About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot


Bibliography Options Menu

30 Mar 2020 at 01:31
Hide Abstracts   |   Hide Additional Links
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: Alzheimer Disease — Current Literature


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Mar 2020 at 01:31 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] OR 2020[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2020-03-29

Battistella V, Camara VD, Nogueira CB, et al (2020)

Transcranial Doppler could help to differentiate the types of dementia? A pilot study when CSF biomarkers are not available.

Journal of neural transmission (Vienna, Austria : 1996) pii:10.1007/s00702-020-02178-y [Epub ahead of print].

Our objective was to find a mean flow velocity (MFV) cut-off point to differentiate between normal and cognitive impaired patients using Clinical Dementia Rating (CDR) as a comparison method. To evaluate MFV (in cm/s) and pulsatility index (PI) from the left middle cerebral artery (MCA) and basilar artery using transcranial Doppler in a pilot study from an outpatient cognition unit and compare with cognitively normal older adults (at the age of sixty or older) from the Geriatric Ambulatory of Fluminense Federal University. We hypothesized that there is a MFV and PI cut-off point to potentially distinguish between normal and impaired cognition. Sixty-one patients with cognitive decline, including 18 with amnestic mild cognitive impairment (aMCI), 31 with probable Alzheimer disease (AD), 12 with vascular dementia (VD), and 10 cognitively normal older adults were included in the study. Patients with dementia (both AD and VD, p < 0.01) and aMCI (p < 0.05) had lower MFV than the control group in the MCA (32.2 cm/s, 31.9 cm/s, and 36.6 cm/s, respectively) and dementia patients had higher PI compared to control (AD and VD, both p < 0.05). Basilar MFV showed to be no difference between the patients and the control group. A cut off value of 39.1 cm/s was found in a ROC curve (area under de curve value 0.85, 95% CI 0.75-0.95) for mean MCA MFV to be predictive of cognitive impairment (CDR ≥ 0.5). In this study, the values of MCA MFV below 39.1 cm/s were predictive of cognitive impairment according to CDR. TCD is an inexpensive method that could be used in a clinical scenario to help differentiate normal cognition from cognitive decline. Multicentric and longitudinal studies should be done to validate that.

RevDate: 2020-03-28

Mortazavizadeh Z, Maercker A, Roth T, et al (2020)

Quality of the caregiving relationship and quality of life in mild Alzheimer's dementia.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society [Epub ahead of print].

BACKGROUND: The present study aims to investigate the quality of the dyadic relationship between mild Alzheimer patients and their caregivers. The main objective is to evaluate the consistency, agreement and validity of the German version of the Scale for Quality of the Current Relationship in Caregiving (SQCRC). The secondary objective was to examine the association of relationship quality with quality of life (QOL) in patients with mild Alzheimer's disease (AD) and their caregivers.

METHODS: In this study, a sample of 50 patients diagnosed with mild AD and their primary caregivers were included. Participants underwent a full neuropsychological evaluation. The quality of the relationship between persons with AD and their caregivers was assessed using the SQCRC. Furthermore, other scales of relationship quality, well-being of the person with AD, and well-being of the caregiver were used.

RESULTS: The results showed that the SQCRC has a good internal consistency and high validity. Also, relationship quality as rated by the AD patients (r = 0.37, P < 0.1) and their caregivers (r = 0.51, P < 0.1) was significantly correlated with QOL.

CONCLUSIONS: The findings suggest that many persons with mild AD can rate their relationship quality and that the patient's self-rated relationship quality is a substantial predictor of their QOL.

RevDate: 2020-03-28

Katdare A, Khunt D, Thakkar S, et al (2020)

Comparative evaluation of fish oil and butter oil in modulating delivery of galantamine hydrobromide to brain via intranasal route: pharmacokinetic and oxidative stress studies.

Drug delivery and translational research pii:10.1007/s13346-020-00739-y [Epub ahead of print].

The present study investigates the role of fish oil (FO)- and butter oil (BO)-enriched microemulsion-based system of galantamine hydrobromide (GH), an anti-Alzheimer drug, for its potential role in brain permeation enhancement and neuroprotection against oxidative stress. Microemulsion (ME)-based system of GH was prepared using water phase titration. The prepared ME was characterized by several physicochemical parameters like particle size, polydispersity index, and ex vivo drug permeation. Cell-based oxidative stress assays and pharmacokinetic studies were performed using C6 glial cell lines, and Sprague Dawley rats, respectively. The optimized ME comprised 5.3% v/v of Capmul MCM EP (as oil),15.8% v/v of Tween-80 (as surfactant), 5.3% v/v of Transcutol P (as co-surfactant), and 73.6% v/v of water (as aqueous phase). The addition of FO and BO resulted in a slight increase in the droplet size and decrease in transparency of ME. Cell-based anti-oxidative stress assays (glutathione assay, nitrite assay, and lipid peroxidation assay) showed the efficacy of formulation in the order of ME, BO ME, and FO ME, respectively. A similar trend was also observed in in vivo animal studies, wherein GH FO ME showed a comparatively higher percentage of drug reaching the brain when administered by intranasal route than by IV route. The study concluded the potential benefits of co-administering FO- and BO-enriched microemulsion is not only enhancing the permeation of drugs across BBB but also improving efficacy against lipopolysaccharide-induced oxidative stress. Graphical abstract.

RevDate: 2020-03-28

Yang R, P Bogdan (2020)

Controlling the Multifractal Generating Measures of Complex Networks.

Scientific reports, 10(1):5541 pii:10.1038/s41598-020-62380-6.

Mathematical modelling of real complex networks aims to characterize their architecture and decipher their underlying principles. Self-repeating patterns and multifractality exist in many real-world complex systems such as brain, genetic, geoscience, and social networks. To better comprehend the multifractal behavior in the real networks, we propose the weighted multifractal graph model to characterize the spatiotemporal complexity and heterogeneity encoded in the interaction weights. We provide analytical tools to verify the multifractal properties of the proposed model. By varying the parameters in the initial unit square, the model can reproduce a diverse range of multifractal spectrums with different degrees of symmetry, locations, support and shapes. We estimate and investigate the weighted multifractal graph model corresponding to two real-world complex systems, namely (i) the chromosome interactions of yeast cells in quiescence and in exponential growth, and (ii) the brain networks of cognitively healthy people and patients exhibiting late mild cognitive impairment leading to Alzheimer disease. The analysis of recovered models show that the proposed random graph model provides a novel way to understand the self-similar structure of complex networks and to discriminate different network structures. Additionally, by mapping real complex networks onto multifractal generating measures, it allows us to develop new network design and control strategies, such as the minimal control of multifractal measures of real systems under different functioning conditions or states.

RevDate: 2020-03-28

Montoya Y, Balbim GM, Glover CM, et al (2020)

"My Parent's Body Is Sacred": Perspectives From Adult Latino Children About Brain Donation for Alzheimer Disease Research.

Alzheimer disease and associated disorders [Epub ahead of print].

INTRODUCTION: Brain donation is a critical part of advancing research addressing Alzheimer disease and related dementias (ADRD). Studies on ADRD with an option for brain donation are reliant on family members to fulfill the research participant's plan for brain donation. Thus, family members play a pivotal role in increasing brain donation rates, particularly among under-represented groups.

METHODS: This study examines knowledge, attitudes, and beliefs about brain donation for research among Latinos. Latino men (N=4) and Latina women (N=11) 18 years of age or older with a parental figure age 65 years and over were invited to participate in a focus group.

RESULTS: Data analyses revealed 3 themes. Two themes focused on factors influencing a family's willingness to support brain donation: (a) social and cultural contexts, and (b) lack of knowledge and information about the brain donation process. The last theme provided recommendations for engaging older Latino adults in ADRD research and brain donation.

DISCUSSION: Results suggest being inclusive of family members during all stages of the research process, from recruitment to dissemination. In addition, addressing information gaps among Latinos about the process and benefits of brain donation may help mitigate mistrust and misperceptions and increase participation rates in brain donation.

RevDate: 2020-03-28

Carvalho DZ, St Louis EK, Schwarz CG, et al (2020)

Witnessed apneas are associated with elevated tau-PET levels in cognitively unimpaired elderly.

Neurology pii:WNL.0000000000009315 [Epub ahead of print].

OBJECTIVE: To assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.

METHODS: From the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.

RESULTS: Forty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010-0.087, p = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006-0.067, p = 0.019) in the inferior temporal cortex after controlling for confounders.

CONCLUSION: We identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.

RevDate: 2020-03-28

Kouzuki M, Ichikawa J, Shirasagi D, et al (2020)

Detection and recognition thresholds for five basic tastes in patients with mild cognitive impairment and Alzheimer's disease dementia.

BMC neurology, 20(1):110 pii:10.1186/s12883-020-01691-7.

BACKGROUND: Patients with Alzheimer's disease dementia (ADD) are thought to exhibit taste disorders; however, this has not been extensively studied. We investigated gustatory functions and factors affecting taste in patients with ADD or mild cognitive impairment (MCI) and in non-demented controls (NDCs) and evaluated associations between cognitive impairment and gustatory functions.

METHODS: We recruited 29 patients with ADD, 43 with MCI, and 14 with NDCs. We obtained medical and medication history, measured salivary secretion volumes, and performed cognitive function tests, blood tests, whole-mouth gustatory tests, and dietary and gustatory questionnaires.

RESULTS: Patients with ADD showed significantly higher recognition threshold values than NDCs (p < 0.05). Many individuals did not recognize umami at the maximum concentration, and this happened more frequently in patients with ADD or MCI than in NDCs. Evaluation items other than cognitive function tests did not show significant differences among the groups, but many individuals had decreased salivation, low serum zinc levels, and were on multiple medications. We found a significant correlation between recognition threshold and age (r = 0.229, p < 0.05) and cognitive function test score (r = 0.268, p < 0.05).

CONCLUSIONS: Patients with ADD showed impairment of gustatory function. Gustatory impairment in patients with MCI could not be confirmed. However, many individuals with MCI did not recognize umami, either. Our results suggest that taste disorders in elderly people with cognitive decline occur independently of factors affecting taste such as salivation, zinc levels, or prescription drugs.

TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trials Registry on February 10, 2017, with reference number UMIN000026087.

RevDate: 2020-03-27

Leblhuber F, Huemer J, Steiner K, et al (2020)

Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?.

Wiener klinische Wochenschrift pii:10.1007/s00508-020-01638-5 [Epub ahead of print].

BACKGROUND: Alzheimer's disease has chronic inflammatory components, which can be enhanced by systemic immune activation resulting in inflammation or vice versa. There is growing evidence that chronic periodontitis drives systemic inflammation and finally Alzheimer's disease. Thus, a link might exist between oral pathogens and Alzheimer's disease. This may be of special significance as there is an age-related incidence of chronic periodontitis.

METHODS: In this study, 20 consecutive patients with probable Alzheimer's disease were investigated. Diagnosis was established by cognitive tests, routine laboratory tests and cerebral magnetic resonance tomography. In 35% of these patients with cognitive impairment pathogenic periodontal bacteria were found.

RESULTS: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p < 0.03) and with a tendency to lower scores in the clock drawing test (p = 0.056). Furthermore, association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p < 0.01) as well as of kynurenine were found in Alzheimer patients positive vs. negative for Tannerella forsytia (p < 0.05).

CONCLUSIONS: Data indicate a possible association of specific periodontal pathogens with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in Alzheimer's disease. Albeit still preliminary, findings of the study may point to a possible role of an altered salivary microbiome as a causal link between chronic periodontitis and cognitive impairment in Alzheimer's disease.

RevDate: 2020-03-27

Cai B, Zhang Y, Wang Z, et al (2020)

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances.

Oxidative medicine and cellular longevity, 2020:3153082.

Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson's disease, Alzheimer's disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

RevDate: 2020-03-27

Espinosa-Val MC, Martín-Martínez A, Graupera M, et al (2020)

Prevalence, Risk Factors, and Complications of Oropharyngeal Dysphagia in Older Patients with Dementia.

Nutrients, 12(3): pii:nu12030863.

The prevalence of older patients with dementia and oropharyngeal dysphagia (OD) is rising and management is poor. Our aim was to assess the prevalence, risk factors, and long-term nutritional and respiratory complications during follow-up of OD in older demented patients. We designed a prospective longitudinal quasi-experimental study with 255 patients with dementia. OD was assessed with the Volume-Viscosity Swallowing Test and a geriatric evaluation was performed. OD patients received compensatory treatments based on fluid viscosity and texture modified foods and oral hygiene, and were followed up for 18 months after discharge. Mean age was 83.5 ± 8.0 years and Alzheimer's disease was the main cause of dementia (52.9%). The prevalence of OD was 85.9%. Up to 82.7% patients with OD required fluid thickening and 93.6% texture modification, with poor compliance. OD patients were older (p < 0.007), had worse functionality (p < 0.0001), poorer nutritional status (p = 0.014), and higher severity of dementia (p < 0.001) than those without OD and showed higher rates of respiratory infections (p = 0.011) and mortality (p = 0.0002) after 18 months follow-up. These results show that OD is very prevalent among patients with dementia and is associated with impaired functionality, malnutrition, respiratory infections, and increased mortality. New nutritional strategies should be developed to increase the compliance and therapeutic effects for this growing population of dysphagic patients.

RevDate: 2020-03-27

Ryan J, Storey E, Murray AM, et al (2020)

Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline.

Neurology pii:WNL.0000000000009277 [Epub ahead of print].

OBJECTIVE: To determine the effect of low-dose aspirin vs placebo on incident all-cause dementia, incident Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive decline in older individuals.

METHODS: Aspirin in Reducing Events in the Elderly (ASPREE) was a double-blind, placebo-controlled trial of low-dose aspirin. In the United States and Australia, community-dwelling individuals aged ≥70 years (US minorities ≥65 years) and free of cardiovascular disease, physical disability, and diagnosed dementia were enrolled. Participants were randomized 1:1-100 mg daily aspirin or placebo. The Modified Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test assessed cognition at baseline and over follow-up. Additional cognitive testing was performed in participants with suspected dementia ("trigger") based on within-study assessments or clinical history. Dementia was adjudicated according to DSM-IV criteria. National Institute on Aging-Alzheimer's Association criteria were used for AD and MCI subclassification.

RESULTS: A total of 19,114 participants were followed over a median 4.7 years and 964 triggered further dementia assessments. There were 575 adjudicated dementia cases, and 41% were classified as clinically probable AD. There was no substantial difference in the risk of all dementia triggers (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91-1.17), probable AD (HR, 0.96; 95% CI, 0.74-1.24), or MCI (HR, 1.12; 95% CI, 0.92-1.37) between aspirin and placebo. Cognitive change over time was similar in the aspirin and placebo groups.

