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Bibliography on: Alzheimer Disease — Current Literature

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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 16 Sep 2021 at 01:32 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] OR 2021[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-09-15

Kauwe G, TE Tracy (2021)

Amyloid beta emerges from below the neck to disable the brain.

PLoS biology, 19(9):e3001388 pii:PBIOLOGY-D-21-01832.

Accumulation of amyloid beta (Aβ) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aβ from the liver can promote brain pathology, supporting that peripheral Aβ can contribute to neurodegeneration.

RevDate: 2021-09-15

Chiong W, Tsou AY, Simmons Z, et al (2021)

Ethical Considerations in Dementia Diagnosis and Care: AAN Position Statement.

Neurology, 97(2):80-89.

Alzheimer disease and other dementias present unique practical challenges for patients, their families, clinicians, and health systems. These challenges reflect not only the growing public health effect of dementia in an aging global population, but also more specific ethical complexities including early loss of patients' capacity to make decisions regarding their own care, the stigma often associated with a dementia diagnosis, the difficulty of balancing concern for patients' welfare with respect for patients' remaining independence, and the effect on the physical, emotional, and financial well-being of family caregivers. Caring for patients with dementia requires respecting patient autonomy while acknowledging progressively diminishing decisional capacity and continuing to provide care in accordance with other core ethical principles (beneficence, justice, and nonmaleficence). Whereas these ethical principles remain unchanged, neurologists must reconsider how to apply them given changes across multiple domains including our understanding of disease, clinical and legal tools for addressing manifestations of illness, our expanding awareness of the crucial role of family caregivers in providing care and maintaining patient quality of life, and societal conceptions of dementia and individuals' personal expectations for aging. This revision to the American Academy of Neurology's 1996 position statement summarizes ethical considerations that often arise in caring for patients with dementia; although it addresses how such considerations influence patient management, it is not a clinical practice guideline.

RevDate: 2021-09-15

Parker K, Vincent B, Rhee Y, et al (2021)

The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.

Aging clinical and experimental research [Epub ahead of print].

BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis.

AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization.

METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years.

RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%).

DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless.

CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.

RevDate: 2021-09-15

Hassanzadeh M, Hassanzadeh F, Khodarahmi GA, et al (2021)

Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.

Research in pharmaceutical sciences, 16(5):482-492 pii:RPS-16-482.

Background and purpose: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects.

Experimental approach: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds.

Findings/Results: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 μM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 μM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons.

Conclusion and implications: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.

RevDate: 2021-09-15

Teymuori M, Yegdaneh A, M Rabbani (2021)

Effects of Piper nigrum fruit and Cinnamum zeylanicum bark alcoholic extracts, alone and in combination, on scopolamine-induced memory impairment in mice.

Research in pharmaceutical sciences, 16(5):474-481 pii:RPS-16-474.

Background and purpose: Alzheimer's disease is a progressive brain disorder that is thought to be triggered via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, antioxidant phytochemicals with the ability to fortify cholinergic function should help in preventing the progress of the disease. This study aimed at evaluating the combinational effects of two popular herbs one with anticholinesterase activity namely Piper nigrum and the other with antioxidant capacity, Cinnamomum zeylanicum.

Experimental approach: In this study, P. nigrum extract (PN) (50, 100 mg/kg, ip) and C. zeylanicum extract (CZ) (100, 200, 400 mg/kg, ip) and their combinations were administered for 8 days before the injection of scopolamine (1 mg/kg, ip). Mice were then tested for their memory using two behavioral models, namely the object recognition test and the passive avoidance task.

Findings/Results: Administration of scopolamine significantly impaired memory performance in both memory paradigms. In the passive avoidance test (PAT) model, PN at doses up to 100 mg/kg and CZ at doses up to 400 mg/kg did not significantly alter the memory impairment induced by scopolamine. The combination of these two plant extracts did not change the PAT parameters. In the object recognition test (ORT) model, however, administration of 100 mg/kg CZ alone and a combination of PN (50 mg/kg) with CZ (400 mg/kg), significantly increased the recognition index (P < 0.05).

Conclusion and implications: Two plant extracts when administered alone or in combinations affected the memory performance differently in two memory paradigms. In the PAT model, the extracts did not show any memory improvement, in ORT, however, some improvements were observed after plant extracts.

RevDate: 2021-09-15

Bettcher BM, Tansey MG, Dorothée G, et al (2021)

Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus.

Nature reviews. Neurology [Epub ahead of print].

Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates that pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.

RevDate: 2021-09-15

Wen J, Zhao M, Sun W, et al (2021)

Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.

BMC neuroscience, 22(1):53.

BACKGROUND: The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.

RESULTS: In this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important "carrier" for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.

CONCLUSIONS: This is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.

RevDate: 2021-09-14

Houlihan LM, Staudinger Knoll AJ, Jubran JH, et al (2021)

Nancy Davis Reagan, First Lady with a Neurosurgical Legacy.

World neurosurgery, 155:64-73 pii:S1878-8750(21)01180-3 [Epub ahead of print].

Various well-known people associated with the history of the presidency of the United States have experienced neurologic disease or injury, especially trauma to the head or spine. Nancy Reagan, however, as the wife of President Ronald Reagan and First Lady, would leave a significant and lasting mark on the progress of neurosurgical science and education. Recognized for endeavors against drug abuse, Alzheimer disease, and polio, her interest in neurosurgical research is less well known. Nancy's father Loyal Davis was a remarkable neurosurgeon and educator of extraordinary influence. When Barrow Neurological Institute (BNI) founder John Green experienced complications after an illness, Davis served as BNI director during 1966 - 1967. After Davis's death in 1982, Robert Spetzler, who had been a student of Davis at Northwestern University Medical School and was then BNI director, convinced Green, despite his misgivings, to support a neurosurgical laboratory recognizing Davis. In 1988, Nancy Reagan, then First Lady, dedicated the Loyal and Edith Davis Neurosurgical Research Laboratory. At the dedication, she remarked on her years growing up in the home of a pioneering neurosurgeon and remarked that "my father believed deeply in the importance of research to develop new methods for treating patients." Green and Spetzler's unified efforts honored the extraordinary career of Davis in a manner he would have appreciated, were supported by a First Lady with deep involvement in politics and philanthropy dedicated to promoting advances in medicine, and are part of neurosurgery's unique heritage.

RevDate: 2021-09-14

Jeong SH, Kim HR, Kim J, et al (2021)

Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Patients With Diabetes and AD-Related Cognitive Impairment.

Neurology, 97(11):e1110-e1122.

BACKGROUND AND OBJECTIVE: To investigate whether dipeptidyl peptidase-4 inhibitors (DPP-4i) have beneficial effects on amyloid aggregation and longitudinal cognitive outcome in diabetic Alzheimer disease-related cognitive impairment (ADCI).

METHODS: We retrospectively reviewed 282 patients with ADCI with positive 18F-florbetaben amyloid PET images. Patients were classified into 3 groups according to prior diagnosis of diabetes and DPP-4i use: diabetic patients being treated with (ADCI-DPP-4i+, n = 70) or without DPP-4i (ADCI-DPP-4i-, n = 71) and nondiabetic patients (n = 141). Multiple linear regression analyses were performed to determine intergroup differences in global and regional amyloid retention using standardized uptake value ratios calculated from cortical areas. We assessed longitudinal changes in Mini-Mental State Examination (MMSE) score using a linear mixed model.

RESULTS: The ADCI-DPP-4i+ group had lower global amyloid burden than the ADCI-DPP-4i- group (β = 0.075, SE = 0.024, p = 0.002) and the nondiabetic ADCI group (β = 0.054, SE = 0.021, p = 0.010) after adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status. The ADCI-DPP-4i+ group had lower regional amyloid burden in temporo-parietal areas than either the ADCI-DPP-4i- group or the nondiabetic ADCI group. The ADCI-DPP-4i+ group showed a slower longitudinal decrease in MMSE score (β = 0.772, SE = 0.272, p = 0.005) and memory recall subscore (β = 0.291, SE = 0.116, p = 0.012) than the ADCI-DPP-4i- group.

DISCUSSION: These findings suggest that DPP-4i use is associated with low amyloid burden and favorable long-term cognitive outcome in diabetic patients with ADCI.

RevDate: 2021-09-14

Lam V, Takechi R, Hackett MJ, et al (2021)

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

PLoS biology, 19(9):e3001358 pii:PBIOLOGY-D-20-02462.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

RevDate: 2021-09-14

Kozlowska U, Nichols C, Wiatr K, et al (2021)

From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders.

Journal of neurochemistry [Epub ahead of print].

The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.

RevDate: 2021-09-14

Watt JA, Marple R, Hemmelgarn B, et al (2021)

Should Canadian patients look forward to aducanumab for Alzheimer disease?.

CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 193(36):E1430-E1431.

RevDate: 2021-09-14

Hassenstab J, Nicosia J, LaRose M, et al (2021)

Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease.

Alzheimer's research & therapy, 13(1):153.

BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.

METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer's Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness.

RESULTS: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong's test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = - 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15-0.16, ps < 0.007).

CONCLUSIONS: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.

RevDate: 2021-09-09

Lee SR, Choi EK, Park SH, et al (2021)

Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.

Stroke [Epub ahead of print].

BACKGROUND AND PURPOSE: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin.

METHODS: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant-naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia.

RESULTS: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709-0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820-0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740-0.931]).

CONCLUSIONS: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.

RevDate: 2021-09-13

Di Lauro C, Bianchi C, Sebastián-Serrano Á, et al (2021)

P2 × 7 receptor blockade reduces Tau induced toxicity, therapeutic implications in Tauopathies.

Progress in neurobiology pii:S0301-0082(21)00187-8 [Epub ahead of print].

Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2 × 7 receptors (P2 × 7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2 × 7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2 × 7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau (eTau) levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2 × 7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2 × 7 overexpression caused a significant worsening of Tau-induced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2 × 7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies.

RevDate: 2021-09-13

Schwartz JB, S Weintraub (2021)

Treatment for Alzheimer Disease-Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials.

JAMA network open, 4(9):e2124386 pii:2783987.

RevDate: 2021-09-13

Martinkova J, Quevenco FC, Karcher H, et al (2021)

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis.

JAMA network open, 4(9):e2124124 pii:2783983.

Importance: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.

Objective: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.

Data Sources: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020.

Study Selection: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment.

Data Extraction and Synthesis: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model.

Main Outcomes and Measures: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied.

Results: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P < .001) and Europe (68.2%; difference, -10.67% [95% CI, -12.39% to -8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03).

Conclusions and Relevance: In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.

RevDate: 2021-09-13

Planche V, N Villain (2021)

US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?.

JAMA neurology pii:2784255 [Epub ahead of print].

RevDate: 2021-09-13

Ford JN, Sweeney EM, Skafida M, et al (2021)

Heuristic scoring method utilizing FDG-PET statistical parametric mapping in the evaluation of suspected Alzheimer disease and frontotemporal lobar degeneration.

American journal of nuclear medicine and molecular imaging, 11(4):313-326.

