual fear memory freezing time, and three studies showed improvement in the 14 unit maze number of errors.

CONCLUSIONS: Cognitive decline in preclinical AD finds tauopathy has a more impact than Aβ-42. This systematic review showed that PDE-5 inhibitors might help prevent cognitive impairment in AD, and while its mechanism of action is non-related to Aβ-42, it might include decrease p-Tau, increase CREB and BDNF or suppressing apoptosis and inflammation. However, the efficacy of PDE-5 inhibitors in preventing cognitive impairment remains unclear due to various limitations, such as the small number of included studies, the high risk of bias, the lack of an integrated study design, and low reporting quality.

RevDate: 2019-06-04

Gardner OK, Wang L, Van Booven D, et al (2019)

RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.

Human molecular genetics pii:5510615 [Epub ahead of print].

Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute to AD pathogenesis due to its roles in neuronal development and immune regulation. Here, we pursued one of the first transcriptome-wide RNA editing studies in AD by examining RNA sequencing data from individuals of both African-American (AA) and non-Hispanic White (NHW) ethnicities. Whole transcriptome RNA sequencing and RNA editing analysis were performed on peripheral blood specimens from 216 AD cases (105 AA, 111 NHW) and 212 gender matched controls (105 AA, 107 NHW). 449 positions in 254 genes and 723 positions in 371 genes were differentially edited in AA and NHW, respectively. While most differentially edited sites localized to different genes in AA and NHW populations, these events converged on the same pathways across both ethnicities, especially endocytic and inflammatory response pathways. Furthermore, these differentially edited sites were preferentially predicted to disrupt miRNA binding and induce nonsynonymous coding changes in genes previously associated with AD in molecular studies, including PAFAH1B2 and HNRNPA1. These findings suggest RNA editing is an important post-transcriptional regulatory program in AD pathogenesis.

RevDate: 2019-06-04

Wahidi N, AJ Lerner (2019)

Blood Pressure Control and Protection of the Aging Brain.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-019-00747-y [Epub ahead of print].

Hypertension and dementia are both common disorders whose prevalence increases with age. There are multiple mechanisms by which hypertension affects the brain and alters cognition. These include blood flow dynamics, development of large and small vessel pathology and diverse molecular mechanisms including formation of reactive oxygen species and transcriptional cascades. Blood pressure interacts with Alzheimer disease pathology in numerous and unpredictable ways, affecting both β-amyloid and tau deposition, while also interacting with AD genetic risk factors and other metabolic processes. Treatment of hypertension may prevent cognitive decline and dementia, but methodological issues have limited the ability of randomized clinical trials to show this conclusively. Recent studies have raised hope that hypertension treatment may protect the function and structure of the aging brain from advancing to mild cognitive impairment and dementia.

RevDate: 2019-06-04

Mondragón JD, Maurits NM, PP De Deyn (2019)

Functional Neural Correlates of Anosognosia in Mild Cognitive Impairment and Alzheimer's Disease: a Systematic Review.

Neuropsychology review pii:10.1007/s11065-019-09410-x [Epub ahead of print].

Functional neuroimaging techniques (i.e. single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging) have been used to assess the neural correlates of anosognosia in mild cognitive impairment (MCI) and Alzheimer's disease (AD). A systematic review of this literature was performed, following the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement, on PubMed, EMBASE, and PsycINFO databases. Twenty-five articles met all inclusion criteria. Specifically, four brain connectivity and 21 brain perfusion, metabolism, and activation articles. Anosognosia is associated in MCI with frontal lobe and cortical midline regional dysfunction (reduced perfusion and activation), and with reduced parietotemporal metabolism. Reduced within and between network connectivity is observed in the default mode network regions of AD patients with anosognosia compared to AD patients without anosognosia and controls. During initial stages of cognitive decline in anosognosia, reduced indirect neural activity (i.e. perfusion, metabolism, and activation) is associated with the cortical midline regions, followed by the parietotemporal structures in later stages and culminating in frontotemporal dysfunction. Although the current evidence suggests differences in activation between AD or MCI patients with anosognosia and healthy controls, more evidence is needed exploring the differences between MCI and AD patients with and without anosognosia using resting state and task related paradigms.

RevDate: 2019-06-04

von Arnim CAF, Bartsch T, Jacobs AH, et al (2019)

Diagnosis and treatment of cognitive impairment.

Zeitschrift fur Gerontologie und Geriatrie pii:10.1007/s00391-019-01560-0 [Epub ahead of print].

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.