CONCLUSIONS: There was no evidence that aspirin was effective in reducing risk of dementia, MCI, or cognitive decline. Follow-up of these outcomes after initial exposure is ongoing.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for healthy older individuals, low-dose aspirin does not significantly reduce the incidence of dementia, probable AD, MCI, or cognitive decline.


RevDate: 2020-03-27

Cui W, Fu W, Lin Y, et al (2020)

Application of nanomaterials in neurodegenerative diseases.

Current stem cell research & therapy pii:CSCR-EPUB-105486 [Epub ahead of print].

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease are very harmful brain lesions. Due to the difficulty in obtaining therapeutic drugs, the best treatment for neurodegenerative diseases is often not available. In addition, the blood-brain barrier can effectively prevent the transfer of cells, particles and macromolecules (such as drugs) in the brain, resulting in the failure of the traditional drug delivery system to provide adequate cellular structure repair and connection modes, which are crucial for the functional recovery of neurodegenerative diseases. Nanomaterials are designed to carry drugs across the blood-brain barrier for targets. Nanotechnology uses engineering materials or equipment to interact with biological systems at the molecular level to induce physiological responses through stimulation, response and target site interactions, while minimizing side effects, thus revolutionizing the treatment and diagnosis of neurodegenerative diseases. Some magnetic nanomaterials play a role as imaging agents or nanoprobes for Magnetic Resonance Imaging to assist in the diagnosis of neurodegenerative diseases. Although the current research on nanomaterials is not as useful as expected in clinical applications, it achieves a major breakthrough and guides the future development direction of nanotechnology in the application of neurodegenerative diseases. This review briefly discusses the application and advantages of nanomaterials in neurodegenerative diseases. Data for this review were identified by searches of PubMed, and references from relevant articles published in English between 2015 and 2019 were using the search terms "nanomaterials", "neurodegenerative diseases" and "blood-brain barrier".

RevDate: 2020-03-27

Martínez-Tomé M, Murcia MA, Rosario C, et al (2020)

Different Methods to Assess the Nutritional Status of Alzheimer Patients.

Journal of the American College of Nutrition [Epub ahead of print].

Objective: To assess the body composition and nutritional state of patients with Alzheimer's (Global Deterioration Scale GDS-4) using different methods and to investigate the correlation among methods.Methods: A total of 25 Alzheimer GDS-4 patients participated in this transversal descriptive observational study, which used anthropometry, Mini Nutritional Assessment (MNA), the Nutrition Screening Initiative Check List (NSI) and a 24-hour recall questionnaire (R24h).Results: Anthropometric observations pointed to obesity in patients of both sexes. The MNA showed that 76% of the population was "at risk of malnutrition", and the NSI suggested that 32% had a high nutritional risk, 48% had an "average" nutritional risk, and the remaining 20% a low nutritional risk. The Bland-Alman concordance plot between the NSI and MNA tests pointed to a high degree of agreement, meaning that both tests provided similar results for the group of studied subjects. The nutritional analysis, based on the Kruskal-Wallis test, showed there were significant differences between R24h and MNA in the case of ascorbic acid, iron, zinc and potassium (p < 0.05), and between R24h and NSI in the case of the double unsaturation index and vitamin D3 (p < 0.05). These results suggest that both questionnaires are equally valid for evaluating the nutritional status of Alzheimer patients.Conclusion: Although the NSI and MNA tests provide similar results, we recommend an initial nutritional assessment using the NSI since it is short but provides information on any alteration in food intake as a result of restrictions and/or metabolic alterations.

RevDate: 2020-03-26

Kutzsche J, Jürgens D, Willuweit A, et al (2020)

Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study.

Alzheimer's & dementia (New York, N. Y.), 6(1):e12001 pii:TRC212001.

Introduction: PRI-002 is an orally available anti-amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease.

Methods: Two placebo-controlled clinical phase I trials with oral dosing of PRI-002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI-002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI-002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters.

Results: PRI-002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI-002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady-state conditions were reached after 1 to 2 weeks.

Conclusions: The safety and PK results encourage further clinical development of PRI-002.

RevDate: 2020-03-26

Day GS, Rappai T, Sathyan S, et al (2020)

Deciphering the factors that influence participation in studies requiring serial lumbar punctures.

Alzheimer's & dementia (Amsterdam, Netherlands), 12(1):e12003 pii:DAD212003.

Introduction: Cerebrospinal fluid biomarkers increasingly inform the causes of dementia and may provide objective markers of disease progression. There is a need to decipher participant and procedural factors that promote participation in studies incorporating longitudinal biomarker measures.

Methods: Participant and procedural factors associated with participation in longitudinal biomarker studies were determined in individuals enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (Saint Louis, MO, USA).

Results: Complications were encountered following 331 of 1484 lumbar punctures (22.3%; LPs), affecting 280 of 929 participants (30.1%); in >95% complications were minor. Three hundred fifteen of 679 eligible participants (46.4%) completed multiple LPs. Younger age (odds ratio [OR] 2.08 per decade [95% confidence interval (CI) 1.61-2.94]), normal cognition (OR 21.4 [2.85-160.1]), and the absence of heart disease (OR 2.0 [1.01-3.85]) or seizures at study entry identified participants with increased odds of completing three or more LPs.

Discussion: Factors influencing participation may be leveraged to improve recruitment and retention within observational and therapeutic studies requiring serial LPs.

RevDate: 2020-03-26

Martínez-Iglesias O, Carrera I, Carril JC, et al (2020)

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders.

International journal of molecular sciences, 21(6): pii:ijms21062220.

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.

RevDate: 2020-03-26

Kaskikallio A, Karrasch M, Koikkalainen J, et al (2020)

White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study.

Dementia and geriatric cognitive disorders pii:000506124 [Epub ahead of print].

BACKGROUND: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD.

OBJECTIVE: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data.

METHODS: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86).

RESULTS: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically.

CONCLUSIONS: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.

RevDate: 2020-03-26

Alber J, Maruff P, Santos CY, et al (2020)

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

Alzheimer's research & therapy, 12(1):31 pii:10.1186/s13195-020-00599-1.

BACKGROUND: Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval.

METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam.

RESULTS: Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period.

CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

RevDate: 2020-03-26

Raghuvanshi R, S Bharate (2020)

Preclinical and clinical studies on bryostatins, a class of marine-derived protein kinase C modulators: A mini-review.

Current topics in medicinal chemistry pii:CTMC-EPUB-105477 [Epub ahead of print].

Bryostatins are complex macrolactones isolated from marine organism Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacopjoric features important for PKC modulation. The low natural abundance and long synthetic route has promoted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton primarily comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity, however the cyclic framework appears to be essential for desired potency. Another simplified analog 17 ("picolog") exhibited potent in vitro and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown acceptable IV pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials, however it has shown minimal effect as a single agent, however provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Apart from cancer, bryostatin-1 was also investigated in clinical studies for Alzheimer disease and HIV infection. In nutshell, the natural as well as synthetic bryostatins have generated strong hope to emerge as treatment for cancer or Alzheimer disease.

RevDate: 2020-03-24

Branigan GL, Soto M, Neumayer L, et al (2020)

Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer.

JAMA network open, 3(3):e201541 pii:2763234.

Importance: The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear.

Objective: To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer.

This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from private-payer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020.

Exposure: Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors).

Main Outcomes and Measures: Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias.

Results: Of the 326 485 women with breast cancer in the Humana data set between 2007 and 2017, 57 843 met the study criteria. Of these, 18 126 (31.3%; mean [SD] age, 76.2 [7.0] years) received HMT, whereas 39 717 (68.7%; mean [SD] age, 76.8 [7.0] years) did not receive HMT. Mean (SD) follow-up was 5.5 (1.8) years. In the propensity score-matched population, exposure to HMT was associated with a decrease in the number of women who received a diagnosis of NDD (2229 of 17 878 [12.5%] vs 2559 of 17 878 [14.3%]; relative risk, 0.89; 95% CI, 0.84-0.93; P < .001), Alzheimer disease (877 of 17 878 [4.9%] vs 1068 of 17 878 [6.0%]; relative risk, 0.82; 95% CI, 0.75-0.90; P < .001), and dementia (1862 of 17 878 [10.4%] vs 2116 of 17 878 [11.8%]; relative risk, 0.88; 95% CI, 0.83-0.93; P < .001). The number needed to treat was 62.51 for all NDDs, 93.61 for Alzheimer disease, and 69.56 for dementia.

Conclusions and Relevance: Among patients with breast cancer, tamoxifen and steroidal aromatase inhibitors were associated with a decrease in the number who received a diagnosis of NDD, specifically Alzheimer disease and dementia.

RevDate: 2020-03-24

Butterfield DA (2020)


Ageing research reviews pii:S1568-1637(19)30498-2 [Epub ahead of print].

Brains from persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), exhibit high levels of oxidative damage, including that to phospholipids. One type of oxidative damage is lipid peroxidation, the most important index of which is protein-bound 4-hydroxy-2-trans-nonenal (HNE). This highly reactive alkenal changes the conformations and lowers the activities of brain proteins to which HNE is covalently bound. Evidence exists that suggests that lipid peroxidation is the first type of oxidative damage associated with amyloid β-peptide (Aβ), a 38-42 amino acid peptide that is highly neurotoxic and critical to the pathophysiology of AD. The Butterfield laboratory is one of, if not the, first research group to show that Aβ42 oligomers led to lipid peroxidation and to demonstrate this modification in brains of subjects with AD and MCI. The Mattson laboratory, particularly when Dr. Mattson was a faculty member at the University of Kentucky, also showed evidence for lipid peroxidation associated with Aβ peptides, mostly in in vitro systems. Consequently, there is synergy between our two laboratories. Since this special tribute issue of Aging Research Reviews is dedicated to the career of Dr. Mattson, a review of some aspects of this synergy of lipid peroxidation and its relevance to AD, as well as the role of lipid peroxidation in the progression of this dementing disorder seems germane. Accordingly, this review outlines some of the individual and/or complementary research on lipid peroxidation related to AD published from our two laboratories either separately or jointly.

RevDate: 2020-03-23

Peng C, Trojanowski JQ, VM Lee (2020)

Protein transmission in neurodegenerative disease.

Nature reviews. Neurology pii:10.1038/s41582-020-0333-7 [Epub ahead of print].

Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.

RevDate: 2020-03-23

Fyfe I (2020)

Closer to a blood test for Alzheimer disease.

Nature reviews. Neurology pii:10.1038/s41582-020-0347-1 [Epub ahead of print].

RevDate: 2020-03-23

Nitsche A, Arnold C, Ueberham U, et al (2020)

Alzheimer-related genes show accelerated evolution.

Molecular psychiatry pii:10.1038/s41380-020-0680-1 [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disorder of unknown cause with complex genetic and environmental traits. While AD is extremely prevalent in human elderly, it hardly occurs in non-primate mammals and even non-human-primates develop only an incomplete form of the disease. This specificity of AD to human clearly implies a phylogenetic aspect. Still, the evolutionary dimension of AD pathomechanism remains difficult to prove and has not been established so far. To analyze the evolutionary age and dynamics of AD-associated-genes, we established the AD-associated genome-wide RNA-profile comprising both protein-coding and non-protein-coding transcripts. We than applied a systematic analysis on the conservation of splice-sites as a measure of gene-structure based on multiple alignments across vertebrates of homologs of AD-associated-genes. Here, we show that nearly all AD-associated-genes are evolutionarily old and did not originate later in evolution than not-AD-associated-genes. However, the gene-structures of loci, that exhibit AD-associated changes in their expression, evolve faster than the genome at large. While protein-coding-loci exhibit an enhanced rate of small changes in gene structure, non-coding loci show even much larger changes. The accelerated evolution of AD-associated-genes indicates a more rapid functional adaptation of these genes. In particular AD-associated non-coding-genes play an important, as yet largely unexplored, role in AD. This phylogenetic trait indicates that recent adaptive evolution of human brain is causally involved in basic principles of neurodegeneration. It highlights the necessity for a paradigmatic change of our disease-concepts and to reconsider the appropriateness of current animal-models to develop disease-modifying strategies that can be translated to human.

RevDate: 2020-03-23

Stavrovskaya AV, Voronkov DN, Shestakova EA, et al (2019)

[Streptozocin-induced Alzheimer's disease as an independent risk factor for the development of hyperglycemia in Wistar rats].

Problemy endokrinologii, 65(5):351-361.

BACKGROUND: In recent years the theme of the relationship of Alzheimers disease (AD) and metabolic disorders has been widely discussed. Nevertheless, it remains unclear whether AD is a direct cause of carbohydrate metabolism disorders or it is the presence of classical risk factors for type 2 diabetes mellitus (DM 2), primarily obesity, that significantly increases the risk of AD.

AIM: To evaluate the separate contribution of two factors to the development of disorders of carbohydrate metabolism: (1) weight gain due to a high-calorie diet and (2) experimental-induced AD.

METHODS: Male Wistar rats were injected with streptozocin (STZ) in the lateral ventricles of the brain to induce AD or saline (sham operated animals - SO) during stereotactic operations. After 2 weeks, the animals were divided into four groups: 1) the SO group, which was assigned to the normal calorie (NCD) diet (SO NCD); 2) the SO group, which was assigned to the high-calorie diet (SO HCD); 3) the group to which the norm-calorie diet was prescribed after the administration of STZ into the lateral ventricles of the brain (STZ NCD); 4) the group to which the HCD was assigned after the administration of STZ (STZ HCD). The animals were on a diet for 3 months. Intraperitoneal glucose tolerance tests were carried out before the diet and after 3 months. At the end of the study, a morphological assessment of brain tissue, pancreas, and liver was performed.

RESULTS: 3 months after surgical interventions and the appointment of diets, the glycemic curves significantly differed in the 4 studied groups: normoglycemia persisted only in the SO + NCD group, while HCD and the STZ administration were accompanied by the development of hyperglycemia (p = 0.0001). The STZ + NСD group, which represented the isolated effect of AD, was also characterized by impaired carbohydrate metabolism. A morphological study showed that HCD leads to a more pronounced ectopic accumulation of fat in the liver and pancreas tissue than NCD. The administration of STZ, regardless of the diet, led to changes typical for the AD model an increase in the size of the ventricles of the brain, degeneration of white matter, and the accumulation of -amyloid in the hypothalamus.

CONCLUSIONS: The STZ-induced brain damage typical for AD led to impaired carbohydrate metabolism regardless of diet and was an independent risk factor for hyperglycemia.