Distinguishing frontotemporal lobar degeneration (FTLD) and Alzheimer Disease (AD) on FDG-PET based on qualitative review alone can pose a diagnostic challenge. SPM has been shown to improve diagnostic performance in research settings, but translation to clinical practice has been lacking. Our purpose was to create a heuristic scoring method based on statistical parametric mapping z-scores. We aimed to compare the performance of the scoring method to the initial qualitative read and a machine learning (ML)-based method as benchmarks. FDG-PET/CT or PET/MRI of 65 patients with suspected dementia were processed using SPM software, yielding z-scores from either whole brain (W) or cerebellar (C) normalization relative to a healthy cohort. A non-ML, heuristic scoring system was applied using region counts below a preset z-score cutoff. W z-scores, C z-scores, or WC z-scores (z-scores from both W and C normalization) served as features to build random forest models. The neurological diagnosis was used as the gold standard. The sensitivity of the non-ML scoring system and the random forest models to detect AD was higher than the initial qualitative read of the standard FDG-PET [0.89-1.00 vs. 0.22 (95% CI, 0-0.33)]. A categorical random forest model to distinguish AD, FTLD, and normal cases had similar accuracy than the non-ML scoring model (0.63 vs. 0.61). Our non-ML-based scoring system of SPM z-scores approximated the diagnostic performance of a ML-based method and demonstrated higher sensitivity in the detection of AD compared to qualitative reads. This approach may improve the diagnostic performance.

RevDate: 2021-09-13

Finneran DJ, Njoku IP, Flores-Pazarin D, et al (2021)

Toward Development of Neuron Specific Transduction After Systemic Delivery of Viral Vectors.

Frontiers in neurology, 12:685802.

Widespread transduction of the CNS with a single, non-invasive systemic injection of adeno-associated virus is now possible due to the creation of blood-brain barrier-permeable capsids. However, as these capsids are mutants of AAV9, they do not have specific neuronal tropism. Therefore, it is necessary to use genetic tools to restrict expression of the transgene to neuronal tissues. Here we compare the strength and specificity of two neuron-specific promoters, human synapsin 1 and mouse calmodulin/calcium dependent kinase II, to the ubiquitous CAG promoter. Administration of a high titer of virus is necessary for widespread CNS transduction. We observed the neuron-specific promoters drive comparable overall expression in the brain to the CAG promoter. Furthermore, the neuron-specific promoters confer significantly less transgene expression in peripheral tissues compared with the CAG promoter. Future experiments will utilize these delivery platforms to over-express the Alzheimer-associated pathological proteins amyloid-beta and tau to create mouse models without transgenesis.

RevDate: 2021-09-13

Tsolaki M, Tsatali M, Gkioka M, et al (2021)

Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.

Frontiers in neurology, 12:683131.

Background: This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. Methods: The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. Results: In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. Conclusion: In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.

RevDate: 2021-09-13

Sevinc G, Rusche J, Wong B, et al (2021)

Mindfulness Training Improves Cognition and Strengthens Intrinsic Connectivity Between the Hippocampus and Posteromedial Cortex in Healthy Older Adults.

Frontiers in aging neuroscience, 13:702796.

Maintaining optimal cognitive functioning throughout the lifespan is a public health priority. Evaluation of cognitive outcomes following interventions to promote and preserve brain structure and function in older adults, and associated neural mechanisms, are therefore of critical importance. In this randomized controlled trial, we examined the behavioral and neural outcomes following mindfulness training (n = 72), compared to a cognitive fitness program (n = 74) in healthy, cognitively normal, older adults (65-80 years old). To assess cognitive functioning, we used the Preclinical Alzheimer Cognitive Composite (PACC), which combines measures of episodic memory, executive function, and global cognition. We hypothesized that mindfulness training would enhance cognition, increase intrinsic functional connectivity measured with magnetic resonance imaging (MRI) between the hippocampus and posteromedial cortex, as well as promote increased gray matter volume within those regions. Following the 8-week intervention, the mindfulness training group showed improved performance on the PACC, while the control group did not. Furthermore, following mindfulness training, greater improvement on the PACC was associated with a larger increase in intrinsic connectivity within the default mode network, particularly between the right hippocampus and posteromedial cortex and between the left hippocampus and lateral parietal cortex. The cognitive fitness training group did not show such effects. These findings demonstrate that mindfulness training improves cognitive performance in cognitively intact older individuals and strengthens connectivity within the default mode network, which is particularly vulnerable to aging affects. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT02628548], identifier [NCT02628548].

RevDate: 2021-09-13

Islam MS, Mia MAK, Rahman MS, et al (2021)

Frequent contiguous pattern mining over biological sequences of protein misfolded diseases.

BMC bioinformatics, 22(1):435.

BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools.

RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method.

CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.

RevDate: 2021-09-12

Maayan G, Behar AE, Sabater L, et al (2021)

A Water-Soluble Peptoid Chelator that Can Remove Cu2+ from Amyloid-β and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease.

Angewandte Chemie (International ed. in English) [Epub ahead of print].

Cu bound to Amyloid-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer's disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn2+ ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex. Herein we describe P3, a water-soluble peptidomimetic chelator that selectively removes Cu(II) from Cu-Aβ in the presence of Zn and prevent the formation of ROS even in a reductive environment. We demonstrate, based on extensive spectroscopic analysis, that although P3 extracts Zn from Cu,Zn-Aβ faster than in removes Cu, the formed Zn complexes are kinetic products that further dissociate, while CuP3 is formed as an exclusive stable thermodynamic product. Our unique findings, combined with the bioavailability of peptoids, make P3 an excellent drug candidate in the context of AD.

RevDate: 2021-09-12

George KM, Peterson RL, Gilsanz P, et al (2021)

Stroke Belt Birth State and Late-life Cognition in The Study of Healthy Aging in African Americans (STAR).

Annals of epidemiology pii:S1047-2797(21)00284-2 [Epub ahead of print].

PURPOSE: We examined the association of Stroke Belt birth state with late-life cognition in The Study of Healthy Aging in African Americans (STAR).

METHODS: STAR enrolled 764 Black Americans ages 50+ who were long-term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check-ups (MHC;1964-1985) where early-life overweight/obesity, hypertension, diabetes, and hyperlipidemia were measured. At STAR (2018), birth state, self-reported early-life socioeconomic status (SES), and executive function, verbal episodic memory, and semantic memory scores were collected. We used linear regression to examine the association between Stroke Belt birth and late-life cognition adjusting for birth year, gender, and parental education. We evaluated early-life SES and cardiovascular risk factors (CVRF) as potential mechanisms.

RESULTS: Twenty-seven percent of participants were born in the Stroke Belt with a mean age of 69(SD=9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β(95% CI):-0.18(-0.33,-0.02)) and semantic memory (-0.37(-0.53, -0.21)), but not verbal episodic memory (-0.04(-0.20, 0.12)). Adjustment for SES and CVRF attenuated associations of Stroke Belt birth with cognition (executive function (-0.05(-0.25, 0.14)); semantic memory (-0.28(-0.49, -0.07))).

CONCLUSION: Black Americans born in the Stroke Belt had worse late-life cognition than those born elsewhere, underscoring the importance of early-life exposures on brain health.

RevDate: 2021-09-12

Bello-Medina PC, González-Franco DA, Vargas-Rodríguez I, et al (2021)

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.

Neurologia (Barcelona, Spain) pii:S2173-5808(21)00131-0 [Epub ahead of print].

INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response.

DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address 2 factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment.

CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.

RevDate: 2021-09-11

Baldinotti R, Fronza MG, Silva L, et al (2021)

Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.

European journal of pharmacology pii:S0014-2999(21)00653-1 [Epub ahead of print].

Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of STZ. To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated icv infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.

RevDate: 2021-09-10

Flugon SJ, Jøranson N, GG Tangen (2021)

Mobility and Depressive Symptoms in Persons With Mild Cognitive Impairment and Alzheimer Dementia.

Journal of neurologic physical therapy : JNPT pii:01253086-900000000-99710 [Epub ahead of print].

BACKGROUND AND PURPOSE: Persons with mild cognitive impairment (MCI) and Alzheimer dementia (AD) often experience gait and balance disturbances and depressive symptoms alongside their cognitive impairment. The aim of this study was to explore the relationship between mobility and depressive symptoms in community-dwelling persons with MCI and mild to moderate AD.

METHODS: Ninety-nine participants with MCI and AD from the memory clinic at Oslo University Hospital, Ullevål, Norway, were included. The Balance Evaluation Systems Test (BESTest), 10-m walk test regular (gait speed), and dual task (naming animals, dual-task cost in percent) were used to assess mobility. The Cornell Scale for Depression in Dementia, with validated cut-off 5/6 points, was used to assess presence of depressive symptoms. Multiple regression analysis was used to explore the relationship between mobility (3 separate models) and depressive symptoms, controlled for demographic factors, comorbidity, and Mini-Mental State Examination.

RESULTS: One-third of the participants had depressive symptoms, mean (SD) gait speed was 1.09 (0.3) m/s, and median (interquartile range) BESTest percent score was 81.5 (17.6). No statistically significant associations were found between depression and BESTest, gait speed or dual-task cost, neither in the simple models (P = 0.15-0.85), nor in the 3 multivariate models (P = 0.57-0.69).

DISCUSSION AND CONCLUSIONS: In this study, we found no associations between mobility and depressive symptoms in persons with MCI and AD recruited at a memory clinic. Few participants had major symptoms of depression, which may have influenced the results. Longitudinal studies are needed to explore the long-time associations between mobility and depression.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A366).

RevDate: 2021-09-10

Brenowitz WD, Xiang Y, McEvoy CT, et al (2021)

Current Alzheimer disease research highlights: evidence for novel risk factors.

Chinese medical journal pii:00029330-900000000-98450 [Epub ahead of print].

ABSTRACT: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.

RevDate: 2021-09-10

Sanders OD, Rajagopal L, JA Rajagopal (2021)

The oxidatively damaged DNA and amyloid-β oligomer hypothesis of Alzheimer's disease?.

Free radical biology & medicine pii:S0891-5849(21)00479-2 [Epub ahead of print].

The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still dominates the field, yet the clinical trial evidence does not robustly support it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should be elevated in the brain regions and at the disease stages where and when neuron death and synaptic protein loss begin and are the most severe, but we review previous evidence to demonstrate that this is not consistently the case. To rescue the Aβ oligomer hypothesis from falsification, we propose the novel ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally produce Aβ peptides even in healthily aging individuals, and hippocampal oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate and drive Aβ peptide aggregation into oligomers and spreading, neuron death, synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight additional evidence consistent with the underwhelming efficacy of Aβ oligomer-lowering agents, such as aducanumab, and of antioxidants, such as vitamin E, versus the so far isolated case report that DNase-I treatment for 2 months resulted in a severe AD patient's Mini-Mental State Exam score increasing from 3 to 18, reversing his diagnosis to moderate AD, according to the Mini-Mental State Exam.

RevDate: 2021-09-10

Xiromerisiou G, Bourinaris T, Houlden H, et al (2021)

SORL1 mutation in a Greek family with Parkinson's disease and dementia.

Annals of clinical and translational neurology [Epub ahead of print].

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.

RevDate: 2021-09-10

Kshirsagar S, Sawant N, Morton H, et al (2021)

Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.

Human molecular genetics pii:6367977 [Epub ahead of print].