RevDate: 2019-06-04

Takechi H, Yabuki T, Takahashi M, et al (2019)

Dementia Cafés as a Community Resource for Persons With Early-Stage Cognitive Disorders: A Nationwide Survey in Japan.

Journal of the American Medical Directors Association pii:S1525-8610(19)30378-0 [Epub ahead of print].

OBJECTIVES: Dementia cafés are expected to serve as a new community resource based on the national dementia strategy in Japan. The objective of the present study was to examine effective ways to manage dementia cafés through an overview of dementia cafés in Japan and an analysis of the factors related to their effectiveness on attendees.

DESIGN: Cross-sectional analysis.

SETTING AND PARTICIPANTS: Representatives of 1477 dementia cafés in Japan.

MEASURES: Questionnaires regarding the dementia cafés' characteristics, management members, staff, their guests and effectiveness on people with dementia, their families, and community members were sent to the cafés, with instructions to have them completed by the café representatives. Logistic regression analysis was performed with the effect on each guest attribute as a dependent variable, and factors related to the effectiveness of dementia cafés were analyzed.

RESULTS: Questionnaires were sent to a total of 2728 dementia cafés in Japan, and responses were received from 1477 (54.1%). The most common meeting frequency and meeting hours were once a month (64.8%) and 2 hours (53.8%), respectively. Analysis of the effectiveness of dementia cafés on 3 groups of guests indicated the following preferences for café program: people with dementia preferred frequent meetings and activities, families of people with dementia preferred having a place for private consultation and advice and peer meetings, and community members preferred frequent meetings and both mini-lectures and private consultation and advice. Logistic regression analysis further revealed that all types of guests preferred the presence of the same types of guests.

CONCLUSIONS/IMPLICATIONS: This study revealed the multicomponent nature of dementia cafés. The results suggest that a good balance of programs and guests would enhance the cafés' effectiveness among the multiple stakeholders in regard to dementia, especially in the early stage of the disease.

RevDate: 2019-06-04

Poptsi E, Moraitou D, Eleftheriou M, et al (2019)

Normative Data for the Montreal Cognitive Assessment in Greek Older Adults With Subjective Cognitive Decline, Mild Cognitive Impairment and Dementia.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

OBJECTIVE: The aim of the study was to provide normative data for the MoCA in a Greek cohort of people older than 60 years who meet criteria for subjective cognitive decline (SCD), mild cognitive impairment (MCI), or dementia in order to optimize cutoff scores for each diagnostic group.

METHOD: Seven hundred forty-six community-dwelling older adults, visitors of the Day Center of Alzheimer Hellas were randomly chosen. Three hundred seventy-nine of them met the criteria for dementia, 245 for MCI and 122 for SCD.

RESULTS: Initial statistical analyses showed that the total MoCA score is not affected by gender (P = .164), or age (P = .144) but is affected by educational level (P < .001). A cutoff score of 23 for low educational level (≤6 years) can distinguish people with SCD from MCI (sensitivity 71.4%, specificity 84.2%), while 26 is the cutoff score for middle educational level (7-12 years; sensitivity 73.2%, specificity 67.0%) and high educational level (≥13 years; sensitivity 77.6%, specificity 74.7%). Montreal Cognitive Assessment can discriminate older adults with SCD from dementia, with a cutoff score of 20 for low educational level (sensitivity 100%, specificity 92.3%) and a cutoff score 23 for middle educational level (sensitivity 97.6%, specificity 92.7%) and high educational level (sensitivity 98.5%, specificity 100%).

CONCLUSION: Montreal Cognitive Assessment is not affected by age or gender but is affected by the educational level. The discriminant potential of MoCA between SCD and MCI is good, while the discrimination of SCD from dementia is excellent.

RevDate: 2019-06-10

Baldacci F, Lista S, Vergallo A, et al (2019)

A frontline defense against neurodegenerative diseases:the development of early disease detection methods.

Expert review of molecular diagnostics [Epub ahead of print].

RevDate: 2019-06-07

Van Acker ZP, Declerck K, Luyckx E, et al (2019)

Non-Methylation-Linked Mechanism of REST-Induced Neuroglobin Expression Impacts Mitochondrial Phenotypes in a Mouse Model of Amyotrophic Lateral Sclerosis.

Neuroscience pii:S0306-4522(19)30369-0 [Epub ahead of print].