RevDate: 2020-03-23

André C, Rehel S, Kuhn E, et al (2020)

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

JAMA neurology pii:2763344 [Epub ahead of print].

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.

Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism.

This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses.

Main Outcomes and Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes.

Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms.

Conclusions and Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

RevDate: 2020-03-23

Tower J, Pomatto LCD, KJA Davies (2020)

Sex differences in the response to oxidative and proteolytic stress.

Redox biology pii:S2213-2317(19)31045-6 [Epub ahead of print].

Sex differences in diseases involving oxidative and proteolytic stress are common, including greater ischemic heart disease, Parkinson disease and stroke in men, and greater Alzheimer disease in women. Sex differences are also observed in stress response of cells and tissues, where female cells are generally more resistant to heat and oxidative stress-induced cell death. Studies implicate beneficial effects of estrogen, as well as cell-autonomous effects including superior mitochondrial function and increased expression of stress response genes in female cells relative to male cells. The p53 and forkhead box (FOX)-family genes, heat shock proteins (HSPs), and the apoptosis and autophagy pathways appear particularly important in mediating sex differences in stress response.

RevDate: 2020-03-22

Lyu M, Liu H, Ye Y, et al (2020)

Inhibition effect of thiol-type antioxidants on protein oxidative aggregation caused by free radicals.

Biophysical chemistry, 260:106367 pii:S0301-4622(20)30075-2 [Epub ahead of print].

This study was aimed to investigate the inhibition effect of thiol-type antioxidants on protein oxidative aggregation caused by free radicals and the underlying mechanisms using six different thiol-type antioxidants (N-acetyl-L-cysteine, methionine, taurine, alpha-lipoic acid, glutathione and thioproline), Cu2+-H2O2 as a free radical generator (mainly a hydroxyl radical generator) and bovine serum albumin as the model protein. The inhibition effect of these antioxidants on protein oxidative aggregation and protective effect against oxidative damage in mouse brain tissues were investigated using SDS-PAGE, intrinsic fluorescence, simultaneous fluorescence, thioflavin T fluorescence, Congo red absorbance and inverted microscope. The results showed that all six antioxidants could inhibit protein oxidative aggregation by scavenging free radicals. In addition, alpha-lipoic acid could also bind to proteins via hydrophobic interactions and thioproline could bind to proteins via hydrogen bonds and van der Waals forces, thereby showing much stronger inhibition effect than others. Moreover, alpha-lipoic acid and thioproline could effectively prevent oxidative damage of mouse brain tissues. These results suggest that alpha-lipoic acid and thioproline can effectively inhibit free radical-induced protein aggregation and brain damage, which are worth testing for further anti-Alzheimer properties.

RevDate: 2020-03-22

Eckert GP, Eckert SH, Eckmann J, et al (2020)

Olesoxime improves cerebral mitochondrial dysfunction and enhances Aβ levels in preclinical models of Alzheimer's disease.

Experimental neurology pii:S0014-4886(20)30117-5 [Epub ahead of print].

BACKGROUND: Approved drugs for Alzheimer's disease (AD) only have a symptomatic effect and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AβPP) and mitochondrial dysfunction.

METHODS: Three months old Thy-1-AβPPSL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aβ1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aβ1-40 levels were also determined in HEK-AβPPsw-cells.

RESULTS: Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2 μg/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aβ1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells.

CONCLUSIONS: TRO19622 improves mitochondrial dysfunction but enhances Aβ levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aβ, which could be harmful.

RevDate: 2020-03-21

Riancho J, Sanchez de la Torre JR, Paz-Fajardo L, et al (2020)

The role of magnetic fields in neurodegenerative diseases.

International journal of biometeorology pii:10.1007/s00484-020-01896-y [Epub ahead of print].

The term neurodegenerative diseases include a long list of diseases affecting the nervous system that are characterized by the degeneration of different neurological structures. Among them, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are the most representative ones. The vast majority of cases are sporadic and results from the interaction of genes and environmental factors in genetically predisposed individuals. Among environmental conditions, electromagnetic field exposure has begun to be assessed as a potential risk factor for neurodegeneration. In this review, we discuss the existing literature regarding electromagnetic fields and neurodegenerative diseases. Epidemiological studies in AD, PD, and ALS have shown discordant results; thus, a clear correlation between electromagnetic exposure and neurodegeneration has not been demonstrated. In addition, we discuss the role of electromagnetic radiation as a potential non-invasive therapeutic strategy for some neurodegenerative diseases, particularly for PD and AD.

RevDate: 2020-03-21

Strandberg TE, Tienari PJ, M Kivimäki (2020)

Vascular and Alzheimer Disease in Dementia.

RevDate: 2020-03-20

Dyer AH, Lawlor B, Kennelly SP, et al (2020)

Sexual dimorphism in the association of APOE ε4 genotype with cognitive decline and dementia progression in mild-to-moderate Alzheimer disease.

RevDate: 2020-03-20

Lektemur Alpan A, Çalişir M, Kizildağ A, et al (2020)

Effects of a Glycogen Synthase Kinase 3 Inhibitor Tideglusib on Bone Regeneration With Calvarial Defects.

The Journal of craniofacial surgery [Epub ahead of print].

Tideglusib is a glycogen synthase kinase 3 (GSK-3) inhibitor which has shown the effects of bone regeneration, used for the treatment of Alzheimer disease. The aim of the study was to determine the effects of Tideglusib in the apoptosis and the bone regeneration in rats with calvarial defects. Twenty male Wistar rats (aged 11-13 weeks) were used for the study. Full-thickness flap elevated to exposure calvarial bone. Two 5 mm critical size calvarial defects were created on each rat calvarium. The defects were divided into 4 study groups: 1-Control (n = 10); 2- Gelatin sponge+Tideglusib (Gs+TDG; n = 10); 3- Autogenous bone (AB; n = 10); 4-Autogenous bone+Tideglusib (AB+TDG; n = 10). Then, the rats were sacrificed at fourth week. Three-dimensional imaging, histopathologic and immunohistochemical examinations were performed to evaluate the samples. The most increased bone formation and interaction between graft and new bone were observed in AB+TDG group. Bone morphogenic protein-2 (BMP-2), alkaline phosphatase (ALP), collagen type 1 (Col 1) and osteocalcin (OCN) was determined significantly higher in Tideglusib received groups compared with those of Control and AB groups (P < 0.05). Osteoclast numbers found to be higher in Gs+TDG and AB+TDG groups as well as RANKL expression dis not affected in Gs+TDG group but decreased in AB+TDG group comparing those of Control and AB groups. In addition, Tideglusib increased the Bcl-2 levels (P < 0.05) and decreased Bax levels (P > 0.05) in Tideglusib received groups compared with their controls. The administration of Tideglusib in calvarial bone defects increased bone mineral density, new bone area and total bone area by decreasing apoptosis and increasing osteoblastogenesis.

RevDate: 2020-03-20

Giorgio A, Zhang J, Costantino F, et al (2020)

Altered Large-Scale Brain Functional Connectivity in Ocular Hypertension.

Frontiers in neuroscience, 14:146.

We hypothesized that assessment of brain connectivity may shed light on the underpinnings of ocular hypertension (OHT), characterized by raised intraocular pressure (IOP) and no typical glaucomatous findings. OHT carries a risk for future glaucoma development, thus representing a model of presymptomatic condition. In previous studies on glaucoma, we showed altered brain connectivity since the early stage and in case of normal IOP. In this pilot study, we used a multimodal MRI approach by modeling voxelwise measures of gray matter volume, anatomical connectivity along white matter(WM) tracts, and large-scale functional connectivity in OHT subjects (n = 18, age: 58.3 ± 9.8 years) and demographically matched normal controls (n = 29). While OHT brain had no structural alterations, it showed significantly decreased functional connectivity in key cognitive networks [default mode network, frontoparietal working memory network (WMN), ventral attention network (VAN), and salience network (SN)] and altered long-range functional connectivity, which was decreased between default mode and SNs and increased between primary and secondary visual networks (VN). Overall, such findings seem to delineate a complex neuroplasticity in the OHT brain, where decreased functional connectivity in non-visual networks may reflect a type of temporarily downregulated functional reserve while increased functional connectivity between VN may be viewed as a very early attempt of adaptive functional reorganization of the visual system.

RevDate: 2020-03-20

Pastore A, Raimondi F, Rajendran L, et al (2020)

Why does the Aβ peptide of Alzheimer share structural similarity with antimicrobial peptides?.

Communications biology, 3(1):135 pii:10.1038/s42003-020-0865-9.

The Aβ peptides causally associated with Alzheimer disease have been seen as seemingly purposeless species produced by intramembrane cleavage under both physiological and pathological conditions. However, it has been increasingly suggested that they could instead constitute an ancient, highly conserved effector component of our innate immune system, dedicated to protecting the brain against microbial attacks. In this antimicrobial protection hypothesis, Aβ aggregation would switch from an abnormal stochastic event to a dysregulated innate immune response. In this perspective, we approach the problem from a different and complementary perspective by comparing the structure and sequence of Aβ(1-42) with those of bona fide antimicrobial peptides. We demonstrate that Aβ(1-42) bears convincing structural similarities with both viral fusion domains and antimicrobial peptides, as well as sequence similarities with a specific family of bacterial bacteriocins. We suggest a model of the mechanism by which Aβ peptides could elicit the immune response against microbes.

RevDate: 2020-03-19

Papuć E, K Rejdak (2020)

The role of myelin damage in Alzheimer's disease pathology.

Archives of medical science : AMS, 16(2):345-351 pii:33217.

Although Alois Alzheimer described myelin disruption in Alzheimer's disease (AD) as early as in 1911, his observation has escaped the attention of researchers since that time. Alzheimer's disease has been mainly considered as a grey matter disorder; nevertheless, recent evidence suggests that myelin impairment may play an important role in AD pathology. Classical neuropathological changes in AD, e.g. the accumulation of aggregated Aβ 42 and the presence of neurofibrillary tangles, are responsible for neuronal loss, but they may also induce death of oligodendrocytes and myelin damage. There is also evidence that myelin pathology may even precede Aβ and tau pathologies in AD. The state of the art does not allow us to determine whether myelin damage is a primary or a secondary injury in AD subjects. The article presents an overview of current knowledge on the role of myelin in AD pathology and its interactions with Aβ and tau pathologies.

RevDate: 2020-03-19

Semba RD (2020)

Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease.

Advances in nutrition (Bethesda, Md.) pii:5809990 [Epub ahead of print].

Alzheimer disease (AD), the most common cause of dementia, is a progressive disorder involving cognitive impairment, loss of learning and memory, and neurodegeneration affecting wide areas of the cerebral cortex and hippocampus. AD is characterized by altered lipid metabolism in the brain. Lower concentrations of long-chain PUFAs have been described in the frontal cortex, entorhinal cortex, and hippocampus in the brain in AD. The brain can synthesize only a few fatty acids; thus, most fatty acids must enter the brain from the blood. Recent studies show that PUFAs such as DHA (22:6) are transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC) via a specific LPC receptor at the BBB known as the sodium-dependent LPC symporter 1 (MFSD2A). Higher dietary PUFA intake is associated with decreased risk of cognitive decline and dementia in observational studies; however, PUFA supplementation, with fatty acids esterified in triacylglycerols did not prevent cognitive decline in clinical trials. Recent studies show that LPC is the preferred carrier of PUFAs across the BBB into the brain. An insufficient pool of circulating LPC containing long-chain fatty acids could potentially limit the supply of long-chain fatty acids to the brain, including PUFAs such as DHA, and play a role in the pathobiology of AD. Whether adults with low serum LPC concentrations are at greater risk of developing cognitive decline and AD remains a major gap in knowledge. Preventing and treating cognitive decline and the development of AD remain a major challenge. The LPC pathway is a promising area for future investigators to identify modifiable risk factors for AD.

RevDate: 2020-03-19

Rashid MH, Zahid MF, Zain S, et al (2020)

The Neuroprotective Effects of Exercise on Cognitive Decline: A Preventive Approach to Alzheimer Disease.

Cureus, 12(2):e6958.

Alzheimer's disease (AD) is a progressive disorder that causes brain cells to slowly degenerate and die. This leads to a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. AD is the most common cause of dementia globally. Neuroinflammation caused by intracellular neurofibrillary tangles and extracellular amyloid deposits leads to atrophy of brain cells especially the hippocampus, which is associated with memory formation. This atrophy leads to dementia and cognitive decline. Among the many preventive factors being studied, exercise is thought to play a vital role in not only preventing the pre-clinical stage of AD but also slowing the clinical progression of AD. It is also deployed as a treatment option for late-stage AD along with pharmacological treatment options. Various studies and clinical trials in both human and animal models are of the opinion that exercise slows the onset and progression of cognitive decline in AD patients. Some studies suggest that this effect is due to a decrease in neurofibrillary tangles and amyloid deposits in brain parenchyma. Others suggest that exercise causes an increase in angiogenesis, neurogenesis, and synaptogenesis mainly due to an increase in blood flow, brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), hormones, and second messengers.

RevDate: 2020-03-19

Aljanabi NM, Mamtani S, Al-Ghuraibawi MMH, et al (2020)

Alzheimer's and Hyperglycemia: Role of the Insulin Signaling Pathway and GSK-3 Inhibition in Paving a Path to Dementia.

Cureus, 12(2):e6885.

In this project, we are trying to review the articles that discuss the relationship between insulin signaling and Alzheimer's disease (AD). Another focus of this project is to find the best treatment regimen that can reduce the progression of AD in patients with impaired glucose metabolism. We used Pubmed database to collect our data and used the following keywords: Alzheimer's disease, insulin signaling pathway, type 3 diabetes, type 2 diabetes, insulin, and insulin resistance in our revision; we included free articles that were published in the last 10 years and excluded articles that were written in any language other than English. We reviewed 68 articles. Forty-nine out of 68 articles were containing materials that are relevant for this project. We found that there is a relation between AD and the insulin signaling pathway. Insulin signaling pathway impairment leads to hyperphosphorylation of Tau protein, which plays a vital role in AD pathology. The effect of insulin on cognition is bidirectional; the intranasal route of insulin showed to have a promising effect on cognition improvement. Subcutaneous and intravenous insulin can increase the risk of dementia. Further studies are encouraged to use a specific anti-diabetic medication that can reduce the progression of AD.

RevDate: 2020-03-19

Casadesus G, Servizi S, R Corrigan (2020)

The Importance of Understanding Amylin Signaling Mechanisms for Therapeutic Development in the Treatment of Alzheimer's Disease.

Current pharmaceutical design pii:CPD-EPUB-105356 [Epub ahead of print].

Type II Diabetes (T2D) is a major risk factor for Alzheimer's Disease (AD). These two diseases share several pathological features including amyloid accumulation, inflammation, oxidative stress, cell death and cognitive decline. The metabolic hormone amylin and amyloid beta are both amyloids known to self-aggregate in T2D and AD, respectively, and are thought to be the main pathogenic entities in their respective diseases. Furthermore, studies suggest amylin's ability to seed amyloid beta aggregation, the activation of common signaling cascades in the pancreas and the brain, and the ability of amyloid beta to signal through amylin receptors (AMYR), at least in vitro. However, paradoxically, non-aggregating forms of amylin such as pramlintide are given to treat T2D and functional and neuroprotective benefits of amylin and pramlintide administration have been reported in AD transgenic mice. These paradoxical results beget a deeper study of AMYR changes and signaling in T2D to be able to fully understand its potential role in mediating AD development or prevention. The AMYR is composed of the Calcitonin Receptor complexed to a Receptor Activity Modifying Protein (RAMP). Studies have shown that RAMPs 1 & 3 are the two isoforms most responsible for signaling in the brain. However, how, specifically, amylin signals through these two isoforms to potentially drive toxicity or neuroprotection remains unknown. The goal of this review is to summarize the known functions of amylin through different biological systems and to begin to elucidate the relationship between T2D, AMYR signaling, and how these factors may influence mechanisms of AD pathogenesis.

RevDate: 2020-03-18

Yu C, Wang L, Kong L, et al (2018)

Acupoint combinations used for treatment of Alzheimer's disease: A data mining analysis.

Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan, 38(6):943-952.

OBJECTIVE: To identify the acupoint combinations used in the treatment of Alzheimer's disease (AD).

METHODS: The clinical literature regarding acupuncture and moxibustion for AD was searched and collected from databases including Chinese Biomedical Medicine, China National Knowledge Infrastructure, Wanfang Database and PubMed. The database of acupuncture and moxibustion prescriptions for AD was established by using Excel software so as to conduct the descriptive analysis, association analysis on the data.

RESULTS: Baihui (GV 20), Sishencong (EX-HN 1), Shenmen (HT 7), Zusanli (ST 36), Neiguan (PC 6), Fengchi (GB 20), Taixi (KI 3), Dazhui (GV 14), Shenshu (BL 23), Sanyinjiao (SP 6), Shenting (GV 24), Fenglong (ST 40), Xuanzhong (GB 39), Shuigou (GV 26) and Taichong (LR 3) were of higher frequency in the treatment of AD with acupnucture and moxibustion. Most acupoints were selected from the Governor Vessel. The commonly used acupoints were located on the head, face, neck and lower limbs. The combination of the local acupoints with the distal ones was predominated. The crossing points among the specific points presented the advantage in the treatment. The association analysis indicated that the correlation among Fengchi (GB 20)-Baihui (GV 20) was the strongest, followed by combinations of Dazhui (GV 14)-Baihui (GV 20), Shenshu (BL 23)- Baihui (GV 20) and Neiguan (PC 6)- Baihui (GV 20) and indicated the common rules of the clinical acupoint selection and combination for AD.

CONCLUSION: Our findings provide a reference for acupoints selection and combination for AD in clinical acupuncture practice.

RevDate: 2020-03-18

Liu L, Yu C, J Liu (2018)

Effect of Cuzhi liquid on learning and memory dysfunction in a mouse model of Alzheimer's disease.

Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan, 38(6):890-895.

OBJECTIVE: To examine the effects of Cuzhi liquid on learning and memory abilities in a mouse model of Alzheimer's disease (AD).

METHODS: One hundred mice were divided into the normal, AD model, piracetam group, Cuzhi liquid low dose and Cuzhi liquid high dose, each group 20 mice. The AD mouse model was induced by daily intraperitoneal injection of D-galactose and sodium nitrite. AD mice then received intragastric administration of piracetam or Cuzhi liquid for 60 d, and changes in learning and memory abilities were assessed using the water maze test. The activity of acetylcholinsterase (AchE) and monamine oxidase (MAO), and the levels of nitrogen monoxidum (NO) and malonaldehyde (MDA), were measured in brain tissues. Amyloid protein deposition was assessed by methyl violet staining, and B-cell lymphoma-2 (Bcl-2) expression in the hippocampal cornus ammonis 1 region was detected by immunohistochemistry.

RESULTS: In the water maze test, the escape latency of the model group was longer than that of the normal group (P < 0.01). The escape latency of the three using drug treatment groups was significantly less than that of the normal group (P < 0.05). The activity of AchE and MAO, and the levels of NO and MDA, in the brain of the model group were significantly higher than that of the normal group (P < 0.01), but significantly reduced in the three drug treatment groups compared with the model group (P < 0.05). AchE activity showed a greater reduction in the two Cuzhi liquid groups compared with the piracetam group (P < 0.01), to levels similar to the normal group. There were no differences in MAO activity or NO levels between the three drug treatment groups, while MDA levels were reduced more in the high-dose Cuzhi liquid group compared with the other treatment groups (P < 0.01). Hippocampal Bcl-2 expression was significantly reduced in the model group compared with the normal group (P < 0.01), but significantly improved in the three drug treatment groups (P < 0.05). The high-dose Cuzhi liquid group showed a significantly greater recovery in Bcl-2 expression compared with the other treatment groups.

CONCLUSION: Cuzhi liquid can improve learning and memory impairment in an AD mouse model. The mechanism of action may relate to reduced AchE and MAO activity, and reduced NO and MDA levels, in the brain, and improved Bcl-2 expression, an inhibitor of apoptosis.

RevDate: 2020-03-18

Gauthreaux K, Bonnett TA, Besser LM, et al (2020)

Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy.

Journal of neuropathology and experimental neurology pii:5809581 [Epub ahead of print].

It remains unclear what clinical features inform the accuracy of a clinical diagnosis of Alzheimer disease (AD). Data were obtained from the National Alzheimer's Coordinating Center to compare clinical and neuropathologic features among participants who did or did not have Alzheimer disease neuropathologic changes (ADNC) at autopsy. Participants (1854) had a clinical Alzheimer dementia diagnosis and ADNC at autopsy (Confirmed-AD), 204 participants had an AD diagnosis and no ADNC (AD-Mimics), and 253 participants had no AD diagnosis and ADNC (Unidentified-AD). Compared to Confirmed-AD participants, AD-Mimics had less severe cognitive impairment, while Unidentified-AD participants displayed more parkinsonian signs, depression, and behavioral problems. This study highlights the importance of developing a complete panel of biomarkers as a tool to inform clinical diagnoses, as clinical phenotypes that are typically associated with diseases other than AD may result in inaccurate diagnoses.

RevDate: 2020-03-18

Chi H, Liu T, Pan W, et al (2019)

Shen-Zhi-Ling oral solution improves learning and memory ability in Alzheimer's disease mouse model.

Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan, 39(5):667-677.

OBJECTIVE: To investigate the effector mechanisms and effector targets of Shen-Zhi-Ling (SZL) oral solution in the treatment of Alzheimer's disease (AD).

METHODS: In this study, we carried out gavage with SZL oral solution in an APP/PS-1 heterozygous double transgenic AD mouse model for 12 continuous weeks. Haematoxylin and eosin staining, Nissl staining and Annexin V/Propidium Iodide staining were used to detect the brain histopathology in AD mouse model. Immunofluorescence staining was used to detect the expression levels of autophagy's proteins. Morris water maze test was used to detect the learning and memory ability in AD mouse model.

RESULTS: Pathological results showed that neuronal loss in the hippocampus of mice in the SZL intervention group was significantly alleviated and the number of apoptotic neurons was significantly decreased compared with the control group (physiological saline and non-intervention groups). Immunofluorescence staining results showed that the expression of autophagy activators, Beclin-1 and LC3B, was significantly increased in the hippocampal neurons of mice of the SZL intervention group, while the expression of the apoptotic factor, caspase-3, was significantly decreased. At the same time, hippocampal accumulation of Aβ42 protein was significantly decreased. In addition, results of the water maze experiment showed that the latency period in mice from the SZL intervention group was significantly reduced.

CONCLUSION: In summary, we believe that the SZL oral solution significantly activates autophagy in hippocampal neurons, effectively reducing the accumulation of Aβ42 peptides, alleviating neuronal injury and apoptosis, and ultimately improving the cognitive function in a mouse model of AD.

RevDate: 2020-03-18

Jessen F (2020)

[Pharmacological prevention of cognitive decline and dementia].

Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz pii:10.1007/s00103-020-03120-z [Epub ahead of print].

BACKGROUND: Dementias are among the most feared diseases and pose a threat to social and healthcare systems in aging societies. A cure for Alzheimer's or other dementias will not be achieved in the coming years, which makes prevention of cognitive decline and dementia a priority for research and patient-related services.

AIM: Summary of evidence for drug and other compound-related prevention of cognitive decline and dementia.

MATERIAL AND METHODS: Literature review of epidemiological evidence and clinical trials of antidementia drugs, anti-amyloid drugs under development, nonsteroidal anti-inflammatory drugs, statins, hormone replacement therapy, lithium, ginkgo biloba, and Fortasyn Connect.

RESULTS: There is evidence for effects on single endpoints and subgroups for some of the reviewed compounds, but there is no consistent evidence for efficacy.

DISCUSSION: There is no sufficient evidence to provide any specific or general recommendation for drug- or compound-related prevention of cognitive decline or dementia. It needs to be recognized that prevention trials on cognitive decline in aging and dementia require large numbers of participants and long follow-up times, which create major challenges with regard to conducting and financing such trials. The current state of evidence also supports the potential role of nonpharmacological approaches in dementia prevention.

RevDate: 2020-03-18

Lawrence J, J Sussman (2020)

ABN news.

Practical neurology, 20(2):183.

RevDate: 2020-03-18

Liu H, Ge W, Chen W, et al (2020)

Association between ALDH2 Gene Polymorphism and Late-onset Alzheimer Disease: An Up-to-date Meta-analysis.

OBJECTIVES: Previous case-control studies have focused on the relationship between ALDH2 gene polymorphism and late-onset Alzheimer's disease (LOAD), but no definite unified conclusion has been reached. Therefore, the correlation between ALDH2 Glu504Lys polymorphism and LOAD remains controversial. To analyze the correlation between ALDH2 polymorphism and the risk of LOAD, we implemented this up-to-date meta-analysis to assess the probable association.

METHODS: Studies were searched through China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, China Biology Medicine, PubMed, Cochrane Library, Clinical- Trials.gov, Embase, and MEDLINE from January 1, 1994 to December 31, 2018, without any restrictions on language and ethnicity.

RESULTS: Five studies of 1057 LOAD patients and 1136 healthy controls met our criteria for the analysis. Statistically, the ALDH2 GA/AA genotype was not linked with raising LOAD risk (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 0.96-2.28, p = 0.07). In subgroup analysis, the phenomenon that men with ALDH2*2 had higher risk for LOAD (OR = 1.72, 95%CI = 1.10-2.67, p = 0.02) was observed.

CONCLUSIONS: This study comprehends only five existing case-control studies, and the result is negative. The positive trend might appear when the sample size is enlarged. In the future, more large-scale casecontrol or cohort studies should be done to enhance the association between ALDH2 polymorphism and AD or other neurodegenerative diseases.

RevDate: 2020-03-18

García-Arriaza J, Marín MQ, Merchán-Rubira J, et al (2020)

Tauopathy Analysis in P301S Mouse Model of Alzheimer Disease Immunized With DNA and MVA Poxvirus-Based Vaccines Expressing Human Full-Length 4R2N or 3RC Tau Proteins.

Vaccines, 8(1): pii:vaccines8010127.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C-terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system.

RevDate: 2020-03-18

Cavalli E, Battaglia G, Basile MS, et al (2020)

Exploratory Analysis of iPSCS-Derived Neuronal Cells as Predictors of Diagnosis and Treatment of Alzheimer Disease.

Brain sciences, 10(3): pii:brainsci10030166.

Alzheimer's disease (AD) represents the most common neurodegenerative disorder, with 47 million affected people worldwide. Current treatment strategies are aimed at reducing the symptoms and do slow down the progression of the disease, but inevitably fail in the long-term. Induced pluripotent stem cells (iPSCs)-derived neuronal cells from AD patients have proven to be a reliable model for AD pathogenesis. Here, we have conducted an in silico analysis aimed at identifying pathogenic gene-expression profiles and novel drug candidates. The GSE117589 microarray dataset was used for the identification of Differentially Expressed Genes (DEGs) between iPSC-derived neuronal progenitor (NP) cells and neurons from AD patients and healthy donors. The Discriminant Analysis Module (DAM) algorithm was used for the identification of biomarkers of disease. Drugs with anti-signature gene perturbation profiles were identified using the L1000FWD software. DAM analysis was used to identify a list of potential biomarkers among the DEGs, able to discriminate AD patients from healthy people. Finally, anti-signature perturbation analysis identified potential anti-AD drugs. This study set the basis for the investigation of potential novel pharmacological strategies for AD. Furthermore, a subset of genes for the early diagnosis of AD is proposed.

RevDate: 2020-03-17

Li S, DJ Selkoe (2020)

A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Ab oligomers from Alzheimer brain.

Journal of neurochemistry [Epub ahead of print].

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β-protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease-relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators and diverse signaling pathways have all been suggested. Studies using AD brain-derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory-inhibitory balance, perturbing mGluR, PrP and other neuronal surface proteins, downregulating glutamate transporters, causing glutamate spillover and activating extrasynaptic GluN2B-containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.

RevDate: 2020-03-17

Verny M, C Duyckaerts (2020)

Cognitive deficit, and neuropathological correlates, in the oldest-old.

Revue neurologique pii:S0035-3787(20)30387-8 [Epub ahead of print].

Several disorders are usually involved in the cognitive deficit of the oldest old. Alzheimer disease is the commonest. It is usually characterized by progressive memory impairment - neocortical symptoms occurring much later in the course of the disease. Alzheimer disease should not be considered any more as the single cause of a cognitive deficit in a very old patient. Vascular alterations, possibly causing microinfarcts, are commonly associated, especially in cerebral amyloid angiopathy. A slowly progressive memory deficit with negative CSF biomarkers of Alzheimer's disease may be due to hippocampal sclerosis that may be the consequence of multiple causes: in most of the cases, it is associated with neuronal TDP-43 inclusions. Recently, a distribution of these inclusions to a territory more extensive than the hippocampus has been reported and attributed to a new entity, called Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) with or without hippocampal sclerosis. The presence of cortical Lewy bodies may cause an intellectual deficit or contribute to it. The prevalence of dementia with cortical Lewy bodies in the oldest old is discussed. Tau inclusions in cortical glia have also been shown to participate to the intellectual deficit. Association of neurodegenerative and vascular changes is the most frequent situation in the very old patients. Systemic diseases such as diabetes or heart failure, prescription drugs (when misused), or toxic such as alcohol may also contribute to the cognitive impairment and be amenable to treatment.

RevDate: 2020-03-17

Hanes J, Lacova-Dobakova E, P Majerova (2020)

Brain drug delivery: overcoming the blood-brain barrier to treat tauopathies.

Current pharmaceutical design pii:CPD-EPUB-105261 [Epub ahead of print].

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. These natural functions possessed by BBB are representing a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics delivery through BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with new advanced medical techniques. Their limitations and benefits are discussed.

RevDate: 2020-03-17

Li HC, Luo KX, Wang JS, et al (2020)

Extrapyramidal side effect of donepezil hydrochloride in an elderly patient: A case report.

Medicine, 99(11):e19443.

INTRODUCTION: Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is mainly manifested as memory impairment and a reduced ability to self-care, often accompanied by neuropsychiatric and behavioral disorders. Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD.

PATIENT CONCERNS: An 87-year-old woman presented with a 1-year history of forgetfulness that was aggravated since the past 2 months. She had a long-term history of multiple major conditions, including hypertension, diabetes, osteoporosis, and arterial plaques. Brain imaging showed age-related changes, and her Mini Mental State Examination score was 20. Other tests revealed no abnormalities apart from multiple thyroid nodules on ultrasonography.

DIAGNOSIS: She was diagnosed with AD, hypertension, type 2 diabetes mellitus, diabetic neuropathy, osteoporosis, carotid and lower-extremity arterial plaques, thyroid nodules.

INTERVENTIONS: She was treated with donepezil (5 mg/day), amlodipine besylate (5 mg/day), glimepiride (4 mg/day), methylcobalamin (1.5 mg/day), calcium carbonate D3 (600 mg/day), simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day).

OUTCOMES: Four days later, she experienced fatigue, panic, sweating, and one episode of vomiting. On the 5th day, she developed increased muscle tension, speech difficulty, and involuntary tremors. Imaging and blood tests revealed no obvious abnormality, and the patient was not receiving psychotropic drugs. An extrapyramidal adverse reaction to donepezil was considered, and the drug was discontinued, after which the symptoms gradually disappeared.

CONCLUSION: Serious adverse reactions to donepezil can occur in elderly patients, who typically require multiple medications for a variety of comorbidities. In particular, extrapyramidal reactions have occurred when donepezil is administered in combination with psychotropic drugs. However, in our patient, an extrapyramidal adverse reaction occurred in the absence of psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions and possible serious adverse reactions, and carefully monitor these patients to ensure the timely detection of adverse events and their safe treatment.

RevDate: 2020-03-16

Kim JH, Choi SH, JH Lee (2020)

The R278I Mutation of PSEN1 in the Familial Alzheimer Disease.

Dementia and neurocognitive disorders pii:19.e2 [Epub ahead of print].

RevDate: 2020-03-16

Ren L, Li Q, You T, et al (2020)

Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules.

Journal of cellular and molecular medicine [Epub ahead of print].

HNG, a highly potent mutant of the anti-Alzheimer peptide-humanin, has been shown to protect against ischaemia-reperfusion (I/R) injury. However, the underlying mechanism related to platelet activation remains unknown. We proposed that HNG has an effect on platelet function and thrombus formation. In this study, platelet aggregation, granule secretion, clot retraction, integrin activation and adhesion under flow conditions were evaluated. In mice receiving HNG or saline, cremaster arterial thrombus formation induced by laser injury, tail bleeding time and blood loss were recorded. Platelet microtubule depolymerization was evaluated using immunofluorescence staining. Results showed that HNG inhibited platelet aggregation, P-selectin expression, ATP release, and αIIb β3 activation and adhesion under flow conditions. Mice receiving HNG had attenuated cremaster arterial thrombus formation, although the bleeding time was not prolonged. Moreover, HNG significantly inhibited microtubule depolymerization, enhanced tubulin acetylation in platelets stimulated by fibrinogen or microtubule depolymerization reagent, nocodazole, and inhibited AKT and ERK phosphorylation downstream of HDAC6 by collagen stimulation. Therefore, our results identified a novel role of HNG in platelet function and thrombus formation potentially through stabilizing platelet microtubules via tubulin acetylation. These findings suggest a potential benefit of HNG in the management of cardiovascular diseases.

RevDate: 2020-03-16

Kim D, Yang PS, Jang E, et al (2020)

Blood Pressure Control and Dementia Risk in Midlife Patients With Atrial Fibrillation.

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

Atrial fibrillation (AF) is associated with increased risk of cognitive impairment and dementia, even with no overt stroke. Hypertension has been a potentially modifiable risk factor for dementia, especially in midlife (<70 years) individuals. We aimed to investigate the associations of blood pressure (BP) and hypertension burden with dementia risk among midlife AF patients. From the Korean National Health Insurance Service database, we enrolled 171 228 incident AF patients aged 50 to 69 years with no prior dementia from 2005 to 2016. During a mean of 6.6 years of follow-up, 9909 patients received a first-time diagnosis of dementia. U-shaped relationships were noted between systolic or diastolic BP and dementia risk: A 10 mm Hg increase or decrease in systolic BP starting from 120 mm Hg was associated with 4.4% (95% CI, 2.7%-6.0%) and 4.6% (95% CI, 0.1%-8.2%) higher dementia risk, respectively. An increase or decrease in diastolic BP starting from 80 mm Hg also increased dementia risk. In subtype analyses, Alzheimer disease increases with BP decrease whereas vascular dementia increases according to BP increase. When BP changes over time were accounted for in time-updated models, BP of 120 to 129/80 to 84 mm Hg was associated with the lowest dementia risk. Increasing hypertension burden (the proportion of days with increased BP during follow-up) was associated with higher dementia risk (hazard ratio, 1.10 per 10% increase [95% CI, 1.08-1.12]). Among midlife AF patients, there were a U-shaped association of BP and a log-linear association of hypertension burden with dementia risk. Minimizing the burden of hypertension in AF patients might help to prevent dementia.

RevDate: 2020-03-15

Guillemaud O, Ceyzériat K, Saint-Georges T, et al (2020)

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease.

Neurobiology of aging pii:S0197-4580(20)30037-3 [Epub ahead of print].

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we developed viral vectors targeting astrocytes that either activate or inhibit the Janus kinase-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway, a central cascade controlling astrocyte reaction. We aimed to evaluate whether reactive astrocytes contribute to tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops tau hyper-phosphorylation and amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in 25% of the hippocampus of 3xTg-AD mice did not significantly influence tau phosphorylation or amyloid processing and deposition at early, advanced, and terminal disease stage. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve spatial memory in the Y maze but it did reduce anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show they may impact behavioral outcomes without influencing tau or amyloid pathology.

RevDate: 2020-03-15

Cai T, T Tomita (2020)

Structure-activity relationship of presenilin in γ-secretase-mediated intramembrane cleavage.

Seminars in cell & developmental biology pii:S1084-9521(18)30291-X [Epub ahead of print].

Genetic research on familial cases of Alzheimer disease have identified presenilin (PS) as an important membrane protein in the pathomechanism of this disease. PS is the catalytic subunit of γ-secretase, which is responsible for the generation of amyloid-β peptide deposited in the brains of Alzheimer disease patients. γ-Secretase is an atypical protease composed of four membrane proteins (i.e., presenilin, nicastrin, anterior pharynx defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)) and mediates intramembrane proteolysis. Numerous investigations have been conducted toward understanding the structural features of γ-secretase components as well as the cleavage mechanism of γ-secretase. In this review, we summarize our current understanding of the structure and activity relationship of the γ-secretase complex.

RevDate: 2020-03-14

Wójtowicz S, Strosznajder AK, Jeżyna M, et al (2020)

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer's Disease and Other Neurodegenerative Disorders.

Neurochemical research pii:10.1007/s11064-020-02993-5 [Epub ahead of print].

Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization with retinoid X receptor (RXR) bind in promotor of target genes to PPAR response elements (PPREs) and act as a potent transcription factors. PPAR-α and other receptors from this family, such as PPAR-β/δ and PPAR-γ are expressed in the brain and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and inflammation. PPAR-α takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-α regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of α secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates β secretase (BACE-1), the main enzyme responsible for amyloid beta (Aβ) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregulation may decrease anti-oxidative and anti-inflammatory processes and could be responsible for the alteration of fatty acid transport, lipid metabolism and disturbances of mitochondria function in the brain of AD patients. Specific activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.

RevDate: 2020-03-14

Iizuka T, M Kameyama (2020)

Spatial metabolic profiles to discriminate dementia with Lewy bodies from Alzheimer disease.

Journal of neurology pii:10.1007/s00415-020-09790-8 [Epub ahead of print].

BACKGROUND: To differentiate dementia with Lewy bodies (DLB) from Alzheimer disease (AD) using a single imaging modality is challenging, because of their common hypometabolic findings. Scaled subprofile modeling/principal component analysis (SSM/PCA), an unsupervised artificial intelligence, has the potential to offer an alternative to image analysis.

OBJECTIVE: We aimed to produce spatial metabolic profiles to discriminate DLB from AD and to identify the characteristics of the profiles.

METHODS: Fifty individuals each with DLB, AD, and normal cognition (NL) underwent 18F-FDG-PET and MRI. The spatial metabolic profile to differentiate DLB from AD (DLB-AD discrimination profile) was determined using SSM/PCA with tenfold cross validation. For comparison, we also produced disease-related profiles that can discriminate AD and DLB from NL (AD- and DLB-related profiles, respectively).

RESULTS: The DLB-AD discrimination profile significantly differentiated DLB from AD with comparable accuracy to that of discriminating DLB and AD from NL. The AD- and DLB-related profiles comprised metabolic imaging features typical of each pathology. In contrast, the DLB-AD discrimination profile emphasized preservation in the posterior cingulate cortex (cingulate island sign) and medial temporal lobe, and occipital hypometabolism. Common hypometabolic findings between DLB and AD were less noticeable in the profile. The DLB-related profile significantly correlated with cognitive function and three core features of DLB, whereas the DLB-AD discrimination profile did not.

CONCLUSIONS: Spatial metabolic profile that could discriminate DLB from AD emphasized different imaging features and eliminated common findings between DLB and AD. Neither cognitive function nor core features were associated with the profile.

RevDate: 2020-03-14

Grzybowski A, P Kanclerz (2020)

Comment on Association of Age-Related Macular Degeneration on Alzheimer or Parkinson Disease: A Retrospective Cohort Study.

RevDate: 2020-03-14

Uddin MS, Kabir MT, Niaz K, et al (2020)

Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's Disease.

Molecules (Basel, Switzerland), 25(6): pii:molecules25061267.

Alzheimer's disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer's pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

RevDate: 2020-03-11

Castro-Silva ES, Bello M, Rosales-Hernández MC, et al (2020)

Fucosterol from Sargassum horridum as an amyloid-beta (Aβ1-42) aggregation inhibitor: in vitro and in silico studies.

Journal of biomolecular structure & dynamics [Epub ahead of print].

The number of patients diagnosed with Alzheimer's disease (AD) increases each year, and there are currently few treatment strategies to decrease the symptoms of AD; furthermore, these strategies are not sufficient to reduce memory loss in AD patients. In this work, in vitro and in silico studies were performed to evaluate the effects of fucosterol, which was extracted from an algal source and characterized by liquid chromatography-mass spectra (LC-MS), as an inhibitor of Aβ1-42 aggregation. Experimental studies, including protein gel electrophoresis, atomic force microscopy and fluorescence studies with thioflavin T (ThT), highlighted that fucosterol can decrease oligomer formation more than galantamine, which was used as a positive control. Docking and molecular dynamics simulations coupled with an MMGBSA approach showed that fucosterol is capable of recognizing the hydrophobic regions of monomeric Aβ1-42, suggesting that fucosterol could affect amyloid-beta (Aβ1-42) aggregation by preventing the formation of oligomers, preventing the development of AD.Communicated by Ramaswamy H. Sarma.

RevDate: 2020-03-13

Sadashima S, Honda H, Suzuki SO, et al (2020)

Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques.

Journal of neuropathology and experimental neurology pii:5804970 [Epub ahead of print].

Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.

RevDate: 2020-03-13

Yiannopoulou KG, SG Papageorgiou (2020)

Current and Future Treatments in Alzheimer Disease: An Update.

Journal of central nervous system disease, 12:1179573520907397 pii:10.1177_1179573520907397.

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a "precision medicine" context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

RevDate: 2020-03-13

Cheng C, Hirdes JP, Heckman G, et al (2020)

Predictors of Home Care Costs Among Persons With Dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis in Ontario.

Health services insights, 13:1178632920903731 pii:10.1177_1178632920903731.

Home care is an important service for persons with neurological conditions, but little is known about factors affecting health care costs in this setting. Using administrative data collected with the Resident Assessment Instrument for Home Care (RAI-HC), this study identified factors associated with home care costs for recipients of home care services with Alzheimer disease or related dementias, multiple sclerosis, and/or amyotrophic lateral sclerosis. As part of this study, the effectiveness of the Resource Utilization Groups for Home Care (RUG-III/HC), a case-mix classification system developed for the RAI-HC, in predicting care costs for this population, was also tested. Clinical characteristics indicative of greater disease severity had high levels of significance in predicting home care costs. In particular, the RUG-III/HC was highly predictive of home care costs for 3 neurological conditions, indicating the validity of this case-mix system for this population. With the increasing prevalence of neurological conditions and demand for home care services, future studies should continue to focus on identifying specific predictors care costs for those with neurological conditions in this care setting.

RevDate: 2020-03-12

Lubetzky AV, Gospodarek M, Arie L, et al (2020)

Auditory Input and Postural Control in Adults: A Narrative Review.

JAMA otolaryngology-- head & neck surgery pii:2762719 [Epub ahead of print].

Importance: An increase in the number of mechanistic studies targeting the association between sound and balance has been observed in recent years, but their results appear equivocal.

Observations: A search of PubMed and the Cochrane Database of Systematic Reviews for English-language studies on auditory input and postural control published from database inception through October 31, 2019, yielded 28 articles for review. These articles included 18 (64%) studies of healthy adults, 1 (4%) of participants with Alzheimer disease, 2 (7%) of participants with congenital blindness, 3 (11%) of participants with vestibular loss, and 4 (14%) of participants with diverse levels of hearing loss. Studies varied by the type of audio stimuli (natural vs generated sounds), apparatus (speakers vs headphones), and movement of sounds (eg, stationary, rotational). Most balance measurements involved standing on the floor or foam with eyes open or closed during which sway amount or velocity was quantified. Stationary broadband sounds, including white or environmental noise, may improve balance, but the results regarding stationary pure tone were inconclusive. The implication of moving sounds varied by apparatus (typically destabilizing when headphones were used) and sensory loss (more destabilizing with vestibular or hearing loss but perhaps less with a unilateral cochlear implant).

Conclusions and Relevance: Findings from this review suggest that stationary broadband noise can serve as an auditory anchor for balance primarily when projected via speakers and when the balance task is challenging. More research is needed that includes individuals with sensory loss and that tests paradigms using dynamic, ecologically valid sounds; clinicians should also consider auditory cues and the presence of hearing loss in balance and fall-risk assessments.

RevDate: 2020-03-12

Akimoto H, Negishi A, Oshima S, et al (2020)

Antidiabetic Drugs for the Risk of Alzheimer Disease in Patients With Type 2 DM Using FAERS.

American journal of Alzheimer's disease and other dementias, 35:1533317519899546.

Alzheimer disease (AD) may develop after the onset of type 2 diabetes mellitus (T2DM), and the risk of AD may depend on the antidiabetic drug administered. We compared the risk of AD among 66 085 patients (≥ 65 years) with T2DM (1250 having concomitant AD) who had been administered antidiabetic drug monotherapy for T2DM who had voluntarily reported themselves in the Food and Drug Administration Adverse Event Reporting System. The risk of AD from the use of different antidiabetic drug monotherapies compared to that of metformin monotherapy was assessed by logistic regression. Rosiglitazone (adjusted reporting odds ratio [aROR] = 0.11; 95% confidence interval [CI]: 0.07-0.17; P < .001), exenatide (aROR = 0.22; 95% CI: 0.11-0.37; P < .001), liraglutide (aROR = 0.36; 95% CI: 0.19-0.62; P < .001), dulaglutide (aROR = 0.39; 95% CI: 0.17-0.77; P = .014), and sitagliptin (aROR = 0.75; 95% CI: 0.60-0.93; P = .011) were found to have a significantly lower associated risk of AD than that of metformin. Therefore, the administration of glucagon-like peptide 1 receptor agonists and rosiglitazone may reduce the risk of AD in patients with T2DM.

RevDate: 2020-03-12

Mullard A (2020)

Alzheimer prevention hopes continue to dim.

RevDate: 2020-03-12

Hazif-Thomas C, V Lefebvre des Noëttes (2020)

Issues of the delisting of anti-Alzheimer's drugs in France: between the law and ethics.

Geriatrie et psychologie neuropsychiatrie du vieillissement, 18(1):97-102.

Going back to the delisting of drugs for Alzheimer's disease under the double prism of the jurisprudence of the State Council and from a sidestep of ethics is a requirement about the persistence of still passionate debates: the patients and their families feel abandoned, practitioners in the field distraught, and learned societies alarming the public authorities and their instances without any response to date. How the only drugs available, in responder patients, to slow down the inexorable progression of Alzheimer's disease, can finally be defunded, after three Superior Health Authority reassessments (2007, 2011, 2016) and therefore virtually removed from the therapeutic panel of physicians, while their beneficial effects, although modest on cognition, remained very actual on other symptoms such as apathy or hallucinations? How can this decision not to be understood as a signal of a disengagement from the state? How to maintain the trusting relationships between the patients, their families and caregivers, made of worry and patience?

RevDate: 2020-03-12

Belbeze J, T Gallarda (2020)

Very late onset psychotic symptoms: psychosis or dementia? A phenomenological approach. A systematic review.

Geriatrie et psychologie neuropsychiatrie du vieillissement, 18(1):77-87.

Very-late-onset psychotic symptoms (PS) are a common gateway to both neurodegenerative dementias and primary psychiatric disorders. Despite such similarities of clinical expression, there is no consensual guidelines or specific nosographic frame. The purpose of this systematic review was to establish a phenomenological classification of PS among the main neurodegenerative dementias and late-psychosis. It would allowed 1) the aknowledgement of etiology-specific psychotic phenotypes; 2) where appropriate, it would help the clinician to screen the psychiatric symptoms looking dementias; 3) it would justify the phenomenological research of very-late-onset PS among dementias at a pre-clinical cognitive stage to establish a nosographic frame of these PS based on the prognosis of dementia.

METHODS: A literature review was conducted searching for very-late-onset PS (>60 years old) in late-onset psychosis and among Alzheimer dementia type and Lewy bodies dementia, focusing on the phenomenological data.

RESULTS: The very-late-onset schizophrenia-like psychosis appears to be a primary psychiatric diagnosis clinically distinct from the PS emerging among established dementias, but remains a heterogeneous entity due to its age-based syndromic aspect. It has been possible to distinguish preferential phenotypes depending on the etiology of the dementia.

CONCLUSION: The results confirm the interest of the phenomenological approach to distinguish the etiology of the PS among confirmed dementias. Prospective longitudinal studies must examine the early discriminant characteristics of PS in order to enable a better prognostic prediction of the nosographic frame thereby established.

RevDate: 2020-03-12

Berruchon S, Mac Nab B, V Bréard (2020)

Musical cognitive skills assessment for patients with Alzheimer disease: the music therapy orientation test.

Geriatrie et psychologie neuropsychiatrie du vieillissement, 18(1):19-24.

Music therapy is recommended in the treatment of Alzheimer's disease (AD) but only few tools exist to measure musical skills in AD patients. Our objective was to develop an assessment tool, the MOT (music therapy orientation test) designed to evaluate the musical cognitive abilities of patients and to guide the music therapy plan. This article presents the guidelines and scoring terms for all items, as well as the normal range in older patients. The MOT was administered to 50 healthy elderly subjects (mean, 74.3±8.7 years) and 50 AD patients (mean, 82.8±8.0 years). The diagnosis was based on DSM-IV consensus criteria and all patients had a MMSE score ≤27/30 (mean, 16.16±6.91). The results showed an average success rate to the MOT that was lower in AD compared to cognitively healthy subjects (respectively 22.6±8.3/34 versus 32.4±1/34, p<0.0001). The MOT score was positively correlated with the MMSE score (r=0.80, p<0.001). With a threshold of 30/34, the MOT sensitivity was 74%, its specificity 96% and its positive predictive value 94.9%. Our results showed that a MOT score <30/34 is able to detect musical cognitive disabilities in AD patients. The MOT could be useful for music therapists to guide the music therapy plan.

RevDate: 2020-03-12

Bahadur S, Sachan N, Harwansh RK, et al (2020)

Nanoparticlized System: Promising Approach for the Management of Alzheimer's Disease through Intranasal Delivery.

Current pharmaceutical design pii:CPD-EPUB-105156 [Epub ahead of print].

Nasal drug delivery has been used from the prehistoric times for the treatment of neurological disorders like Alzheimer's disease (AD). AD is a neurodegenerative disease and prime cause of dementia. AD has become most common disease worldwide and its treatment remains challengeable. For delivering a drug to the brain, blood brain barrier is a major limiting factor. Thus, the desired drug concentration could not be achieved through the conventional drug delivery system. Nasal drug delivery has been considered as a most promising route of administration with the enhanced drug concentration in the brain. Several factors and mechanisms need to be considered for treatment of AD. Various nanoparticlized systems such as nanoparticles, liposomes, exosomes, phytosomes, nanoemulsion, nanosphere, etc. have been recognized as an effective drug delivery system for the management of AD. These nanocarriers have been proven for improved bioavailability of the anti-Alzheimer's drugs. Some novel drug delivery systems of anti-Alzheimer drugs are currently in different phase of clinical trials. Present article highlights on the nanotechnology based intranasal drug delivery system for the treatment of Alzheimer's disease. Furthermore, consequences of AD, transportation mechanism, clinical updates and recent patents have been discussed.

RevDate: 2020-03-11

De Rossi P, Nomura T, Andrew RJ, et al (2020)

Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation.

Cell reports, 30(10):3520-3535.e7.

BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal Bin1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease.

RevDate: 2020-03-11

Kaur R, Randhawa K, Kaur S, et al (2020)

Allium cepa fraction attenuates STZ-induced dementia via cholinesterase inhibition and amelioration of oxidative stress in mice.

Journal of basic and clinical physiology and pharmacology pii:/j/jbcpp.ahead-of-print/jbcpp-2019-0197/jbcpp-2019-0197.xml [Epub ahead of print].

Background An earlier study demonstrated significant antioxidant and anticholinesterase activities of hydromethanol extract (HME) of Allium cepa. The aim of the study was to investigate the component responsible for these activities followed by an in vivo study. Methods In vitro antioxidant and anticholinesterase activities of standardized ethylacetate fraction (EAF) of HME were assessed. Bioactivity-guided fractionation showed that, as compared with its subfractions, EAF had most significant activity in 2,2-diphenyl-1-picrylhydrazyl and Ellman assays. Thus, EAF was further examined using a streptozotocin (STZ)-induced model of Alzheimer's disease in mice. STZ was injected intracerebroventricularly on days 1 and 3 (3 mg/kg) in mice. EAF was thereafter administered (42, 84, and 168 mg/kg b.w./day p.o.) from days 9 to 22. The Morris water maze test was used to evaluate learning and memory in mice. Acetylcholinesterase (AChE) activity and oxidative stress markers were assessed in the brain homogenates of mice. Additionally, histopathological studies were performed to observe effects in the brain at the cellular level. EAF was standardized based on quercetin and quercetin 4'-O-glucoside content using a validated thin layer chromatography densitometric method. Results STZ produced significant (p < 0.05) memory impairment along with oxidative stress and a cholinergic deficit in mice. EAF treatment ameliorated STZ-induced behavioral deficits and biochemical alterations in mice in a significant and dose-dependent manner. Conclusions Our results show that EAF is efficacious in improving memory and learning via AChE inhibition and antioxidant activity in the mice brain. Thus, AC could be explored further to find out a lead candidate for Alzheimer's disease.

RevDate: 2020-03-12

Robert P, Manera V, Derreumaux A, et al (2020)

Efficacy of a Web App for Cognitive Training (MeMo) Regarding Cognitive and Behavioral Performance in People With Neurocognitive Disorders: Randomized Controlled Trial.

Journal of medical Internet research, 22(3):e17167 pii:v22i3e17167.

BACKGROUND: Cognitive and behavioral symptoms are the clinical hallmarks of neurocognitive disorders. Cognitive training may be offered to reduce the risks of cognitive decline and dementia and to reduce behavioral symptoms, such as apathy. Information and communication technology approaches, including serious games, can be useful in improving the playful aspect of computerized cognitive training and providing motivating solutions in elderly patients.

OBJECTIVE: The objective of this study was to assess the effectiveness of employing the MeMo (Memory Motivation) Web app with regard to cognitive and behavioral symptoms in patients with neurocognitive disorders.

METHODS: MeMo is a Web app that can be used on any Web browser (computer or tablet). The training activities proposed in MeMo are divided into the following two parts: memory and mental flexibility/attention. The study included 46 individuals (mean age 79.4 years) with a diagnosis of neurocognitive disorders at the Institut Claude Pompidou Memory Center in Nice. This randomized controlled study compared the evolution of cognition and behavior between patients not using MeMo (control group) and patients using MeMo (MeMo group) for 12 weeks (four sessions per week). Patients underwent memory and attention tests, as well as an apathy assessment at baseline, week 12 (end of the training period), and week 24 (12 weeks after the end of the training sessions). In addition, to assess the impact of high and low game uses, the MeMo group was divided into patients who used MeMo according to the instructions (about once every 2 days; active MeMo group) and those who used it less (nonactive MeMo group).

RESULTS: When comparing cognitive and behavioral scores among baseline, week 12, and week 24, mixed model analysis for each cognitive and behavioral score indicated no significant interaction between testing time and group. On comparing the active MeMo group (n=9) and nonactive MeMo group (n=13), there were significant differences in two attention tests (Trial Making Test A [P=.045] and correct Digit Symbol Substitution Test items [P=.045]) and in the Apathy Inventory (AI) (P=.02). Mixed analysis (time: baseline, week 12, and week 24 × number of active days) indicated only one significant interaction for the AI score (P=.01), with a significant increase in apathy in the nonactive MeMo group.

CONCLUSIONS: This study indicates that the cognitive and behavioral efficacies of MeMo, a Web-based training app, can be observed only with regular use of the app. Improvements were observed in attention and motivation.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04142801; https://clinicaltrials.gov/ct2/show/NCT04142801.

RevDate: 2020-03-10

Campos CR, Kemble AM, Niewoehner J, et al (2020)

Brain Shuttle Neprilysin reduces central Amyloid-β levels.

PloS one, 15(3):e0229850 pii:PONE-D-20-00098.

Reducing Amyloid β (Aβ) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer`s disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key Aβ-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central Aβ. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading Aβ in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial Aβ reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an Aβ degrading enzyme across the blood-brain barriers to efficiently reduce Aβ levels in both CSF and brain.

RevDate: 2020-03-10

Itzhaki RF, Golde TE, Heneka MT, et al (2020)

Do infections have a role in the pathogenesis of Alzheimer disease?.

Nature reviews. Neurology pii:10.1038/s41582-020-0323-9 [Epub ahead of print].

The idea that infectious agents in the brain have a role in the pathogenesis of Alzheimer disease (AD) was proposed nearly 30 years ago. However, this theory failed to gain substantial traction and was largely disregarded by the AD research community for many years. Several recent discoveries have reignited interest in the infectious theory of AD, culminating in a debate on the topic at the Alzheimer's Association International Conference (AAIC) in July 2019. In this Viewpoint article, experts who participated in the AAIC debate weigh up the evidence for and against the infectious theory of AD and suggest avenues for future research and drug development.

RevDate: 2020-03-10

Crous-Bou M, Gascon M, Gispert JD, et al (2020)

Impact of urban environmental exposures on cognitive performance and brain structure of healthy individuals at risk for Alzheimer's dementia.

Environment international pii:S0160-4120(19)32113-0 [Epub ahead of print].

BACKGROUND: Air quality might contribute to incidence of dementia-related disorders, including Alzheimer's dementia (AD). The aim of our study is to evaluate the effect of urban environmental exposures (including exposure to air pollution, noise and green space) on cognitive performance and brain structure of cognitively unimpaired individuals at risk for AD.

PARTICIPANTS AND METHODS: The ALFA (ALzheimer and FAmilies) study is a prospective cohort of middle-age, cognitively unimpaired subjects, many of them offspring of AD patients. Cognitive performance was measured by the administration of episodic memory and executive function tests (N = 958). Structural brain imaging was performed in a subsample of participants to obtain morphological information of brain areas, specially focused on cortical thickness, known to be affected by AD (N = 228). Land Use Regression models were used to estimate residential exposure to air pollutants. The daily average noise level at the street nearest to each participant's residential address was obtained from noise maps. For each participant residential green exposure indicators, such as surrounding greenness or amount of green, were generated. General linear models were conducted to assess the association between environmental exposures, cognitive performance and brain structure in a cross-sectional analysis.

RESULTS: No significant associations were observed between urban environmental exposures and the cognitive composite (p > 0.1). Higher exposure to air pollutants, but not noise, was associated with lower cortical thickness in brain regions known to be affected by AD, especially NO2 (β = -16.4; p = 0.05) and PM10 (β = -5.34; p = 0.05). On the other hand, increasing greenness indicators was associated with greater thickness in these same areas (β = 0.08; p = 0.03).

CONCLUSION: In cognitively unimpaired adults with increased risk for AD, increased exposure to air pollution was suggested to be associated with greater global atrophy and reduced volume and thickness in specific brain areas known to be affected in AD, thus suggesting a potential link between environmental exposures and cerebral vulnerability to AD. Although more research in the field is needed, air pollution reduction is crucial for decreasing the burden of age-related disorders.

RevDate: 2020-03-09

Song H, Sieurin J, Wirdefeldt K, et al (2020)

Association of Stress-Related Disorders With Subsequent Neurodegenerative Diseases.

JAMA neurology pii:2762514 [Epub ahead of print].

Importance: Posttraumatic stress disorder (PTSD) has been associated with increased risk for dementia. Less is known, however, about other stress-related disorders and their associations with neurodegenerative diseases.

Objective: To examine the association between stress-related disorders and risk for neurodegenerative diseases.

This population-matched and sibling cohort study was conducted in Sweden using data from nationwide health registers, including the Swedish National Patient Register. Individuals who received their first diagnosis of stress-related disorders between January 1, 1987, and December 31, 2008, were identified. Individuals who had a history of neurodegenerative diseases, had conflicting or missing information, had no data on family links, or were aged 40 years or younger at the end of the study were excluded. Individuals with stress-related disorders were compared with the general population in a matched cohort design; they were also compared with their siblings in a sibling cohort. Follow-up commenced from the age of 40 years or 5 years after the diagnosis of stress-related disorders, whichever came later, until the first diagnosis of a neurodegenerative disease, death, emigration, or the end of follow-up (December 31, 2013), whichever occurred first. Data analyses were performed from November 2018 to April 2019.

Exposures: Diagnosis of stress-related disorders (PTSD, acute stress reaction, adjustment disorder, and other stress reactions).

Neurodegenerative diseases were identified through the National Patient Register and classified as primary or vascular. Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis were evaluated separately. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs after controlling for multiple confounders.

Results: The population-matched cohort included 61 748 exposed individuals and 595 335 matched unexposed individuals. A total of 44 839 exposed individuals and their 78 482 unaffected full siblings were included in the sibling cohort analysis. The median (interquartile range) age at the start of follow-up was 47 (41-56) years, and 24 323 (39.4%) of the exposed individuals were male. The median (interquartile range) follow-up was 4.7 (2.1-9.8) years. Compared with unexposed individuals, individuals with a stress-related disorder were at an increased risk of neurodegenerative diseases (HR, 1.57; 95% CI, 1.43-1.73). The risk increase was greater for vascular neurodegenerative diseases (HR, 1.80; 95% CI, 1.40-2.31) than for primary neurodegenerative diseases (HR, 1.31; 95% CI, 1.15-1.48). A statistically significant association was found for Alzheimer disease (HR, 1.36; 95% CI, 1.12-1.67) but not Parkinson disease (HR, 1.20; 95% CI, 0.98-1.47) or amyotrophic lateral sclerosis (HR, 1.20; 95% CI, 0.74-1.96). Results from the sibling cohort corroborated results from the population-matched cohort.

Conclusions and Relevance: This study showed an association between stress-related disorders and an increased risk of neurodegenerative diseases. The relative strength of this association for vascular neurodegenerative diseases suggests a potential cerebrovascular pathway.

RevDate: 2020-03-09

Chen Y, Zhang J, Zhang T, et al (2020)

Meditation treatment of Alzheimer disease and mild cognitive impairment: A protocol for systematic review.

Medicine, 99(10):e19313.

BACKGROUND: Growing body of scientific researches in recent years have suggested the promising effect of meditation on improving cognitive impairment of Alzheimer disease (AD) and mild cognitive impairment (MCI). This paper aims to provide a protocol for systematic review to evaluate the efficacy of meditation on cognition performance of patient with AD and MCI.

METHODS: The Cochrane Library, PubMed, EMBASE, Web of Science, the Chinese Biological Medicine Database, China National Knowledge Infrastructure, Wanfang database, and VIP information database will be searched systematically and electronically from establishment to March 2020. All published randomized controlled trials related will be included. Assessment of bias risk and data analyses will be implemented by Review Manager (V.5.3.5). The strength of the evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation system.

RESULTS: A high-quality synthesis of current evidence of meditation for patient with AD and mild cognitive impairment will be provided in this study.

CONCLUSION: This protocol of systematic review will be helpful for providing evidence of whether meditation is an effective and safe intervention for cognitive impairment of patient with AD and MCI.

ETHICS AND DISSEMINATION: Ethical approval is unnecessary since this protocol is only for systematic review and does not involve privacy data or conduct an animal experiment. This protocol will be disseminated by a peer-review journal or conference presentation.

PROSPERO CRD42019145932.

RevDate: 2020-03-09

Deiner S, Liu X, Lin HM, et al (2020)

Does Postoperative Cognitive Decline Result in New Disability After Surgery?.

Annals of surgery [Epub ahead of print].

OBJECTIVE: Establish whether POCD is associated with new disability after surgery, which would inform whether POCD impacts patient-centered outcomes.

BACKGROUND: POCD is a decline in neuropsychiatric tests scores from presurgical baseline which occurs in approximately 15% of older patients 3 months after surgery. POCD is a research construct meant to investigate patient and family reports of older adults who were "never the same after surgery." However, many patients with POCD do not perceive difficulty with thinking and memory, and the question remains whether POCD impacts patient function.

METHODS: We performed a prospective cohort study of 167 older adults undergoing major noncardiac surgery (requiring at least a 2-day hospital stay). Exclusion criteria were: history of dementia, cardiac or intracranial procedure, inability to consent for themselves, or emergency surgery. We administered formal neuropsychiatric testing (Alzheimer Disease Research Center UDS battery), basic and instrumental activities of daily living (Alzheimer Disease Research Center IADLs), pain (geriatric pain measure), and depression screening (hospital depression and anxiety scale) before and 3 months after surgery. We recorded all patient refined diagnostic related groups codes, blood pressure, anesthetics and narcotics administered, surgical and anesthesia duration, and measured complications and severity, length of stay, and readmissions.

RESULTS: Patients with POCD (21/167, 14.1%) had twice the proportion of new impairment in IADL as compared to those without POCD (57% vs 27%, P = .01). The most common areas of decline were social activities, ability to find items around the house, remember appointments, shop and pay for items, do laundry, drive a car/use public transport, and do housework. Predictors of IADL change after surgery included POCD, presurgical cognition, presurgical function, postoperative depression, and the development of postoperative complications.

CONCLUSIONS: Patients with POCD experience a much higher incidence of new disability after surgery. Baseline cognitive or functional limitations are also risk factors for new disability. Many patients are not aware of their limitations before surgery. Future study is needed to identify practical ways to routinely screen patients and reduce risk. Patients need to be informed of their risk for new disability after surgery to inform their medical decision making.

RevDate: 2020-03-08

Varkuti BH, Liu Z, Kepiro M, et al (2020)

High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons.

iScience, 23(3):100931 pii:S2589-0042(20)30115-2 [Epub ahead of print].

We developed a high-throughput assay for modulators of mitochondrial function in neurons measuring inner mitochondrial membrane potential (ΔΨm) and ATP production. The assay was used to screen a library of small molecules, which led to the identification of structural/functional classes of mitochondrial modulators such as local anesthetics, isoflavones, COXII inhibitors, adrenergic receptor blockers, and neurotransmitter system effectors. Our results show that some of the isolated compounds promote mitochondrial health, enhance oxygen consumption rate, and protect neurons against toxic insults found in the cellular environment of Alzheimer disease. These studies offer a set of compounds that may provide efficacy in protecting the mitochondrial system in neurodegenerative disorders.

RevDate: 2020-03-07

Ihara M, S Saito (2020)

Drug Repositioning for Alzheimer's Disease: Finding Hidden Clues in Old Drugs.

Journal of Alzheimer's disease : JAD pii:JAD200049 [Epub ahead of print].

Although more than 100 years have passed since Alois Alzheimer reported a case of Alzheimer's disease (AD), a definitive answer to the causes of cognitive impairment in the disease remains elusive. Despite significant enthusiasm and investment from the pharmaceutical industry, clinical trials of many disease-modifying drugs for AD have been largely unsuccessful. Drug repositioning (DR) or repurposing approaches are relatively inexpensive and more reliable compared to de novo drug development in AD. About 30% of clinical trials for AD in progress around the world use the DR method and hold potential in halting the current deadlock in treatment options. By using drugs approved for other indications, these clinical trials target dysregulated pathways in AD with different or a combination of modes of action, including anti-amyloid, cardiovascular, anti-tau, anti-inflammatory, immunomodulatory, metabolic, neuroprotective, and neurotransmission-based approaches. For instance, anti-diabetic drugs, such as insulin, metformin, liraglutide, and dapagliflozin, and cardiovascular drugs, such as cilostazol, candesartan, telmisartan, prazosin, and dabigatran, could serendipitously provide previously unearthed benefits in AD. This is in line with recent thinking, which views AD as a complex multifactorial disorder, not dominated by one dominant biological factor, such as amyloid-β, and likely a confluence of many pathobiological mechanisms, including vascular dysregulation. Such increasingly available knowledge of phenotyping may be used to design 'tailor-made' DR and relatively homogeneous AD subpopulations specifically targeted with existing drugs based on known modes of action. It is thus expected that DR approaches will create a major paradigm shift in AD research and development.

RevDate: 2020-03-07

Yang A, Wang H, Zuo X, et al (2020)

Potassium Chloride Cotransporter 2 Inhibits Neuropathic Pain and Future Development of Neurodegeneration.

Journal of Alzheimer's disease : JAD pii:JAD200027 [Epub ahead of print].

Persistent neuropathic pain (NP) causes future development of neurodegenerative diseases, e.g., Alzheimer' disease, and thus needs to be optimally treated. Surgically-induced neuropathic pain (SNPP) is a persistent pain that occurs in nearly half of the individuals after common operations. Here, we showed that specific activation of 5-hydroxytryptamine (5-HT) type 2A receptors by systemic administration of TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide] improved the function of potassium chloride cotransporter 2 (KCC2), resulting in reduction in neuropathic pain after chronic constriction injury (CCI), a rat model that mimics SNPP. Moreover, TCB-2 administration attenuated both mechanical and thermal hyperalgesia, likely through augmentation of dorsal horn KCC2 levels, since this effect was abolished by intrathecal provision of dihydroindenyl oxy alkanoic acid (DIOA), which blocked the effects of KCC2. Furthermore, TCB-2-mediated re-activation of KCC2 likely reduces future development of neurodegeneration in rats. Together, our data support further studies on the possibility of using this strategy to reduce postoperative pain and future neurodegenerative disorders in clinic.

RevDate: 2020-03-07

Özdemir Z, Alagöz MA, Uslu H, et al (2020)

Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.

Pharmacological reports : PR pii:10.1007/s43440-020-00070-w [Epub ahead of print].

BACKGROUND: Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests.

METHODS: The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software.

RESULTS: Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001 µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 μM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles.

CONCLUSION: It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.

RevDate: 2020-03-07

Cervellati C, Trentini A, Pecorelli A, et al (2020)

Inflammation in neurological disorders: the thin boundary between brain and periphery.

Antioxidants & redox signaling [Epub ahead of print].

SIGNIFICANCE: Accumulating evidence suggests that inflammation is a major contributor in the pathogenesis of several highly prevalent, but also rare, neurological diseases. In particular, the neurodegenerative processes of Alzheimer disease (AD), vascular dementia (VAD), Parkinson's disease (PD), multiple sclerosis (MS) are fueled by neuroinflammation, which in turn is accompanied by a parallel systemic immune dysregulation. This cross-talk between periphery and the brain becomes substantial when the blood brain barrier loses its integrity as often occurs in the course of these diseases. It has been hypothesized the perpetual bidirectional flux of inflammatory mediators is not a mere "static" collateral effect of the neurodegeneration, but represents a proactive phenomenon sparking and driving the neuropathological processes. However, the upstream/downstream relationship between inflammatory events and neurological pathology is still unclear.

RECENT ADVANCES: Solid recent evidence clearly suggest that metabolic factors, systemic infections, Microbiota dysbiosis, and oxidative stress are implicated, although at different extent, in the development in brain diseases CRITICAL ISSUE: Here, we reviewed the most solid published evidence supporting the implication of the axis systemic inflammation-neuroinflammation-neurodegeneration in the pathogenesis of AD, VAD, PD and MS, highlighting the possible cause of the putative downstream component of the axis.

FUTURE DIRECTIONS: Reaching a definitive clinical/epidemiological appreciation of the etiopathogenic significance of the connection between peripheral and brain inflammation in neurologic disorders is pivotal since it could open novel therapeutic avenues for these diseases.

RevDate: 2020-03-06

Blanken AE, Jang JY, Ho JK, et al (2020)

Distilling Heterogeneity of Mild Cognitive Impairment in the National Alzheimer Coordinating Center Database Using Latent Profile Analysis.

JAMA network open, 3(3):e200413 pii:2762381.

RevDate: 2020-03-06

Madadi S, Saidijam M, Yavari B, et al (2020)

Downregulation of serum miR-106b: a potential biomarker for Alzheimer disease.

Archives of physiology and biochemistry [Epub ahead of print].

Analysis of miRNAs has a strong potential for the identification of novel prognostic or predictive biomarkers in the serum of AD patients. In this study, we investigated the serum levels of miR-106b as a diagnostic biomarker for AD and evaluate its predictive value for therapeutic response to the drug rivastigmine. Patients were divided into either responding (n = 33) or non-responding (n = 23) groups according to rivastigmine treatment and to Mini-Mental State Exam score. The serum concentrations of miR-106b were measured with real-time PCR. Here, we found that miR-106b was significantly down-regulated in the serum samples of AD patients compared with those of controls (p < .001). ROC results showed a specificity of 62% and a sensitivity of 94%. The serum values of miR-106b tended to be positively associated with the therapeutic response but were not significant (p = .15). Taken together, detection of serum miR-106b might be a promising serum biomarker for early diagnosis of AD.

RevDate: 2020-03-06

Kamiie J, Aihara N, Uchida Y, et al (2020)

Amyloid-specific extraction using organic solvents.

MethodsX, 7:100770 pii:100770.

Typing of amyloidosis by mass spectrometry (MS) based proteomic analysis contribute to the diagnosis of amyloidosis. For MS analysis, laser microdissection (LMD) is used for amyloid specific sampling. This study aimed to establish a method for selectively extracting amyloids from formalin-fixed, paraffin-embedded (FFPE) specimens by organic solvent instead of LMD. The extracts using dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, trifluoroethanol (TFE) or hexafluoro-2-propanol from FFPE brain of alzheimer's disease mouse model generated protein bands on SDS-PAGE, and Aβ was identified in the extract of DMF using mass spectrometry. The extract using DMSO from the kidney of a AA amyloidosis patient produced a protein band in SDS-PAGE. This protein band was identified to be serum amyloid A (SAA) by Western blotting and mass spectrometry. Circular dichroism spectrometry revealed that the secondary structures of Aβ and transthyretin were converted to α-helices from β-sheets in TFE. Our results suggest that organic solvents can extract amyloids from FFPE specimens by converting their secondary structure. This method could eliminate the LMD step and simplified amyloid typing by MS analysis. •DMSO, DMF, methanol, TFE and HFIP can extract Aβ specifically from the FFPE brain of a Alzheimer' disease mouse model.•DMSO can extract SAA specifically from a FFPE section of AA amyloidosis.•Secondary structures of Aβ and transthyretin converted from β-sheet to α-helix in TFE.

RevDate: 2020-03-06

Terada T, Obi T, Bunai T, et al (2020)

In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease.

Neurology pii:WNL.0000000000009249 [Epub ahead of print].

OBJECTIVE: In vivo glycolysis-related glucose metabolism and electron transport chain-related mitochondrial activity may be different regionally in the brains of patients with Alzheimer disease (AD). To test this hypothesis regarding AD pathophysiology, we measured the availability of mitochondrial complex-I (MC-I) with the novel PET probe [18F]2-tert- butyl-4-chloro-5-2H- pyridazin-3-one ([18F]BCPP-EF), which binds to MC-I, and compared [18F]BCPP-EF uptake with 18F-fluorodeoxyglucose ([18F]FDG) uptake in the living AD brain.

METHODS: First, the total distribution volume (VT) of [18F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether VT could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [18F]BCPP-EF or [18F]FDG, respectively. Second, 32 patients with AD were scanned semiquantitatively with double PET tracers. Interparticipant and intraparticipant comparisons of the levels of MC-I activity ([18F]BCPP-EF) and glucose metabolism ([18F]FDG) were performed.

RESULTS: The [18F]BCPP-EF VT was positively correlated with the [18F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [18F]BCPP-EF SUVRg, but not the [18F]FDG SUVRg, was significantly lower in the parahippocampus in patients with AD, highlighting the prominence of oxidative metabolic failure in the medial temporal cortex. Robust positive correlations between the [18F]BCPP-EF SUVRg and [18F]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD.

CONCLUSIONS: Mitochondrial dysfunction in the parahippocampus was shown in early-stage AD. Mitochondria-related energy failure may precede glycolysis-related hypometabolism in regions with pathologically confirmed early neurodegeneration in AD.

RevDate: 2020-03-06

Swerdlow RH (2020)

Mitochondria in Alzheimer brains: A PET project shows complex changes.

RevDate: 2020-03-05

Osakwe ZT, Sosina OA, Agu N, et al (2020)

Home Health Agency Factors Associated With Acute Care Hospitalization and Emergency Department Use.

Home healthcare now, 38(2):92-97.

We linked the Medicare Provider Utilization and Payment Data for Home Health and the Home Health Compare data for the year 2016 to identify home healthcare agency (HHA) characteristics associated with acute care hospitalization (ACH) or emergency department (ED) use. The study cohort consisted of 9,800 HHAs. Beta regression was used to examine the association between average age, race/ethnic composition, number of skilled nursing visits, number of therapy visits, percentage of dual eligible patients, HHA ownership, HHA location, Medicare tenure, proportion of patients with a diagnosis of schizophrenia, stroke, diabetes, depression, chronic obstructive pulmonary disease (COPD), heart failure, cancer and Alzheimer disease, and ACH or ED use. After controlling for HHA-level characteristics, variations in HHAs' ACH and unplanned ED visits were found. For-profit HHAs were significantly less likely to have patients with ACH. (Odds ratio = -0.05, p = 0.020), HHAs in the Midwest, South, and West had lower odds of ACH. HHAs that serve more than 50% Black patients had significantly decreased odds (β = -0.16, p < 0.001) of ACH. A 1-unit increase in the proportion of patients with a diagnosis of schizophrenia, COPD, stroke, heart failure, and Alzheimer disease was associated with increased odds of hospitalization. For each unit increase in the number of skilled nursing visits, the odds of ACH increased by 0.02 (p = 0.001). For-profit and nonprofit HHAs had a significant decrease in the odds of unplanned ED visits (p < 0.05). An increase in the proportion of patients with COPD was associated with increased odds of unplanned ED visits (p < 0.001). HHA characteristics are associated with hospitalization and ED use without hospitalization. These characteristics point to variation in quality of care measured by ACH and ED use.

RevDate: 2020-03-05

Sparks P, Lawrence T, S Hinze (2020)

Neuroimaging in the Diagnosis of Chronic Traumatic Encephalopathy: A Systematic Review.

Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine, 30 Suppl 1:S1-S10.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repeated subconcussive and concussive head injury. Clinical features include cognitive, behavioral, mood, and motor impairments. Definitive diagnosis is only possible at postmortem. Here, the utility of neuroimaging in the diagnosis of CTE is evaluated by systematically reviewing recent evidence for changes in neuroimaging biomarkers in suspected cases of CTE compared with controls.

DATA SOURCES: Providing an update on a previous systematic review of articles published until December 2014, we searched for articles published between December 2014 and July 2016. We searched PubMed for studies assessing neuroimaging changes in symptomatic suspected cases of CTE with a history of repeated subconcussive or concussive head injury or participation in contact sports involving direct impact to the head. Exclusion criteria were case studies, review articles, and articles focusing on repetitive head trauma from military service, head banging, epilepsy, physical abuse, or animal models.

MAIN RESULTS: Seven articles met the review criteria, almost all of which studied professional athletes. The range of modalities were categorized into structural magnetic resonance imaging (MRI), diffusion MRI, and radionuclide studies. Biomarkers which differed significantly between suspected CTE and controls were Evans index (P = 0.05), cavum septum pellucidum (CSP) rate (P < 0.0006), length (P < 0.03) and ratio of CSP length to septum length (P < 0.03), regional differences in axial diffusivity (P < 0.05) and free/intracellular water fractions (P < 0.005), single-photon emission computed tomography perfusion abnormalities (P < 0.01), positron emission tomography (PET) signals from tau-binding, glucose-binding, and GABA receptor-binding radionuclides (P < 0.0001, P < 0.005, and P < 0.005, respectively). Important limitations include low specificity in identification of suspected cases of CTE across studies, the need for postmortem validation, and a lack of generalizability to nonprofessional athletes.

CONCLUSIONS: The most promising biomarker is tau-binding radionuclide PET signal because it is most specific to the underlying neuropathology and differentiated CTE from both controls and patients with Alzheimer disease (P < 0.0001). Multimodal imaging will improve specificity further. Future research should minimize variability in identification of suspected cases of CTE using published clinical criteria.

RevDate: 2020-03-05

Macoir J, Lafay A, C Hudon (2020)

The Impairment of Number Transcoding Abilities in Individuals with Amnestic Mild Cognitive Impairment and Alzheimer Disease: Associations With Attentional and Executive Functions.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 33(1):33-44.

BACKGROUND: Studies have shown that number transcoding abilities (ie, translating numbers from one numerical code to another) are affected early in the development of Alzheimer disease (AD). However, no study has extensively explored how these abilities are affected in individuals with mild cognitive impairment (MCI).

OBJECTIVE: To determine the contribution that number transcoding tasks make to the identification of MCI, and to pinpoint the cognitive correlates of performance in these tasks.

METHODS: We compared the performance of 20 individuals with the amnestic subtype of MCI, eight individuals with AD, and 20 healthy controls on three number transcoding tasks.

RESULTS: The results confirmed the presence of number transcoding impairment in the individuals with AD. The individuals with MCI were found to be impaired in two of the transcoding tasks; these individuals produced perseverations of the input code-the most noteworthy error type in individuals with AD. In addition, the relationship between impairment in attentional and executive functions and impairment in number transcoding was supported by the correlational analyses.

CONCLUSIONS: This study confirmed that number transcoding abilities are impaired in individuals with MCI, although less severely than in individuals with AD. Our results provide evidence for the clinical value of including number transcoding tasks in the assessment of cognitive deficits associated with pathological aging.

RevDate: 2020-03-05

Abraham M, Seidenberg M, Kelly DA, et al (2020)

Episodic Memory and Hippocampal Volume Predict 5-Year Mild Cognitive Impairment Conversion in Healthy Apolipoprotein ε4 Carriers.

Journal of the International Neuropsychological Society : JINS pii:S1355617720000181 [Epub ahead of print].

OBJECTIVE: The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI.

METHODS: Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65-85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted to z-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes.

RESULTS: At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1-5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1-5 scores were significant predictors of MCI conversion.

CONCLUSIONS: Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

RevDate: 2020-03-05

Zheng J, Akbari M, Schirmer C, et al (2020)

Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy.

Acta neuropathologica communications, 8(1):25 pii:10.1186/s40478-020-00896-8.

Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.

RevDate: 2020-03-04

Vasquez EC, Aires R, Ton AMM, et al (2020)

New Insights on the Beneficial Effects of the Probiotic Kefir on Vascular Dysfunction in Cardiovascular and Neurodegenerative Diseases.

Current pharmaceutical design pii:CPD-EPUB-105012 [Epub ahead of print].

The mechanisms responsible for the cardiovascular and neurodegenerative diseases have been the focus of experimental and clinical studies for decades. Among those studies, the relationship between the gut microbiota and the organs and system tissues, represents the research field that has generated the highest number of publications. Homeostasis of the gut microbiota is important to the host because promotes maturation of the autoimmune system, harmonic integrative functions of the brain and the normal function of organs related with cardiovascular and metabolic systems. On the other hand, when occurs a gut microbiota dysbiosis, the target organs become vulnerable to the onset or aggravation of complex chronic conditions, such as cardiovascular (e.g., arterial hypertension) and neurodegenerative (e.g., dementia) diseases. In the present brief review, we discuss the main mechanisms involved in those disturbances and the promising beneficial effects that have been revealed using functional food (nutraceuticals), such as the traditional probiotic Kefir. Here, we highlight current scientific advances, concerns and limitations about the use of this nutraceutical. The focus of our discussion is the endothelial dysfunction that accompanies the hypertension, and the neurovascular dysfunction that characterizes the ageing-related dementia in patients suffering of Alzheimer disease.

RevDate: 2020-03-04

Oh C, Morris RJ, LaPointe LL, et al (2020)

Spatial-Temporal Parameters of Gait Associated With Alzheimer Disease: A Longitudinal Analysis.

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

Alzheimer's disease (AD) is one of the biggest social and medical concerns in the aging world. A dual task of walking and talking is a particularly practical means to assess AD considering the cognitive and behavioral changes that characterize the disease. The purpose of the study was to assess the effect of the dual task of walking and talking on people with early stage AD under differing cognitive load levels of talking. Participants (9 women and 5 men, mean age (years) = 78.03, standard deviation [SD] = 12.06) with mild or moderate AD (mean Dementia Rating Scale 2 score = 88.14, SD = 7.07) completed 12 monthly walking sessions under no, low, or high cognitive load. They also completed the low and high cognitive load tasks while seated. Linear mixed-effects modeling revealed that values in the Functional Ambulation Profile, stride length, and velocity decreased as tasks became more complex and double support time increased at the same rate. The walking and seated conditions comparison indicated that participants' performance on both low and high cognitive tasks was poor when they were walking rather than seated. The results show that people with early stage AD exhibited gait impairments that increased over time and when completing tasks with greater cognitive load.

RevDate: 2020-03-04

Morris JL, Hu L, Hunsaker A, et al (2020)

Patients' and Family Members' Subjective Experiences of a Diagnostic Evaluation of Mild Cognitive Impairment.

Journal of patient experience, 7(1):124-131.

Background: People with a diagnosis of mild cognitive impairment (MCI) often struggle with uncertainty and fear when learning of and coping with their diagnosis. However, little is known about their experiences and perspectives, and those of their care partners, when seeking out and undergoing a diagnostic evaluation for their cognitive symptoms.

Method: This study is a secondary analysis of a focus group discussion that was initially conducted to learn the perspectives and experiences of participants and their care partners during a mock disclosure session of brain scan results. Participant's broader views on their experience of completing a cognitive evaluation resulting in an MCI diagnosis were evaluated in this study. Analysis used qualitative content methodology and line-by-line coding which generated categories and themes.

Results: The (1) "presence of a threat" and (2) attempts to "minimize the threat" emerged as overarching themes driving the process of seeking out a diagnostic evaluation for cognitive symptoms. Subthemes that highlight the complexity of the presence of a threat included the "fear of stigma," and the "emotional reactions" related to an MCI diagnosis. Three additional subthemes represented approaches that participants and their care partners used to minimize threat of MCI: "use of language" to minimize the threat; "information sharing and withholding"; and the "use of social support to legitimize personal experiences."

Conclusion: These findings add to the literature by elucidating the uncertainty, fears, and coping strategies that accompany a diagnostic evaluation of MCI.


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.

963 Red Tail Lane
Bellingham, WA 98226


E-mail: RJR8222@gmail.com

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 )