The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy enhancers treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, & mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aβ-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with ad.

RevDate: 2021-09-10

Aguilar-Pineda JA, Vera-Lopez KJ, Shrivastava P, et al (2021)

Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease.

iScience, 24(9):102993 pii:S2589-0042(21)00961-5.

Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD.

RevDate: 2021-09-10

Nascimento FP, Macedo-Júnior SJ, Lapa-Costa FR, et al (2021)

Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?.

Frontiers in neuroscience, 15:703783.

Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.

RevDate: 2021-09-10

Schindler S, Li Y, Buckles VD, et al (2021)

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.

Neurology pii:WNL.0000000000012775 [Epub ahead of print].

OBJECTIVE: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).

METHODS: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale using longitudinal data.

RESULTS: Amyloid accumulation was evaluated in 236 individuals who underwent more than one amyloid PET scan. The average age was 66.5 ± 9.2 years and twelve individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the twenty-two individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R2=0.54, p<0.0001, root mean square error (RMSE) 4.5 years); the model was more accurate after exclusion of three likely misdiagnoses (R2=0.84, p<0.0001, RMSE of 2.8 years).

CONCLUSIONS: The age of symptom onset in sporadic AD is strongly correlated with the age that an individual reaches a tipping point in amyloid accumulation.

RevDate: 2021-09-10

Buciuc M, Josephs KA, Jones DT, et al (2021)

Progressive Auditory Verbal Agnosia Secondary to Alzheimer Disease.

Neurology pii:WNL.0000000000012783 [Epub ahead of print].

RevDate: 2021-09-10

Lee YY, Chen CL, Lee IC, et al (2021)

History of Falls, Dementia, Lower Education Levels, Mobility Limitations, and Aging Are Risk Factors for Falls among the Community-Dwelling Elderly: A Cohort Study.

International journal of environmental research and public health, 18(17): pii:ijerph18179356.

BACKGROUND: Falling is a serious issue among elderly community dwellers, often resulting in disability. We aimed to investigate the risk factors for falls among elderly community dwellers.

METHODS: We recruited 232 participants from multiple community learning and care centers, who provided their information through questionnaires. They were divided into two groups, according to their falling events after a 1-year follow-up. Univariate and multivariate logistic regressions were used for statistical analysis.

RESULTS: A total of 64 participants reported a fall at the 1-year follow-up. The falling group comprised older and single people with lower education levels, higher rates of dementia, a history of falls, lower scores on the Mini-Mental State Examination, and more disability functions when compared to the non-falling group (all p < 0.05). The regression model showed that a history of falls (OR: 62.011; p < 0.0001), lower education levels (OR: 4.088; p = 0.039), mild dementia (OR: 20.729; p = 0.028), older age (OR: 1.176; p < 0.0001), walking for 300 m (OR: 4.153; p = 0.030), and running for 30 m (OR: 3.402; p = 0.015) were 1-year risk factors for falls.

CONCLUSION: A history of falling, low education levels, aging, mild dementia, and certain mobility limitations were strong risk factors for future falling accidents in elderly Taiwanese community dwellers.

RevDate: 2021-09-10

Purgatorio R, Gambacorta N, de Candia M, et al (2021)

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.

Molecules (Basel, Switzerland), 26(17): pii:molecules26175208.

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.

RevDate: 2021-09-09

Anderson TS, Ayanian JZ, Souza J, et al (2021)

Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment.

JAMA pii:2784225 [Epub ahead of print].

RevDate: 2021-09-09

Ryan KC, Ashkavand Z, Sarasija S, et al (2021)

Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.

Aging cell [Epub ahead of print].

Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.

RevDate: 2021-09-09

Heger I, Köhler S, Boxtel MV, et al (2021)

[Raising awareness for dementia risk reduction through a public health campaign: a pre-post study].

Tijdschrift voor gerontologie en geriatrie, 52(2):.

This study evaluates a public health campaign initiated by the Alzheimer Center Limburg of Maastricht University. The aim was to increase awareness of the influence of a healthy lifestyle on lowering the risk of dementia in community-dwelling inhabitants of the Province of Limburg (aged 40 - 75 years). The campaign used mass media and public events, supported by a campaign website and mobile application (MijnBreincoach app). An additional district-oriented approach was chosen in the municipalities of Roermond, Landgraaf and Brunssum, in which local stakeholders were involved in the design and execution of campaign-related events. Population-level difference in awareness before and after the campaign was assessed in two independent samples. No pre-post difference was observed in the level of awareness of dementia risk reduction. An additional analyses in the post-campaign sample revealed that the group that reported to have heard of the campaign, was more often aware of dementia risk reduction and reported higher motivation for behavioural change than the group that had not heard of the campaign. The district-oriented approach resulted in better recognition of campaign-material and the mobile application. With regard to the individual lifestyle factors, healthy diet and physical activity were identified more often post-campaign. Cognitive activity was identified most often at both pre- and post-assessment, but there was no increase in awareness after the campaign.

RevDate: 2021-09-09

Fernandes AR, Dujardin S, Maté de Gérando A, et al (2021)

Impact of Sterilization Methods on the Seeding Ability of Human Tau Proteopathic Seeds.

Journal of neuropathology and experimental neurology pii:6366482 [Epub ahead of print].

The protein tau, when misfolded in neurodegenerative diseases, has several prion-like properties including being able to spread by cell-to-cell transfer, induce templated seeding, and exist in distinct conformational strains. These properties of transmission may present health hazards when lesion-containing biospecimens are used in research and neuropathology laboratories. We evaluated the impact standard sterilization and cleaning methods have on the capacity of tau seeds to induce aggregation. We employed a previously developed, highly sensitive FRET-based biosensor assay to assess remnant tau seeding after exposure to these procedures. For tau species derived from human Alzheimer disease tissue (brain homogenate and sarkosyl-insoluble fibrils), both autoclaving and incubation in 90.6% formic acid were sufficient to reduce tau bioactivity. By contrast, boiling was not always effective in completely blocking bioactivity in the seeding assay. Notably, only formic acid incubation was able to produce a similar reduction in tissue from a P301L mutant tau mouse model of tauopathy. Our study highlights nuances in methods for inactivation of tau seeding which may support adapted tissue processing procedures, especially in research settings. These findings also highlight the importance of universal precautions when handling human neuropathological and research laboratory materials.

RevDate: 2021-09-08

Sternin A, McGarry LM, Owen AM, et al (2021)

The Effect of Familiarity on Neural Representations of Music and Language.

Journal of cognitive neuroscience, 33(8):1595-1611.

We investigated how familiarity alters music and language processing in the brain. We used fMRI to measure brain responses before and after participants were familiarized with novel music and language stimuli. To manipulate the presence of language and music in the stimuli, there were four conditions: (1) whole music (music and words together), (2) instrumental music (no words), (3) a capella music (sung words, no instruments), and (4) spoken words. To manipulate participants' familiarity with the stimuli, we used novel stimuli and a familiarization paradigm designed to mimic "natural" exposure, while controlling for autobiographical memory confounds. Participants completed two fMRI scans that were separated by a stimulus training period. Behaviorally, participants learned the stimuli over the training period. However, there were no significant neural differences between the familiar and unfamiliar stimuli in either univariate or multivariate analyses. There were differences in neural activity in frontal and temporal regions based on the presence of language in the stimuli, and these differences replicated across the two scanning sessions. These results indicate that the way we engage with music is important for creating a memory of that music, and these aspects, over and above familiarity on its own, may be responsible for the robust nature of musical memory in the presence of neurodegenerative disorders such as Alzheimer disease.

RevDate: 2021-09-08

Mahmoudi E, Lin P, Kamdar N, et al (2021)

Risk of early- and late-onset Alzheimer disease and related dementia in adults with cerebral palsy.

Developmental medicine and child neurology [Epub ahead of print].

AIM: To examine the risk of Alzheimer disease and related dementia (ADRD) among adults with cerebral palsy (CP).

METHOD: Using administrative insurance claims data for 2007 to 2017 in the USA, we identified adults (45y or older) with a diagnosis of CP (n=5176). Adults without a diagnosis of CP were included as a typically developing comparison group (n=1 119 131). Using age, sex, ethnicity, other demographic variables, and a set of chronic morbidities, we propensity-matched individuals with and without CP (n=5038). Cox survival models were used to estimate ADRD risk within a 3-year follow up.

RESULTS: The unadjusted incidence of ADRD was 9 and 2.4 times higher among cohorts of adults 45 to 64 years (1.8%) and 65 years and older (4.8%) with CP than the respective unmatched individuals without CP (0.2% and 2.0% among 45-64y and 65y or older respectively). Fully adjusted survival models indicated that adults with CP had a greater hazard for ADRD (among 45-64y: unmatched hazard ratio 7.48 [95% confidence interval {CI} 6.05-9.25], matched hazard ratio 4.73 [95% CI 2.72-8.29]; among 65y or older: unmatched hazard ratio 2.21 [95% CI 1.95-2.51], matched hazard ratio 1.73 [1.39-2.15]).

INTERPRETATION: Clinical guidelines for early screening of cognitive function among individuals with CP need updating, and preventative and/or therapeutic services should be used to reduce the risk of ADRD.

RevDate: 2021-09-07

Elliott CL, Ryan L, N Silverberg (2021)

Building Inclusive and Open Alzheimer Disease and Alzheimer Disease-Related Dementias Research Programs.

JAMA neurology pii:2783979 [Epub ahead of print].

RevDate: 2021-09-07

Wang Y, Chi I, Zhan Y, et al (2021)

Effectiveness of Resilience Interventions on Psychosocial Outcomes for Persons With Neurocognitive Disorders: A Systematic Review and Meta-Analysis.

Frontiers in psychiatry, 12:709860.

Background: Neurocognitive disorders, such as mild cognitive impairment (MCI), dementia, and Alzheimer's disease, not only harm people's cognitive function but also lead to negative emotions, poor quality of life (QOL), and unsatisfactory level of well-being. Resilience can be defined as a dynamic and amendable process, which maintains or improves life satisfaction and quick recovery from own dilemma. However, no meta-analysis of randomized controlled trials (RCTs) has thus far examined the effectiveness of resilience interventions among persons with neurocognitive disorders, and the results of RCTs were inconsistent. This systematic review aimed to assess the effectiveness of resilience interventions on psychosocial outcomes among persons with neurocognitive disorders. Methods: Nine electronic Chinese and English databases (the Cochrane Library, PsycINFO, Web of Science, PubMed, Medline, Eric, JSTOR, CNKI, and WANGFANG) were searched through April 2021. Only RCTs were included, and the quality of the included studies was assessed by the Cochrane "Risk of Bias" tool. Meta-analysis was carried out on psychosocial outcomes, and heterogeneity was investigated by subgroup and sensitivity analysis. RevMan 5.4 was used for meta-analysis. Results: Fourteen RCT studies were identified, representing a total of 2,442 participants with neurocognitive disorders. The risk of bias was high or unclear for most included studies in the domains of allocation concealment, blinding participants, and interventionists. Meta-analysis showed that heterogeneity was low or moderate. There were significant differences in favor of resilience interventions compared with control on the outcome of QOL, using the Quality of Life-Alzheimer Disease scale (QOL-AD) [I 2 = 36%, standardized mean difference (SMD) = 0.14, 95% CI (0.02, 0.26), p = 0.02], and no significant differences on depression, using the Cornell Scale for Depression in Dementia (CSDD) [I 2 = 41%, SMD = -0.14, 95% CI (-0.34, 0.05), p = 0.16], and neuropsychiatric symptoms using the Neuropsychiatric Inventory Questionnaire (NPI-Q) [I 2 = 62%, SMD = -0.10, 95% CI (-0.37, -0.16), p ≤ 0.46]. Conclusions: Resilience interventions had a significant benefit on QOL but no significant benefit on depression and neuropsychiatric behavioral symptoms. More evidence is needed to answer questions about how to implement resilience interventions and how to evaluate their effectiveness.

RevDate: 2021-09-07

Ou H, Chien WC, Chung CH, et al (2021)

Association Between Antibiotic Treatment of Chlamydia pneumoniae and Reduced Risk of Alzheimer Dementia: A Nationwide Cohort Study in Taiwan.

Frontiers in aging neuroscience, 13:701899.

Background: Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284-1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.

RevDate: 2021-09-07

Sim AY, Barua S, Kim JY, et al (2021)

Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.

Frontiers in neuroscience, 15:708547.

Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.

RevDate: 2021-09-07

Shafiezadeh A, Heravi-Karimooi M, Mirzaee A, et al (2021)

Correction to: Psychometric characteristics of the Iranian Caregiver Burden Inventory (CBI) in caregivers of elderly patients with Alzheimer.

Health and quality of life outcomes, 19(1):215.

RevDate: 2021-09-07

Nezhadmoghadam F, Martinez-Torteya A, Treviño V, et al (2021)

Robust Discovery of Mild Cognitive Impairment Subtypes and Their Risk of Alzheimer's Disease Conversion Using Unsupervised Machine Learning and Gaussian Mixture Modeling.

Current Alzheimer research pii:CAR-EPUB-117574 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills. The ability to correctly predict the diagnosis of Alzheimer's disease in its earliest stages can help physicians make more informed clinical decisions on therapy plans.

OBJECTIVE: This study aimed to determine whether the unsupervised discovering of latent classes of subjects with mild cognitive impairment (MCI) may be useful in finding different prodromal AD stages and/or subjects with a low MCI to AD conversion risk.

METHODS: Total 18 features relevant to the MCI to AD conversion process led to the identification of 681 subjects with early MCI. Subjects were divided into training (70%) and validation (30%) sets. Subjects from the training set were analyzed using consensus clustering, and Gaussian mixture models (GMM) were used to describe the latent classes. The discovered GMM predicted the latent class of the validation set. Finally, descriptive statistics, rates of conversion, and odds ratios (OR) were computed for each discovered class.

RESULTS: Through consensus clustering, we discovered three different clusters among MCI subjects. The three clusters were associated with low-risk (OR = 0.12, 95%CI = 0.04 to 0.3|), medium-risk (OR = 1.33, 95%CI = 0.75 to 2.37), and high-risk (OR = 3.02, 95%CI = 1.64 to 5.57) of converting from MCI to AD, with the high-risk and low-risk groups highly contrasting. Hence, prodromal AD subjects were present in only two clusters.

CONCLUSION: We successfully discovered three different latent classes among MCI subjects with varied risks of MCI-to- AD conversion through consensus clustering. Two of the discovered classes may represent two different prodromal presentations of Alzheimer´s disease.

RevDate: 2021-08-26

Düzel E, Costagli M, Donatelli G, et al (2021)

Studying Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis with 7-T magnetic resonance.

European radiology experimental, 5(1):36.

Ultra-high-field (UHF) magnetic resonance (MR) scanners, that is, equipment operating at static magnetic field of 7 tesla (7 T) and above, enable the acquisition of data with greatly improved signal-to-noise ratio with respect to conventional MR systems (e.g., scanners operating at 1.5 T and 3 T). The change in tissue relaxation times at UHF offers the opportunity to improve tissue contrast and depict features that were previously inaccessible. These potential advantages come, however, at a cost: in the majority of UHF-MR clinical protocols, potential drawbacks may include signal inhomogeneity, geometrical distortions, artifacts introduced by patient respiration, cardiac cycle, and motion. This article reviews the 7 T MR literature reporting the recent studies on the most widespread neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

RevDate: 2021-08-31
CmpDate: 2021-08-31

Wang Y, Yang Y, Ren L, et al (2021)

Preexisting Mental Disorders Increase the Risk of COVID-19 Infection and Associated Mortality.

Frontiers in public health, 9:684112.

Coronavirus disease 2019 (COVID-19), a respiratory disease of unknown origin, has a high rate of morbidity and mortality. Individuals with mental disorders may have a higher risk of infection and worse clinical outcomes because of a variety of factors such as poorer general resilience and lower immune function. However, there have been no studies to date specifically investigating the risk of COVID-19 and associated mortality in these patients. This was addressed in the present study by analyzing the data of 473,958 subjects included in the UK Biobank, 14,877 of whom tested positive for COVID-19 infection. Logistic regression analysis was performed to evaluate the associations between mental disorders and risks of COVID-19 infection and associated mortality. The results showed that subjects who were diagnosed with a mental disorder had a significantly higher risk of developing COVID-19 and a worse outcome as evidenced by higher rates of COVID-19-related mortality, with the strongest effects observed for dementia. Among dementia subtypes, Alzheimer disease patients had the highest risks of COVID-19 infection (7.39-fold increase) and associated mortality (2.13-fold increase). Late-life anxiety only increased the risk of developing COVID-19 while late-life depression not only was associated with a higher risk of infection but also a worse outcome. These findings highlight the need to prioritize patients with mental disorders-especially those who experience these disorders later in life-when implementing preventive strategies such as vaccinations.

RevDate: 2021-08-25

Hung C, FJ Livesey (2021)

Endolysosome and autophagy dysfunction in Alzheimer disease.

Autophagy [Epub ahead of print].

Abnormalities of the neuronal endolysosome and macroautophagy/autophagy system are an early and prominent feature of Alzheimer disease (AD). SORL1 is notable as a gene in which mutations are causal for a rare, autosomal dominant form of AD, and also variants that increase the risk of developing the common form of late-onset AD. In our recent study, we used patient-derived stem cells and CRISPR engineering to study the effects of SORL1 mutations on the endolysosome and autophagy system in human forebrain neurons. SORL1 mutations causal for monogenic AD are typically truncating mutations, and we found, using stem cells generated from an individual with dementia due to a heterozygous SORL1 truncation mutation, that this class of mutation results in SORL1 haploinsufficiency. Reducing SORL1 protein by half results in disrupted endosomal trafficking in patient-derived neurons, which we confirmed by studying the endolysosomal system in isogenic CRISPR-engineered SORL1 heterozygous null neurons. We also found that SORL1 homozygous null neurons develop more severe phenotypes, with endosome abnormalities, lysosome dysfunction and defects in the degradative phase of autophagy. Endolysosome and autophagy defects in SORL1 mutant neurons are dependent on APP, a key AD gene, as they are rescued by extracellular antisense oligonucleotides that reduce APP protein.

RevDate: 2021-09-06

Kloske CM, Dugan AJ, Weekman EM, et al (2021)

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status.

Journal of neuropathology and experimental neurology pii:6364777 [Epub ahead of print].

Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

RevDate: 2021-09-06

Cardona K, Medina J, Orrego-Cardozo M, et al (2021)

Inflammatory gene expression profiling in peripheral blood from patients with Alzheimer's disease reveals key pathways and hub genes with potential diagnostic utility: a preliminary study.

PeerJ, 9:e12016 pii:12016.

Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease caused by central nervous system disorders. Late-onset Alzheimer disease (LOAD) is the most common neurodegenerative disorder worldwide. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing AD. Peripheral blood genome transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tau for AD research.

Methods: This preliminary study explores molecular pathogenesis of LOAD-related inflammation through next generation sequencing, to assess RNA expression profiles in peripheral blood from five patients with LOAD and 10 healthy controls.

Results: The analysis of RNA expression profiles revealed 94 genes up-regulated and 147 down-regulated. Gene function analysis, including Gene Ontology (GO) and KOBAS-Kyoto Encyclopedia of DEGs and Genomes (KEGG) pathways indicated upregulation of interferon family (INF) signaling, while the down-regulated genes were mainly associated with the cell cycle process. KEGG metabolic pathways mapping showed gene expression alterations in the signaling pathways of JAK/STAT, chemokines, MAP kinases and Alzheimer disease. The results of this preliminary study provided not only a comprehensive picture of gene expression, but also the key processes associated with pathology for the regulation of neuroinflammation, to improve the current mechanisms to treat LOAD.

RevDate: 2021-09-06

Venditto JG, Bender E, ML Lichtenstein (2021)

Psychosis in a Middle-aged Woman: A Case of Presenilin-1 p.Gly206Ala Alzheimer Disease.

Neurology. Clinical practice, 11(4):e573-e575.

RevDate: 2021-09-06

Moinuddin O, Khandwala NS, Young KZ, et al (2021)

Role of Optical Coherence Tomography in Identifying Retinal Biomarkers in Frontotemporal Dementia: A Review.

Neurology. Clinical practice, 11(4):e516-e523.

Purpose of Review: Frontotemporal dementia (FTD) is often misdiagnosed or recognized late. Clinical heterogeneity and overlap with other dementias impede accurate diagnosis. FTD biomarkers are limited, expensive, and invasive. We present a narrative review of the current literature focused on optical coherence tomography (OCT) to identify retinal biomarkers of dementia, discuss OCT findings in FTD, and explore the implications of an FTD-specific ocular biomarker for research and patient care.

Recent Findings: Recent studies suggest that outer retinal thinning detected via OCT may function as a novel ocular biomarker of FTD. The degree and rate of inner retinal thinning may correlate with disease severity and progression. In Alzheimer disease (AD), OCT demonstrates thinning of the inner retina, which may differentiate this condition from FTD. We conducted a comprehensive search of the literature and reviewed published OCT findings in FTD, AD, and mild cognitive impairment, as well as reports on biomarkers of FTD and AD used in the research and patient care settings. Three of the authors (O.M., N.S.K., and K.Z.Y.) independently conducted literature searches using PubMed to identify studies published before May 1, 2020, using the following search terminology: "Alzheimer's disease," "Alzheimer's dementia," "frontotemporal dementia," "FTD," "mild cognitive impairment," "dementia biomarkers," and "neurodegeneration biomarkers." Search results were then refined using one or more of the following keywords: "optical coherence tomography," "optical coherence tomography angiography," "retinal imaging," and "retinal thinning." The selection of published works for inclusion in this narrative review was then limited to full-text articles written in English based on consensus agreement of the authors.

Summary: FTD diagnosis is imprecise, emphasizing the need for improved state and trait biomarkers. OCT imaging of the retina holds considerable potential for establishing effective ocular biomarkers for FTD.

RevDate: 2021-09-06

Mahdavi KD, Jordan SE, Barrows HR, et al (2021)

Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.

Neurology. Clinical practice, 11(3):e294-e302.

Objective: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib.

Methods: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline.

Results: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances.

Conclusions: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.

RevDate: 2021-09-06

Kaasalainen S, Mccleary L, Vellani S, et al (2021)

Improving End-of-Life Care for People with Dementia in LTC Homes During the COVID-19 Pandemic and Beyond.

Canadian geriatrics journal : CGJ, 24(3):164-169 pii:cgj-24-164.

COVID-19 pandemic has resulted in a significant increase in deaths in long-term care homes (LTCH). People with dementia living in LTCHs represent one of the most frail and marginalized populations in Canada. The surge of COVID-19 cases in LTCHs and rationing of health-care resources during the pandemic have amplified the pre-existing need for improvements in palliative and end-of-life care in LTCHs. This position statement, created by a task force commissioned by the Alzheimer Society of Canada, provides recommendations for a multipronged coordinated approach to improving palliative and end-of-life care of people with dementia living in LTCHs during the COVID-19 pandemic and beyond.

RevDate: 2021-09-06

Wynn MJ, Ju CH, PL Hill (2021)

Sense of Purpose Following a Dementia Diagnostic Appointment: Comparing Self- and Other-Reports of Care Recipients and Care Partners.

Frontiers in psychology, 12:703478.

Objective: Purpose in life tends to decline in older adulthood and it is thought that intact cognitive functioning is required for purposeful living. Thus, it is likely that individuals may perceive older adults who are experiencing cognitive declines associated with dementia as having a reduced sense of purpose. Biases such as these may influence how individuals, especially care partners, interact with those with dementia. Method: This study examined how sense of purpose changed following a dementia diagnostic appointment for both the person receiving a diagnosis and their care partner. This study also explored how each individual perceived the other member of the dyad's sense of purpose. Older adults (47 care recipients and 75 care partners, 57% female; Mage = 68.5 years, SDage = 12.0 years) provided self- and other-report ratings of sense of purpose before and after their appointment at a specialized memory clinic. Results: Overall, both care recipients and care partners' sense of purpose declined following a dementia diagnostic appointment [t(85) = 7.01, p < 0.001]. However, when comparing self-reports and other-reports of purpose, care partners reported that care recipients experienced a lower sense of purpose in life than the care recipients reported about themselves. Conclusions: Care recipients and partners reported less purpose in life following their dementia diagnostic appointment. Care partners may hold certain biases regarding sense of purpose toward care recipients. These findings can inform future work regarding how care recipients and care partners can plan purposeful lives following a dementia diagnosis.

RevDate: 2021-09-06

Contini C, Olianas A, Serrao S, et al (2021)

Corrigendum: Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease.

Frontiers in neuroscience, 15:743596.

[This corrects the article DOI: 10.3389/fnins.2021.668852.].

RevDate: 2021-09-05

Sanz-Blasco R, Ruiz-Sánchez de León JM, Ávila-Villanueva M, et al (2021)

Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon.

METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum.

RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion.

DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.

RevDate: 2021-09-04

Nies SH, Takahashi H, Herber CS, et al (2021)

Spreading of Alzheimer Tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.

The Journal of biological chemistry pii:S0021-9258(21)00961-3 [Epub ahead of print].

In Alzheimer's Disease (AD), deposition of pathological Tau and Amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded Tau aggregates extracted from human AD brains drives templated spreading of Tau pathology within wild type mouse brain. Here, we assessed the impact of Aß co-pathology, of deleting loci known to modify AD risk (Ptk2b, Grn, Tmem106b) and of pharmacological intervention with a Fyn kinase inhibitor on Tau spreading after injection of AD Tau extracts. The density and spreading of Tau inclusions triggered by human Tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and AppNL-F/NL-F knock-in mice. In mice with human Tau sequence replacing mouse Tau, template matching enhanced neuritic Tau burden. Human AD brain Tau-enriched preparations contained aggregated Aß, and the Aß co-injection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from Tau accumulation and could be ameliorated by depleting Aβ from Tau extracts. These data suggest that Aβ and Tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer (Aβo) induced signaling, or deleting expression of the PGRN and TMEM106B lysosomal proteins, did not alter the somatic Tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic Tau after injection of human AD Tau seeds into wild type mice. These studies refine our knowledge of factors capable of modulating Tau spreading.

RevDate: 2021-09-04

Tyler KL (2021)

The Link Between Alzheimer Disease and Herpes Simplex Virus Infection: Better Late Than Never, or Better Never Than Late?.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Epub ahead of print].

RevDate: 2021-09-04

Panitch R, Hu J, Chung J, et al (2021)

Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.

Molecular psychiatry [Epub ahead of print].

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

RevDate: 2021-09-04

Tsigas EZ (2021)

The Preeclampsia Foundation: the voice and views of the patient and her family.

American journal of obstetrics and gynecology pii:S0002-9378(20)31289-8 [Epub ahead of print].

Preeclampsia is a disease exclusive to pregnancy and the immediate postpartum period, occurring in 4.6% of pregnancies worldwide. Preeclampsia and other gestational hypertensive disorders can affect any pregnant woman. The consequences of developing this disease can lead to severe maternal and neonatal morbidities and mortalities, including fetal growth restriction, placental abruption, preterm birth, stillbirth, and maternal death. When pregnant women recover, they are at higher risk of long-term complications such as hypertension, stroke, heart failure, renal disease, and Alzheimer disease. The consequences extend to the offspring because they are at higher risk of cardiovascular diseases, and female offspring are at greater risk of developing preeclampsia when they become pregnant. For society, preeclampsia presents an economic burden related to the additional healthcare costs associated with low birthweight, prematurity, and adverse outcomes to the mother and baby. This article shares the unique perspective of affected women and their families, the effect preeclampsia has on us, and what we hope the healthcare system can deliver for our sisters and daughters in the future. Patients and their families established the Preeclampsia Foundation 21 years ago. Devoted to education and patient advocacy to raise awareness, improve healthcare practices, and catalyze research, we share some of the Foundation's realized strategies and achievements. We tell you our stories and struggles, and we issue a call to action for all stakeholders to help fulfill our vision for a world where hypertensive disorders of pregnancy no longer threaten the lives of mothers and their babies.

RevDate: 2021-09-03

Wychowaniec JK, Moffat J, A Saiani (2021)

Quantitative nanomechanical properties evaluation of a family of β-sheet peptide fibres using rapid bimodal AFM.

Journal of the mechanical behavior of biomedical materials, 124:104776 pii:S1751-6161(21)00419-7 [Epub ahead of print].

Self-assembling peptides have become important building blocks for materials design (e.g. hydrogels) and play a crucial role in a range of diseases including Alzheimer and Parkinson. In this context, accessing the nanomechanical properties of ubiquitous β-sheet rich nanofibres (e.g.: amyloids) is key to the formulation of materials and design of therapies. Although the bulk mechanical properties of hydrogels can easily be accessed using common techniques and equipment, the mechanical properties of their constituent fibres, in particular if with radii in the nanometre scale, are more challenging to measure and estimate. In this work we show for the first time how the rapid nanomechanical mapping technique: amplitude modulation-frequency modulation (AM-FM), can be used to determine the heights, Young's moduli and viscosity coefficients of a series of β-sheet peptide nanofibres with high statistical confidence. Our results show how peptide sequence and in particular length, charge and interaction with the substrate affect the viscoelastic properties of the peptide fibres.

RevDate: 2021-09-03

Ullah R, Ali G, Subhan F, et al (2021)

Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone.

International immunopharmacology, 100:108083 pii:S1567-5769(21)00719-0 [Epub ahead of print].

Alzheimer's disease (AD) is classified pathologically as a progressive neurological disorder associated with memory decline. The study was designed to assess the underlying molecular signaling involved in the neuroprotective effect of the 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone (2NCP) as a novel therapeutic agent for AD. In this connection, in vitro cholinesterases inhibitory and antioxidant activities were investigated. In vivo studies were carried out on a well-known 5xFAD mice model in different behavioural models such as light/dark box,balance beam, rotarod, elevated plus maze (EPM),novel object recognition (NOR), paddling Y-maze, and Morris water maze (MWM) tests. Hippocampus (HC) and frontal cortex (FC) homogenates were examined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, glutathione S-transferase (GST), glutathione (GSH), and catalase. Further, we examined the expression of inflammatory cytokines and Nrf2 in the HC and FC through RT-PCR. Computational studies were conducted to predict the binding mode of the 2NCP with target sites of nuclear factor-κB (NF-κB) and cholinesterases. The findings of in vitro assays revealed that the IC50 values of the 2NCP against AChE and BChE were 17 and 23 µg/ml respectively. DPPH antioxidant assay displayed an IC50 value for the 2NCP was 62 µg/ml. Whereas, theex vivo study depicted that the activities of AChE and BChEwere significantly reduced. Moreover, free radicals load, GSH level, catalase and GST activities were significantly declined. Furthermore, in vivostudies showed that the 2NCP treated animals exhibited gradual memory improvement and improved motor functions. RT-PCR study revealed that mRNA levels of the inflammatory mediators (IL-1β, IL-6, TNF-α) were significantly reduced, while the expression of antioxidant Nrf2 was significantly increased.The molecular docking studies further confirmed that the 2NCP showed excellent binding affinities for NF-κB and cholinesterases. Taken together, the 2NCP improves spatial memory and learning, short- and long-term memory,markedly inhibits cholinesterases, reduced neuroinflammation, and mitigated oxidative stress in the 5xFAD mice; hence the 2NCP may be a potential candidate for the management of AD.

RevDate: 2021-09-03

Taheri M, Oryan SH, Eslimi Esfahani D, et al (2021)

Artemisia Absinthium improves spatial performance and neuronal injury induced by amyloid- beta in the CA1 hippocampal area of male Wistar rats.

Neurobiology of learning and memory pii:S1074-7427(21)00128-3 [Epub ahead of print].

Alzheimer's disease is a neurodegenerative disorder. It is characterized by the presence of two aberrant structures in the brain, those are, amyloid plaques and neurofibrillary tangles, along with neuronal death. Amyloid-beta further exacerbates the metabolic decline and results in cognitive impairments. Because of the favorable antioxidant and anti-inflammatory activities of Artemisia absinthium (wormwood), this study aimed to evaluate the effects of hydroalcoholic extract of this plant on spatial memory performance, neuronal injury, and apoptosis induced by amyloid-beta. Forty-eight male Wistar rats (220-250 g) were divided into the following groups: 1) control; 2) sham (solvent; ICV); 3) amyloid-beta 1-40 (ICV); and 4) amyloid-beta plus A. absinthium (10, 50, and 100 mg/kg/day; gavage). Congo red and TUNEL staining were performed to investigate the neuronal injury. Also, the Morris water maze (MWM) test was used to evaluate the spatial memory of the experimental groups. The results showed that spatial memory for finding the hidden platform in the MWM task decreased significantly in the amyloid-beta group, compared to the control and sham groups. In contrast, treatment with A. absinthium improved spatial memory dose-dependently and reduced tissue degeneration, amyloid plaques, and apoptosis. It seems that the hydroalcoholic extract of A. absinthium, due to its antioxidant and anti-inflammatory activities, can effectively reverse spatial memory deficits and reduce amyloid-beta plaques.

RevDate: 2021-08-30

Ibanez L, Cruchaga C, MV Fernández (2021)

Advances in Genetic and Molecular Understanding of Alzheimer's Disease.

Genes, 12(8):.

Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.

RevDate: 2021-09-02

Basilico S, Ciricugno A, Gelosa G, et al (2021)

Clinical Characterization of Atypical Primary Progressive Aphasia in a 3-Year Longitudinal Study: A Case Report.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 34(3):233-244.

The logopenic variant of primary progressive aphasia (lvPPA) is the most recent variant of primary progressive aphasia (PPA) to be identified; thus far, it has been poorly investigated. Despite being typically associated with Alzheimer disease (AD), lvPPA has recently been linked to frontotemporal lobe degeneration (FTLD), with distinctive cognitive and neural features that are worthy of further investigation. Here, we describe the neuropsychological and linguistic profile, as well as cerebral abnormalities, of an individual exhibiting PPA and carrying a pathogenetic variant in the GRN gene, from a 3-year longitudinal perspective. The individual's initial profile resembled lvPPA because it was characterized by word-finding difficulties and phonological errors in spontaneous speech in addition to sentence repetition and phonological short-term memory impairments. The individual's structural and metabolic imaging data demonstrated left temporal and bilateral frontal atrophy and hypometabolism, respectively. On follow-up, as the pathology progressed, dysprosody, stereotypical speech patterns, agrammatism, and orofacial apraxia appeared, suggesting an overlap with the nonfluent variant of PPA (nfvPPA). Severe sentence comprehension impairment also became evident. Our longitudinal and multidisciplinary diagnostic approach allowed us to better characterize the progression of a GRN-positive lvPPA profile, providing neuropsychological and imaging indicators that might be helpful to improve classification between different PPA variants and to address a nosological issue. Finally, we discuss the importance of early diagnosis of PPA given the possible overlap between different PPA variants during the progression of the pathology.

RevDate: 2021-09-02

Smith M, Van N, Roberts A, et al (2021)

Disparities in Alzheimer Disease and Mild Cognitive Impairment Among Native Hawaiians and Pacific Islanders.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 34(3):200-206.

BACKGROUND: Previous studies of racial differences in Alzheimer disease (AD) presentation have not included Native Hawaiians and Pacific Islanders (NHPI).

OBJECTIVE: To explore the presentation of AD and mild cognitive impairment (MCI) in NHPI.

METHOD: We conducted a retrospective review of patient records from Hawaii with a diagnosis of unspecified AD or MCI from September 2000 to September 2019. Variables of interest included age at diagnosis, gender, race, marital status, insurance, comorbidities, and scores on the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA).

RESULTS: We reviewed the medical records of 598 patients, including 224 Asians, 202 Whites, 87 NHPI, and 85 Other. AD was more dominant than MCI across all of the groups, with the highest percentage in NHPI. Among the mean ages of diagnosis, NHPI were the youngest. Across all groups, a higher proportion of women than men had AD, with the highest female prevalence among NHPI. Hypertension, hyperlipidemia, and type II diabetes were highest among NHPI compared with the other groups. Of individuals with MMSE/MoCA scores, there were significant variations in scores by racial group. The mean MMSE/MoCA score was highest among Whites and lowest among NHPI.

CONCLUSION: Compared with other racial groups, NHPI have a higher proportion of AD than MCI at diagnosis, are diagnosed at a younger age, have a higher female prevalence, have more comorbidities that may contribute to AD/MCI onset, and present with lower MMSE scores.

RevDate: 2021-09-02

Hammers DB, Gradwohl BD, Kucera A, et al (2021)

Preliminary Validation of the Learning Ratio for the HVLT-R and BVMT-R in Older Adults.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 34(3):170-181.

BACKGROUND: The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned.

OBJECTIVE: To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology.

METHOD: Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment.

RESULTS: Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported.

CONCLUSION: The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1.

RevDate: 2021-09-02

Vöglein J, Kostova I, Arzberger T, et al (2021)

Seizure prevalence in neurodegenerative diseases - a study of autopsy proven cases.

European journal of neurology [Epub ahead of print].

BACKGROUND: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND.

METHODS: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared among ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined.

RESULTS: 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n=144; LBD, n=103; PSP, n=93; FTLD, n=53; MSA, n=36; CBD, n=25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p=0.017).

CONCLUSIONS: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.

RevDate: 2021-09-02

Montiel-Flores E, Mejía-García OA, Ordoñez-Librado JL, et al (2021)

Alzheimer-like cell death after vanadium pentoxide inhalation.

Heliyon, 7(8):e07856 pii:S2405-8440(21)01959-9.

Vanadium (V) toxicity depends on its oxidation state; it seems that vanadium pentoxide (V2O5) is the most toxic to the living cells. It has been reported that oral administration induces changes in motor activity and learning; in rats, I.P. administration increases lipid peroxidation levels in the cerebellum and the concentration of free radicals in the hippocampus and cerebellum. Mice that inhaled V2O5 presented a reduced number of tubulin+ in Leydig and Sertoli cells; it has also been reported that inhaled V2O5 induces loss of dendritic spines, necrosis, and hippocampus neuropil alterations; considering the direct consequence of the interaction of V with cytoskeletal components, makes us believe that V2O5 exposure could cause neuronal death in the hippocampus similar to that seen in Alzheimer disease. This work aimed to determine pyramidal hippocampal CA1 cytoskeletal alterations with Bielschowsky stain in rats exposed to V2O5. Male Wistar rats inhaled 0.02 M of V2O5 one h two times a week for two and six months. We found that rats, which inhaled V2O5 reached 56,57% of dead neurons after six months of inhalation; we recognize strong argyrophilic and collapsed somas and typical flame-shaped in all V-exposed rats hippocampus CA1 compared to controls. We also observe somatodendritic distortions. Axons and dendrites displayed thick dark bands replaced by noticeable thickening and nodosities and the cytoskeleton fibrillary proteins' linear traces. Our findings suggest that V2O5 inhalation induces Alzheimer-like cell death with evident cytoskeletal alterations.

RevDate: 2021-09-01

Sanabria-Diaz G, Demonet JF, Rodriguez-Herreros B, et al (2021)

Apolipoprotein E allele 4 effects on Single-Subject Gray Matter Networks in Mild Cognitive Impairment.

NeuroImage. Clinical, 32:102799 pii:S2213-1582(21)00243-6 [Epub ahead of print].

There is evidence that gray matter networks are disrupted in Mild Cognitive Impairment (MCI) and associated with cognitive impairment and faster disease progression. However, it remains unknown how these alterations are related to the presence of Apolipoprotein E isoform E4 (ApoE4), the most prominent genetic risk factor for late-onset Alzheimer's disease (AD). To investigate this topic at the individual level, we explore the impact of ApoE4 and the disease progression on the Single-Subject Gray Matter Networks (SSGMNets) using the graph theory approach. Our data sample comprised 200 MCI patients selected from the ADNI database, classified as non-Converters and Converters (will progress into AD). Each group included 50 ApoE4-positive ('Carriers', ApoE4 +) and 50 ApoE4-negative ('non-Carriers', ApoE4-). The SSGMNets were estimated from structural MRIs at two-time points: baseline and conversion. We investigated whether altered network topological measures at baseline and their rate of change (RoC) between baseline and conversion time points were associated with ApoE4 and disease progression. We also explored the correlation of SSGMNets attributes with general cognition score (MMSE), memory (ADNI-MEM), and CSF-derived biomarkers of AD (Aβ42, T-tau, and P-tau). Our results showed that ApoE4 and the disease progression modulated the global topological network properties independently but not in their RoC. MCI converters showed a lower clustering index in several regions associated with neurodegeneration in AD. The SSGMNets' topological organization was revealed to be able to predict cognitive and memory measures. The findings presented here suggest that SSGMNets could indeed be used to identify MCI ApoE4 Carriers with a high risk for AD progression.

RevDate: 2021-09-01

Zarifkar AH, Zarifkar A, Nami M, et al (2019)

Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease.

Galen medical journal, 8:e1440.

Background: Treatment of Alzheimer as a disease that is associated with cognitive impairment has been associated with some restrictions. Recently, researchers have focused on non-pharmacological treatments, including non-invasive stimulation of the brain by transcranial electrical stimulation (tES). Four main paradigms of transcranial electrical current include transcranial direct current stimulation (tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial pulse current stimulation (tPCS). The tDCS is a possible new therapeutic option for patients with cognitive impairment, including Alzheimer disease.

Materials and Methods: The study was done on Sprague-Dawley male rats weighing 250-270 g. to develop Alzheimer's model, the cannula was implanted bilaterally into the hippocampus. Aβ 25-35 (5μg/ 2.5µl/day) was microinjected bilaterally for 4 days. Then, an electrical stimulation paradigm was applied to the animal for 6 days. Animal cognitive capacity was evaluated on day 11 and 12 by novel object recognition (NOR) test.

Results: Our results showed that application of tDCS; tACS; tRNS and tPCS reversed beta-amyloid-induced impairment (P<0.05). The tRNS Group spent total exploration time around the objects compared to other groups (P<0.05). There was no significant difference between the four different paradigms in discrimination ratio and the percentage of total exploration time.

Conclusion: The results of this study showed that the use of multiple sessions of different tES paradigms could improve Aβ-induced memory impairment in the NOR test. Therefore, based on evidence, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD.

RevDate: 2021-09-01

Jeong HT, Youn YC, Sung HH, et al (2021)

Power Spectral Changes of Quantitative EEG in the Subjective Cognitive Decline: Comparison of Community Normal Control Groups.

Neuropsychiatric disease and treatment, 17:2783-2790 pii:320130.

Purpose: The purpose of this study is to compare and analyze the power spectral changes between subjective cognitive decline (SCD) subjects and normal controls (NC) while checking the preclinical stage of AD in the SCD subjects and to use the derived data for biomarker research that can diagnose early-stage AD in the future.

Methods: We recruited 23 SCD patients and 23 normal control subjects and QEEG analysis including power spectral density (PSD) and source-level analysis were performed. An automated preprocessing procedure and statistical analysis were performed by iSync Brain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/) using the international standard 10-20 system (19 electrodes).

Results: Absolute PSD, there was no statistically significant difference in all of the EEG power measurements of the 19 channels. In the relative PSD analysis, the average delta band power of the SCD group was significantly higher in Fp2, F4, and F8 than NC. Alpha1 band power of the O1 channel was 22.56±16.05 for the SCD group and 33.19±19.05 for the NC (p-value <0.05). Source-level analysis did not show a statistically significant difference.

Conclusion: SCD subjects showed a partial increase of delta waves in the frontal lobe region and a partial decrease in alpha1, a fast wave in the occipital region, compared to the NC. SCD is considered one of the earliest clinical symptoms of AD and it is predicted to be related to minor nerve damage. We were able to observe the power spectral changes in SCD subjects in this cross-sectional study, a large number of subjects and longitudinal studies are needed to evaluate their predictability for future deterioration such as conversion to MCI.

RevDate: 2021-08-31

Saranya V, Shankar R, Gatasheh MK, et al (2021)

Impact of Au144 metal clusters on the structural and inhibitory mechanism of Aβ42 peptide: A theoretical approach.

Environmental research pii:S0013-9351(21)01215-9 [Epub ahead of print].

One of the main causes for Alzheimer disease is the abnormal self-assembly of the amyloid-beta (Aβ) peptide, which in turn forms a toxic β-rich aggregation. A recent study suggests that gold nanoparticles (AuNPs) can inhibit the Aβ aggregation. Nevertheless, the effects of AuNPs on Aβ peptide system are still ambiguous and needs exploration that is more detailed. Molecular dynamics simulations have been carried out to investigate the aggregation mechanism of Aβ42 peptide for 500 ns? During simulation, C-terminus regions of Met 35-Ala42 residues exhibits β-sheet conformations. Meanwhile, the Au144MC coordination induces substantial α-helical character, both α-helix and 310-helix structure at 0-500ns, in the region of Asp1-Arg 5 and Val36-Ile41 residues. The Au144MC strongly coordinates with Asp1, Ala2, Glu3, Phe4, Asp7, Tyr10 and Gln15 residues that plays the significant effects to loss the β-sheet geometry in the N-terminal region and it converted into random α-helix, turn and bend conformation. On comparing the RMSF of the Aβ42 peptide and Aβ42-Au144MC complex shows that the coordination of Au144MC results in greater rigidity of the Aβ42 peptide backbone regions with exemptions for the Asp1, Ala2, Glu3, Leu34, Ile41 and Ala42 residues due to the strong binding between the metal cluster and the CHC (Leu17-Ala21) region. The structural stability of the Aβ42 peptide and Aβ42-Au144MC complex is enhanced by the several intermolecular and intramolecular interactions and it was visibly revealed in the H-bond. From the above results, it is very evident that the Au144MC can be used as inhibitor agent for the oligomerization of Aβ42.

RevDate: 2021-08-31

Witkowska-Plusa U (2021)

[Status of everyday activities and cognitive activity in elderly patients with symptoms of Alzheimer's dementia during COVID-19].

Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego, 49(292):266-268.

The consequences of forced isolation due to the risk of SARS-CoV-2 infection in patients with symptoms of dementia in the elderly are only now being analyzed.

AIM: The aim of the study was to conduct a preliminary analysis of the effects of a break in implementing rehabilitation programs in patients with Alzheimer's disease with symptoms of dementia.

MATERIALS AND METHODS: The analysis included data obtained from qualification tests of 19 patients (14 women, 5 men) aged 76 to 91 years (mean 81.2 +/- 9.9 years) qualified in 2021 to return to groups at the Alzheimer Center in Warsaw. The obtained results of the performed Katz, Lawton tests and the Mini-Mental State Examination (MMSE) were compared with the results from 2020.

RESULTS: The initial assessment showed a deterioration of the general and mental condition of patients qualified for the planned activities. The Katz test for the assessment of basic activities of everyday life did not reveal any significant changes in relation to the results obtained one year ago, while the Lawton test for the assessment of complex activities of daily life showed that 13 (68%) of the subjects significantly deteriorated compared to the previous year's study. On the other hand, in the MMSE, deterioration was noted in 12 (63%) analyzed compared to their state from a year ago.

CONCLUSIONS: During the year of forced isolation due to the risk of SARS-CoV-2 infection, there was a significant deterioration in the daily activities and cognitive functions of patients with symptoms of dementia in the elderly.

RevDate: 2021-08-31

Zhou Y, Li J, Nordberg A, et al (2021)

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils.

ACS chemical neuroscience [Epub ahead of print].

Alzheimer's disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer's disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.

RevDate: 2021-08-31

Kapila YL (2021)

Oral health's inextricable connection to systemic health: Special populations bring to bear multimodal relationships and factors connecting periodontal disease to systemic diseases and conditions.

Periodontology 2000, 87(1):11-16.

The landscape in dentistry is changing as emerging studies continue to reveal that periodontal health impacts systemic health, and vice versa. Population studies, clinical studies, and in vitro animal studies underscore the critical importance of oral health to systemic health. These inextricable relationships come to the forefront as oral diseases, such as periodontal disease, take root. Special populations bring to bear the multimodal relationships between oral and systemic health. Specifically, periodontal disease has been associated with diabetes, metabolic syndrome, obesity, eating disorders, liver disease, cardiovascular disease, Alzheimer disease, rheumatoid arthritis, adverse pregnancy outcomes, and cancer. Although bidirectional relationships are recognized, the potential for multiple comorbidities, relationships, and connections (multimodal relationships) also exists. Proposed mechanisms that mediate this connection between oral and systemic health include predisposing and precipitating factors, such as genetic factors (gene polymorphisms), environmental factors (stress, habits-such as smoking and high-fat diets/consumption of highly processed foods), medications, microbial dysbiosis and bacteremias/viremias/microbemias, and an altered host immune response. Thus, in a susceptible host, these predisposing and precipitating factors trigger the onset of periodontal disease and systemic disease/conditions. Further, high-throughput sequencing technologies are shedding light on the dark matter that comprises the oral microbiome. This has resulted in better characterization of the oral microbial dysbiosis, including putative bacterial periodontopathogens and shifts in oral virome composition during disease. Multiple laboratory and clinical studies have illustrated that both eukaryotic and prokaryotic viruses within subgingival plaque and periodontal tissues affect periodontal inflammation, putative periodontopathogens, and the host immune response. Although the association between herpesviruses and periodontitis and the degree to which these viruses directly aggravate periodontal tissue damage remain unclear, the benefits to periodontal health found from prolonged administration of antivirals in immunocompromised or immunodeficient individuals demonstrates that specific populations are possibly more susceptible to viral periodontopathogens. Thus, it may be important to further examine the implications of viral pathogen involvement in periodontitis and perhaps it is time to embrace the viral dark matter within the periodontal environment to fully comprehend the pathogenesis and systemic implications of periodontitis. Emerging data from the coronavirus disease 2019 pandemic further underscores the inextricable connection between oral and systemic health, with high levels of the severe acute respiratory syndrome coronavirus 2 angiotensin-converting enzyme 2 receptor noted on oral tissues (tongue) and an allostatic load or overload paradigm of chronic stress likely contributing to rapid breakdown of oral/dental, periodontal, and peri-implant tissues. These associations exist within a framework of viremias/bacteremias/microbemias, systemic inflammation, and/or disturbances of the immune system in a susceptible host. A thorough review of systemic and oral diseases and conditions and their mechanistic, predisposing, and precipitating factors are paramount to better addressing the oral and systemic health and needs of our patients.

RevDate: 2021-08-31

Ryder MI, P Xenoudi (2021)

Alzheimer disease and the periodontal patient: New insights, connections, and therapies.

Periodontology 2000, 87(1):32-42.

Loss of cognitive function in the aging population, particular those with Alzheimer disease, presents unique challenges to health practitioners. For the dental practitioner these include management of periodontal diseases, caries, and other dental conditions in this special population. It is well established in the cognitively impaired patient that a lack of adherence to dental hygiene routines and professional care leads to increases in the prevalence and severity of these dental conditions, leading to increased loss of teeth. More recent evidence has indicated a possible role of the microbiota of dental plaque associated with periodontal diseases in the development and progression of Alzheimer disease, thereby supporting a two-way interaction of these two diseases. New therapies are needed to address the potential upstream events that may precede overt signs of Alzheimer disease. One of these approaches would be to target these various bacterial, viral, and other microbial pathogens associated with periodontal disease that can translocate into the bloodstream and then to distal sites, such as the brain. Such microbial translocation would lead to local inflammation and buildup of the hallmark signs of Alzheimer disease, including amyloid beta deposits, tau fragmentation and tangles, breakdown of host protective molecules, such as the apolipoproteins, and neuron toxicity. In this review, evidence for the biological basis of the role of the periodontal disease microflora on the initiation and progression of Alzheimer disease will be presented with a focus on the potential role of the keystone pathogen Porphyromonas gingivalis with its family of gingipain enzymes. The various mechanisms for which P. gingivalis gingipains may contribute to the initiation and progression of Alzheimer disease are presented. Small-molecule inhibitors of these gingipains and their effects on reducing biological markers of Alzheimer disease may have beneficial effects for the initiation and progression of loss of cognitive function in Alzheimer disease. In addition to these targeted therapies for specific periodontal pathogens, considerations for the dental practitioner in applying more general approaches to reducing the periodontal plaque microflora in the management of the cognitively impaired patient are discussed for this special population.

RevDate: 2021-08-31

Fox-Fuller JT, Artola A, Chen K, et al (2021)

Sex Differences in Cognitive Abilities Among Children With the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort.

JAMA network open, 4(8):e2121697 pii:2783629.

Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid β overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant.

Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex.

This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020.

Main Outcomes and Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates.

Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P < .001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P = .03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P = .009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P = .001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P = .04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P = .009) without the variant.

Conclusions and Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.

RevDate: 2021-08-30

Gambi E, Ricciuti M, A De Santis (2020)

Food Intake Actions Detection: An Improved Algorithm Toward Real-Time Analysis.

Journal of imaging, 6(3): pii:jimaging6030012.

With the increase in life expectancy, one of the most important topic for scientific research, especially for the elderly, is good nutrition. In particular, with an advanced age and health issues because disorders such as Alzheimer and dementia, monitoring the subjects' dietary habits to avoid excessive or poor nutrition is a critical role. Starting from an application aiming to monitor the food intake actions of people during a meal, already shown in a previously published paper, the present work describes some improvements that are able to make the application work in real time. The considered solution exploits the Kinect v1 device that can be installed on the ceiling, in a top-down view in an effort to preserve privacy of the subjects. The food intake actions are estimated from the analysis of depth frames. The innovations introduced in this document are related to the automatic identification of the initial and final frame for the detection of food intake actions, and to the strong revision of the procedure to identify food intake actions with respect to the original work, in order to optimize the performance of the algorithm. Evaluation of the computational effort and system performance compared to the previous version of the application has demonstrated a possible real-time applicability of the solution presented in this document.

RevDate: 2021-08-30

Winer JR, Deters KD, Kennedy G, et al (2021)

Association of Short and Long Sleep Duration With Amyloid-β Burden and Cognition in Aging.

JAMA neurology pii:2783664 [Epub ahead of print].

Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid β [Aβ]), depression, and cardiovascular disease.

Objective: To investigate the associations between self-reported sleep duration and brain Aβ burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition.

This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Aβ positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021.

Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Aβ burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables.

Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Aβ burden (β [SE] = -0.01 [0.00]; P = .005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Aβ was found between long and normal sleep duration groups (β [SE] = 0.00 [0.01]; P = .99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: β [SE] = 0.48 [0.17], P = .01; long vs normal sleep duration: β [SE] = 0.97 [0.31], P = .002), depressive symptoms (short vs normal sleep duration: β [SE] = 0.31 [0.05], P < .001; long vs normal sleep duration: β [SE] = 0.39 [0.09], P < .001), and daytime napping (short vs normal sleep duration: β [SE] = 2.66 [0.77], P = .001; long vs normal sleep duration: β [SE] = 3.62 [1.38], P = .01). Long sleep duration was associated with worse performance across multiple cognitive domains.

Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Aβ burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.

RevDate: 2021-08-30

Al-Hamed FS, Kouniaris S, Tamimi I, et al (2021)

Acetylcholinesterase inhibitors and risk of bleeding and acute ischemic events in non-hypertensive Alzheimer's patients.

Alzheimer's & dementia (New York, N. Y.), 7(1):e12184 pii:TRC212184.

Introduction: Acetylcholinesterase inhibitors (AChEIs) are commonly used to treat mild to moderate cases of Alzheimer disease (AD). To the best of our knowledge, there has been no study estimating the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Therefore, this study aimed to estimate the association between AChEIs and the risk of bleeding and cardiovascular ischemic events in patients with non-hypertensive AD.

Methods: A nested case-control study was conducted to estimate the risk of bleeding and ischemic events (angina, myocardial infarction [MI], and stroke) in patients with AD. This study was conducted using the UK Clinical Practice Research Datalink and Hospital Episode Statistics (HES) databases. The study cohort consisted of AD patients ≥65 years of age. The case groups included all AD subjects in the database who had a bleeding or ischemic event during the cohort follow-up. Four controls were selected for each case. Patients were classified as current users or past users based on a 60-day threshold of consuming the drug. Simple and multivariable conditional logistic regression analyses were used to calculate the adjusted odds ratio for bleeding events and cardiovascular events.

Results: We identified 507 cases and selected 2028 controls for the bleeding event cohort and 555 cases and 2220 controls for the ischemic event cohort. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association of AChEI use was 0.93 (0.75 to 1.16) for bleeding events, 2.58 (1.01 to 6.59) for angina, and 1.89 (1.07 to 3.33) for MI. Past users of AChEIs were also at increased risk of stroke (1.51 [1.00 to 2.27]).

Discussion: This is the first study assessing the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Our findings could be of great interest for clinicians and researchers working on AD.

RevDate: 2021-08-30

Dickerson B, A Atri (2020)

Molecular Imaging Biomarkers in Dementia: Amyloid and tau PET imaging aids evaluation of patients suspected of having Alzheimer disease or other dementias.

Practical neurology (Fort Washington, Pa.), 19(9):34-45.

RevDate: 2021-08-28

Jiang L, Lin W, Zhang C, et al (2021)

Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.

Molecular cell pii:S1097-2765(21)00622-5 [Epub ahead of print].

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.

RevDate: 2021-08-28

Thakur A, Moyo P, van der Westhuizen CJ, et al (2021)

A Novel Cardenolide Glycoside Isolated from Xysmalobium undulatum Reduces Levels of the Alzheimer's Disease-Associated β-Amyloid Peptides Aβ42 In Vitro.

Pharmaceuticals (Basel, Switzerland), 14(8): pii:ph14080743.

Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer's disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-d-glucopyranoside (2), and crotoxigenin 3-O-glucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD's β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.

RevDate: 2021-08-27

Liang Z, Wu L, Gong S, et al (2021)

The cognitive dysfunction related to Alzheimer disease or cerebral small vessel disease: What's the differences.

Medicine, 100(34):e26967.

ABSTRACT: Alzheimer disease (AD) and sporadic cerebral small vessel disease (CSVD) are common cognitive disorders. Both AD and CSVD have mental symptoms including chronic progressive cognitive impairment, dysfunction, and behavioral abnormalities. However, the differences on the cognitive dysfunction of AD and CSVD remain unclear. It is necessary to elucidate the cognitive dysfunction differences of AD and CSVD, and to identify the potential risk factors.AD or sporadic CSVD patients treated in our hospital from December 1, 2018 to May 31, 2019 were included. And we selected healthy participants as controls. The mini-mental state examination and Montreal Cognitive Assessment Scale were used for neuropsychological assessment, and related medical information were collected and compared.A total of 190 patients were included. The total mini-mental state examination scores in AD, CSVD group were significantly less than that of control group, there were significant differences in the domains of directional ability, attention and computing ability, delayed recall, and visual perception (all P < .05); the total Montreal Cognitive Assessment Scale scores in AD, CSVD group were significantly less than that of control group. There were significant differences in the domains of visual space and execution, immediate remember, attention and computing ability, language, delayed recall, and directional ability (all P < .05); diabetes was a risk factor both for AD (hazard ratio = 1.63, 95% confidence interval: 1.35-1.97) and CSVD (hazard ratio = 1.15, 95% confidence interval: 1.08-1.27).The cognitive dysfunctions of AD are difference to that of CSVD patients, and diabetes is the risk factor both for AD and CSVD, future studies are needed to further identify the prevention and treatment of AD and CSVD.

RevDate: 2021-08-27

Kim JW, Kim DK, Lee HS, et al (2021)

Androgen Deprivation Therapy in Patients with Prostate Cancer is Associated with the Risk of Subsequent Alzheimer's Disease but not with Vascular Dementia.

The world journal of men's health pii:39.e39 [Epub ahead of print].

PURPOSE: We aimed to investigate the association between androgen deprivation therapy (ADT) and the risk of dementia according to subtypes of dementia in men with prostate cancer.

MATERIALS AND METHODS: We performed a nationwide population-based cohort study using the nationwide claims database in Korea. A total of 195,308 men with newly diagnosed prostate cancer were identified between January 2008 and December 2017, and 132,700 men were selected for analysis after applying inclusion and exclusion criteria. The patients were divided into ADT and non-ADT groups. To adjust for imbalances in relevant comorbidities between the groups, exact matching was performed. Study events included newly developed Alzheimer's disease, vascular dementia, and overall dementia. Cox proportional hazard regression models were used.

RESULTS: After exact matching, 44,854 men with prostate cancer were selected for the main analysis. In age-adjusted Cox regression analysis, the ADT group was significantly associated with increased risks for overall dementia (hazard ratio [HR], 1.070; 95% confidence interval [CI], 1.009-1.134; p=0.0232) and Alzheimer's disease (HR, 1.086; 95% CI, 1.018-1.160; p=0.0127), compared to the non-ADT group. No difference in vascular dementia risk was observed between the two groups (HR, 0.990; 95% CI, 0.870-1.126; p=0.8792).

CONCLUSIONS: The risk of overall dementia increased in men who received ADT. According to dementia subtypes, ADT was associated with an increased risk of Alzheimer's disease, but not with vascular dementia.

RevDate: 2021-08-27

Soureshjani FH, Kheirollahi M, Yaghmaei P, et al (2021)

Possible Preventive Effect of Donepezil and Hyoscyamoside by Reduction of Plaque Formation and Neuroinflammation in Alzheimer's Disease.

International journal of preventive medicine, 12:66 pii:IJPVM-12-66.

Background: Alzheimer disease (AD) is the most common age-dependent dementia. The complex natural accumulation of amyloid beta (Aβ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats.

Methods: Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)-4 and IL-6 were evaluated by ELISA. The RNA expression of cyclin-dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR.

Results: The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0.01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL-6, and the IL-4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups.

Conclusions: In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.

RevDate: 2021-08-27

Wang S, Ma J, Zeng Y, et al (2021)

Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review.

Drug design, development and therapy, 15:3619-3641 pii:310686.

Icariin is a biologically active substance in Epimedii herba that is used for the treatment of neurologic disorders. However, a comprehensive analysis of the molecular mechanisms of icariin is lacking. In this review, we present a brief history of the use of icariin for medicinal purposes; describe the active chemical components of Epimedii herba; and examine the evidence from experimental studies that have uncovered molecular targets of icariin in different diseases. We also constructed a protein-protein interaction network and carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to predict the therapeutic actions of icariin in nervous system diseases including Alzheimer disease, Parkinson disease, ischemic stroke, depressive disorder, multiple sclerosis, glioblastoma, and hereditary spastic paraplegias. The results of our analyses can guide future studies on the application of icariin to the treatment of neurologic disorders.

RevDate: 2021-08-27

Wohlschlegel J, Argentini M, Michiels C, et al (2021)

First identification of ITM2B interactome in the human retina.

Scientific reports, 11(1):17210.

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

RevDate: 2021-08-27

Oleksak P, Novotny M, Patocka J, et al (2021)

Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.

International journal of molecular sciences, 22(16): pii:ijms22168908.

At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

RevDate: 2021-08-27

Sini P, Dang TBC, Fais M, et al (2021)

Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons.

International journal of molecular sciences, 22(16): pii:ijms22168726.

The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are generally thought to progress as a consequence of genetic susceptibility and environmental influences. Up to now, several environmental triggers have been associated with NDs, and recent studies suggest that some cyanotoxins, produced by cyanobacteria and acting through a variety of molecular mechanisms, are highly neurotoxic, although their roles in neuropathy and particularly in NDs are still controversial. In this review, we summarize the most relevant and recent evidence that points at cyanotoxins as environmental triggers in NDs development.

RevDate: 2021-08-27

Manoliu LCE, Martin EC, Milac AL, et al (2021)

Effective Use of Empirical Data for Virtual Screening against APJR GPCR Receptor.

Molecules (Basel, Switzerland), 26(16): pii:molecules26164894.

Alzheimer's disease is a neurodegenerative disorder incompatible with normal daily activity, affecting one in nine people. One of its potential targets is the apelin receptor (APJR), a G-protein coupled receptor, which presents considerably high expression levels in the central nervous system. In silico studies of APJR drug-like molecule binding are in small numbers while high throughput screenings (HTS) are already sufficiently many to devise efficient drug design strategies. This presents itself as an opportunity to optimize different steps in future large scale virtual screening endeavours. Here, we ran a first stage docking simulation against a library of 95 known binders and 3829 generated decoys in an effort to improve the rescoring stage. We then analyzed receptor binding site structure and ligands binding poses to describe their interactions. As a result, we devised a simple and straightforward virtual screening Stage II filtering score based on search space extension followed by a geometric estimation of the ligand-binding site fitness. Having this score, we used an ensemble of receptors generated by Hamiltonian Monte Carlo simulation and reported the results. The improvements shown herein prove that our ensemble docking protocol is suited for APJR and can be easily extrapolated to other GPCRs.

RevDate: 2021-08-27

Wongrattanakamon P, Jiaranaikulwanitch J, Vajragupta O, et al (2021)

Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions.

Molecules (Basel, Switzerland), 26(16): pii:molecules26164863.

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ1-42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ1-42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ1-42 monomer. TGN4 also reduces the conformational transition of the Aβ1-42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ1-42 monomer, which could be valuable for the further development of new anti-Alzheimer agents.

RevDate: 2021-08-27

Morales-de-Jesús V, Gómez-Adorno H, Somodevilla-García M, et al (2021)

Conversational System as Assistant Tool in Reminiscence Therapy for People with Early-Stage of Alzheimer's.

Healthcare (Basel, Switzerland), 9(8): pii:healthcare9081036.

Reminiscence therapy is a non-pharmacological intervention that helps mitigate unstable psychological and emotional states in patients with Alzheimer's disease, where past experiences are evoked through conversations between the patients and their caregivers, stimulating autobiographical episodic memory. It is highly recommended that people with Alzheimer regularly receive this type of therapy. In this paper, we describe the development of a conversational system that can be used as a tool to provide reminiscence therapy to people with Alzheimer's disease. The system has the ability to personalize the therapy according to the patients information related to their preferences, life history and lifestyle. An evaluation conducted with eleven people related to patient care (caregiver = 9, geriatric doctor = 1, care center assistant = 1) shows that the system is capable of carrying out a reminiscence therapy according to the patient information in a successful manner.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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

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Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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