Neuroglobin (Ngb) is a REST/NRSF-regulated protein, active in reactive oxygen species detoxification and cytochrome c inhibition, which provides a beneficial outcome in pathologies as Alzheimer's disease and strokes. Considering that oxidative stress and cell death are typical hallmarks of amyotrophic lateral sclerosis (ALS), we sought to explore Ngb's involvement along this disease progression. Ngb transcription was detected to be two-fold down-regulated in late-stage SODG93A mice, similarly as previously described for Alzheimer disease. Interestingly, in accordance with REST/NRSF transcription, Ngb expression is higher in spinal cords than in cortices. Hence, downstream REST/NRSF mechanisms were studied. A methylation cluster in Ngb's exon 1 (Chr12:87101763-87,102,586) was selected to assess methylation alterations, based on significantly altered positions in GEO DataSets of human c9orf72 and sporadic ALS cases. However, only the methylation percentage on position Chr12.87102586 was significantly increased in SODG93A mice. A larger impact can therefore be expected from the detected altered REST splicing; with levels of alternatively spliced, gene-activating REST4 to be lower than those of the gene-inhibitory full variant. To look further into the link between Ngb and ALS, we generated a double mutant Ngb-/-SODG93A mouse model, which shows an earlier onset and severity of hind limb deficits. Mitochondria derived thereof showed an altered mean volume, granularity and Ca2+-induced swelling as compared to NgbWt/WtSODG93A mice. These results indicate Ngb to be involved in and affected by the SOD1G93A pathology, which could in part be attributed to its role in halting destabilizing events of mitochondrial swelling and phenotypes.

RevDate: 2019-06-03

Hanseeuw BJ, Betensky RA, Jacobs HIL, et al (2019)

Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study.

JAMA neurology pii:2735107 [Epub ahead of print].

Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials.

Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.

Prospective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple Aβ and tau PET observations available on October 31, 2017.

Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in Aβ and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment.

Results: Of the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high Aβ burden. An antecedent rise in Aβ was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P = .02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P = .001), covarying baseline Aβ and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not (n = 11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P = .001). A serial mediation model demonstrated that the association between initial Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.

Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.

RevDate: 2019-06-10

Wagner JM, Sichler ME, Schleicher EM, et al (2019)

Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer's Disease.

Frontiers in behavioral neuroscience, 13:107.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. Hallmarks of AD are memory impairments and cognitive deficits, but non-cognitive impairments, especially motor dysfunctions are also associated with the disease and may even precede classic clinical symptoms. With an aging society and increasing hospitalization of the elderly, motor deficits are of major interest to improve independent activities in daily living. Consistent with clinical findings, a variety of AD mouse models develop motor deficits as well. We investigated the motor function of 3- and 7-month-old Tg4-42 mice in comparison to wild-type controls and 5XFAD mice and discuss the results in context with several other AD mouse model. Our study shows impaired balance and motor coordination in aged Tg4-42 mice in the balance beam and rotarod test, while general locomotor activity and muscle strength is not impaired at 7 months. The cerebellum is a major player in the regulation and coordination of balance and locomotion through practice. Particularly, the rotarod test is able to detect cerebellar deficits. Furthermore, supposed cerebellar impairment was verified by 18F-FDG PET/MRI. Aged Tg4-42 mice showed reduced cerebellar glucose metabolism in the 18F-FDG PET. Suggesting that, deficits in coordination and balance are most likely due to cerebellar impairment. In conclusion, Tg4-42 mice develop motor deficits before memory deficits, without confounding memory test. Thus, making the Tg4-42 mouse model a good model to study the effects on cognitive decline of therapies targeting motor impairments.

RevDate: 2019-06-10

Krashia P, Nobili A, M D'Amelio (2019)

Unifying Hypothesis of Dopamine Neuron Loss in Neurodegenerative Diseases: Focusing on Alzheimer's Disease.

Frontiers in molecular neuroscience, 12:123.

RevDate: 2019-06-10

Yang F, Roy Chowdhury S, Jacobs HIL, et al (2019)

A longitudinal model for tau aggregation in Alzheimer's disease based on structural connectivity.

Information processing in medical imaging : proceedings of the ... conference, 11492:384-393.

Tau tangles are a pathological hallmark of Alzheimer?s disease (AD) with strong correlations existing between tau aggregation and cognitive decline. Studies in mouse models have shown that the characteristic patterns of tau spatial spread associated with AD progression are determined by neural connectivity rather than physical proximity between different brain regions. We present here a network diffusion model for tau aggregation based on longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI). White matter fiber bundles reconstructed via tractography from the DTI data were used to compute normalized graph Laplacians which served as graph diffusion kernels for tau spread. By linearizing this model and using sparse source localization, we were able to identify distinct patterns of propagative and generative buildup of tau at a population level. A gradient descent approach was used to solve the sparsity-constrained optimization problem. Model fitting was performed on subjects from the Harvard Aging Brain Study cohort. The fitted model parameters include a scalar factor controlling the network-based tau spread and a network-independent seed vector representing seeding in different regions-of-interest. This parametric model was validated on an independent group of subjects from the same cohort. We were able to predict with reasonably high accuracy the tau buildup at a future time-point. The network diffusion model, therefore, successfully identifies two distinct mechanisms for tau buildup in the aging brain and offers a macroscopic perspective on tau spread.

RevDate: 2019-06-09

Thirunavu V, McCullough A, Su Y, et al (2019)

Higher Body Mass Index Is Associated with Lower Cortical Amyloid-β Burden in Cognitively Normal Individuals in Late-Life.

Journal of Alzheimer's disease : JAD, 69(3):817-827.

BACKGROUND: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer's disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology.

OBJECTIVE: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45-60 years) or late-life (>60).

METHODS: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n = 96 and n = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex.

RESULTS: Higher BMI was associated with lower cortical Aβ burden in late-life (β= -0.81, p = 0.0066), but no relationship was found in mid-life (β= 0.04, p > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p = 0.41; β= 0.64, p = 0.13) or the late-life (β= 0.17, p > 0.5; β= 0.50, p = 0.43) groups.

CONCLUSION: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals.

RevDate: 2019-06-03

Mohammadi-Khanaposhtani M, Barazandeh Tehrani M, Rezaei Z, et al (2019)

Design, synthesis, and cholinesterase inhibition assay of coumarin-3-carboxamide-N-morpholine hybrids as new anti-Alzheimer agents.

Chemistry & biodiversity [Epub ahead of print].

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid for produce corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholin derivative 5g bearing an unsubstituented coumarin moiety and ethylmorpholine derivative 5d bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of the compound 5g against AChE was 1.78 times more than that of rivasetigmin and anti-BuChE activity of compound 5d is approximately same with rivasetigmin. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

RevDate: 2019-06-02

Agüera Sánchez MÁ, Barbancho Ma MÁ, N García-Casares (2019)

[Effect of physical exercise on Alzheimer's disease. A sistematic review].

Atencion primaria pii:S0212-6567(18)30468-2 [Epub ahead of print].

OBJECTIVE: The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment.

DESIGN: Systematic review.

DATA SOURCES: We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles.

DATA EXTRACTION: The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus.

RESULTS: We identified 75 articles, of which 23 were finally included in the review.

CONCLUSIONS: Most of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association.

RevDate: 2019-06-01

Cognat E, Mouton Liger F, Troussière AC, et al (2019)

What is the clinical impact of cerebrospinal fluid biomarkers on final diagnosis and management in patients with mild cognitive impairment in clinical practice? Results from a nation-wide prospective survey in France.

BMJ open, 9(5):e026380 pii:bmjopen-2018-026380.

OBJECTIVES: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics.

DESIGN: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey.

SETTING: 29 secondary and tertiary memory clinics in France.

PARTICIPANTS: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP.

Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine.

RESULTS: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4).

CONCLUSION: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.

RevDate: 2019-05-31

El-Hawary SS, Fathy FI, Sleem AA, et al (2019)

Anticholinesterase activity and metabolite profiling of Syagrus romanzoffiana (Cham.) Glassman leaves and fruits via UPLC-QTOF-PDA-MS.

Natural product research [Epub ahead of print].

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of Syagrus romanzoffiana (Cham.) Glassman via UPLC-QTOF-PDA-MS and to evaluate their anticholinesterase activities in a model of Alzheimer disease. The current study has identified 39 metabolites belonging to various chemical classes (i.e. flavonols, phenolic acids, fatty acids, stilbenoids and lignans). While the fatty acids predominated in both leaves and fruits, the stilbenoids were more predominant in leaves. Their neuroprotective effect was comparable to Aricept; the standard drug used in treatment of Alzheimer disease. Both extracts significantly decreased the acetylcholinesterase activity and improved the histopathological changes in the cerebral cortex and cerebellum of rat model of aluminium chloride-induced Alzheimer disease. In light of the current study, Syagrus romanzoffiana (Cham.) Glassman is recommended as promising candidate for palliative treatment in Alzheimer disease through inhibition of the acetylcholinesterase activity.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )