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Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse.Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.Results: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD. [ABSTRACT FROM AUTHOR]

Background: Hearing loss is highly prevalent in older adults, particularly among those living with dementia and residing in long-term care homes (LTCHs). Sensory declines can have deleterious effects on functioning and contribute to frailty, but the hearing needs of residents are often unrecognized or unaddressed.Objective: To identify valid and reliable screening measures that are effective for the identification of hearing loss and are suitable for use by nursing staff providing care to residents with dementia in LTCHs.Methods: Electronic databases (Embase, Medline, PsycINFO, CENTRAL, and CINAHL) were searched using comprehensive search strategies, and a stepwise approach based on Arksey & O'Malley's scoping review and appraisal process was followed.Results: There were 193 scientific papers included in the review. Pure-tone audiometry was the most frequently reported measure to test hearing in older adults living with dementia. However, measures including self- or other-reports and questionnaires, review of medical records, otoscopy, and the whisper test were found to be most suitable for use by nurses working with older adults living with dementia in LTCHs.Conclusion: Although frequently used, the suitability of pure-tone audiometry for use by nursing staff in LTCHs is limited, as standardized audiometry presents challenges for many residents, and specific training is needed to successfully adapt test administration procedures and interpret results. The whisper test was considered to be more suitable for use by staff in LTCH; however, it yields a limited characterization of hearing loss. There remains an urgent need to develop new approaches to screen hearing in LTCHs. [ABSTRACT FROM AUTHOR]

Background: Objectively measuring auditory functions has been proposed as an avenue in differentiating normal age-related cognitive dysfunction from Alzheimer's disease (AD) and its prodromal states. Previous research has suggested auditory event-related potentials (AERPs) to be non-invasive, cost-effective, and efficient biomarkers for the diagnosis of AD.Objective: The objective of this paper is to review the published literature on AERPs measures in older adults diagnosed with AD and those at higher risk of developing AD, i.e., mild cognitive impairment (MCI) and subjective cognitive decline.Methods: The search was performed on six major electronic databases (Ovid MEDLINE, OVID EMBASE, PsycINFO, PubMed, Scopus, and CINAHL Plus). Articles identified prior to 7 May 2019 were considered for this review. A random effects meta-analysis and analysis of between study heterogeneity was conducted using the Comprehensive Meta-Analysis software.Results: The search identified 1,076 articles; 74 articles met the full inclusion criteria and were included in the systematic review, and 47 articles were included into the analyses. Pooled analysis suggests that AD participants can be differentiated from controls due to significant delays in ABR, N100, P200, N200, and P300 latencies. P300 amplitude was significantly smaller in AD participants compared to controls. P300 latencies differed significantly between MCI participants and controls based on the pooled analysis.Conclusion: The findings of this review indicate that some AERPs may be valuable biomarkers of AD. In conjunction with currently available clinical and neuropsychological assessments, AERPs can aid in screening and diagnosis of prodromal AD. [ABSTRACT FROM AUTHOR]

Background: Early identification of Alzheimer's disease (AD) may be extremely beneficial for delaying disease progression. Subjective cognitive decline (SCD) may be an early indicator of AD pathology. Not all individuals with SCD will eventually develop AD, making it critical to identify biomarkers during the SCD stage which indicate likely clinical progression.Objective: The present review aims to summarize available data on structural MRI and cerebrospinal fluid (CSF) biomarkers and their association with clinical progression to mild cognitive impairment (MCI) or AD in people with SCD.Methods: Database searches were conducted using Embase and PubMed until June 2020. Longitudinal studies assessing biomarkers in individuals with SCD and assessing clinical progression to MCI/AD were included. Two assessors performed data extraction and assessed the risk of bias in the included studies. Data were synthesized narratively.Results: An initial search identified 1,065 papers; after screening and review 14 studies were included. Sample size of the included studies ranged from 28-674, mean age was 60.0-68.6 years, and 10.2%-52%of participants converted to MCI/AD. Lower levels of CSF Aβ42 were consistently associated with clinical progression. Combination measures identifying an AD-like profile of Aβ42 and tau levels were strongly associated with clinical progression. Biomarkers identified with structural MRI were less conclusive, as some studies found significant associations while others did not.Conclusion: Biomarkers may be able to predict clinical progression in those with cognitive complaints. Aβ42, or combinations of Aβ42 and tau may be useful biomarkers in identifying individuals with SCD who will progress to MCI/AD. [ABSTRACT FROM AUTHOR]

Background: The largest proportion of people with dementia worldwide live in low- and middle- income countries (LMICs), with dementia prevalence continuing to rise. Assessment and diagnosis of dementia involves identifying the impact of cognitive decline on function, usually measured by instrumental activities of daily living (IADLs).Objective: This review aimed to identify IADL measures which are specifically developed, validated, or adapted for use in LMICs to guide selection of such tools.Methods: A systematic search was conducted (fourteen databases) up to April 2020. Only studies reporting on development, validation, or adaptation of IADL measures for dementia or cognitive impairment among older adults (aged over 50) in LMICs were included. The QUADAS 2 was used to assess quality of diagnostic accuracy studies.Results: 22 papers met inclusion criteria; identifying 19 discrete IADL tools across 11 LMICs. These were either translated from IADL measures used in high-income countries (n = 6), translated and adapted for cultural differences (n = 6), or newly developed for target LMIC populations (n = 7). Seven measures were investigated in multiple studies; overall quality of diagnostic accuracy was moderate to good.Conclusion: Reliability, validity, and accuracy of IADL measures for supporting dementia diagnosis within LMICs was reported. Key components to consider when selecting an IADL tool for such settings were highlighted, including choosing culturally appropriate, time-efficient tools that account for gender- and literacy-bias, and can be conducted by any volunteer with appropriate training. There is a need for greater technical and external validation of IADL tools across different regions, countries, populations, and cultures. [ABSTRACT FROM AUTHOR]

Background: Family caregivers of people living with dementia benefit from supportive service use to address care needs associated with caregiving. Yet, research consistently demonstrates low rates of service use. Existing research has focused on barriers and facilitators to service use, with few studies examining the influence of caregivers' environmental context which often patterns social advantage and health services accessibility.Objective: To describe the perspectives of caregivers residing in socially disadvantaged areas have in regards to utilizing supportive services.Methods: Ten informal caregivers residing in socially disadvantaged areas participated in in-depth interviews that were analyzed using thematic analysis.Results: Across all interviews, caregivers spontaneously described common precedents of service use (crisis or accumulation of unmet needs) and a distinct sequence of stages (seeking, initiating, and utilizing) surrounding service engagement. Major themes characterizing caregivers' experiences throughout service engagement highlight the varied influence of personal, familial, health, and social system-related factors. Findings demonstrate that caregivers may have different service needs as dementia progresses and that gerontological social work practice can facilitate service use.Conclusion: While preliminary, these findings provide important insights into new domains that can be further examined in future research and intervention efforts to improve supportive service use in socially disadvantaged and underserved communities. [ABSTRACT FROM AUTHOR]

Background: Reduction in cerebral blood flow (CBF) plays an essential role in the cognitive impairment and dementia in obesity. However, current conclusions regarding CBF changes in patients with obesity are inconsistent.Objective: A systematic review and meta-analysis was performed to evaluate the relationship between obesity and CBF alterations.Methods: We systematically screened published cross-sectional and longitudinal studies focusing on the differences in CBF between obese and normal-weight individuals. Eighteen studies including 24,866 participants, of which seven articles reported longitudinal results, were evaluated in the present study.Results: The results of the meta-analysis showed that in cross-sectional studies, body mass index (BMI) was negatively associated with CBF (β= -0.31, 95% confidence interval [CI]: -0.44, -0.19). Moreover, this systematic review demonstrated that obese individuals showed global and regional reductions in the CBF and increased CBF in diverse functional areas of the frontal lobe, including the prefrontal cortex, left frontal superior orbital, right frontal mid-orbital cortex, and left premotor superior frontal gyrus.Conclusion: Our findings suggest that BMI, rather than waist circumference and waist-to-hip ratio, is inversely associated with CBF in cross-sectional studies. The CBF of obese individuals showed global and regional reductions, including the frontal lobe, temporal and parietal lobes, cerebellum, hippocampus, and thalamus. [ABSTRACT FROM AUTHOR]

Background: Abnormal blood lipids are associated with cognitive impairment and amyloid-β (Aβ) deposition in the brain. However, the effects of statins on Alzheimer's disease (AD) have not been determined.Objective: Considering that plasma Aβ are related to Aβ deposition in the brain, we investigated the effects of simvastatin on plasma Aβ transport.Methods: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma Aβ, sLRP1, sRAGE, and lipid levels were measured at baseline and at the 6-week and 12-week visits.Results: The ITT database ultimately included 108 participants (placebo group: n = 53; simvastatin group: n = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2±6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, ΔAβ42 levels (the change of Aβ42 levels from baseline at week 12) increased more and ΔsRAGE levels decreased more in the simvastatin group (Aβ42: β= 5.823, p = 0.040; sRAGE: β= -72.012, p = 0.031), and a significant negative association was found between ΔAβ42 and ΔsRAGE levels (β= -0.115, p = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with Aβ40 (β= -16.79, p = 0.023), Aβ42 (β= -6.10, p = 0.001), and sRAGE (β= -51.16, p = 0.003).Conclusion: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma Aβ42 levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma Aβ transport. [ABSTRACT FROM AUTHOR]

Background: Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of α-synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker.Objective: The aim of this study was to assess the diagnostic power of CSF α-synuclein in discriminating CJD from non-prion disorders.Methods: The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR α-synuclein). The difference in CSF α-synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I2 > 50%) or fixed-effects models (I2 < 50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger's test.Results: Ten studies were included in this study. The concentrations of CSF α-synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95% CI 1.60 to 2.36, p < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68, p < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44, p < 0.00001), or Alzheimer's (SMD = 1.14, 95% CI 0.95 to 1.33, p < 0.00001). CSF α-synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80-95%), specificity of 92% (95% CI 86-95%), and AUC of 0.96 (95% CI: 0.94-0.97).Conclusion: CSF α-synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility. [ABSTRACT FROM AUTHOR]

Background: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline.Objective: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes).Methods: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n = 73), or a control condition (n = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A.Results: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26-1.19), p = 0.001].Conclusion: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass. [ABSTRACT FROM AUTHOR]

Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent.Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC).Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models.Results: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy.Conclusion: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD. [ABSTRACT FROM AUTHOR]

Background: There is currently a lack of a comprehensive review identifying the broad scope of factors that impact quality of life (QoL) of informal carers of people with dementia in order to validate existing measures and inform the provision of support services for carers of people with dementia that impact QoL domains important to them.Objective: To explore and identify QoL impacts on informal carers from providing care to people with dementia.Methods: A systematic review was conducted across four databases: EMBASE, CINAHL, PsychINFO, and Medline. Eligible studies consisted of published, peer-reviewed, qualitative studies focusing on lived experiences of informal carers of people with dementia. Non-English studies and quantitative studies were excluded. Screening of included studies was conducted independently by three reviewers. A "best-fit" framework synthesis was used to combine the qualitative data, applying deductive and inductive analysis techniques. Quality assessment was conducted using the Critical Appraisal Skills Programme.Results: Of the 4,251 articles identified, 59 articles were included. Five main themes pertaining to QoL aspects were identified that included coping (emotion-coping and problem-coping), relationship with the person with dementia (sense of loss and change in relationship), support (formal support and informal support), interference with life (control over caring situation, and freedom and independence), and health (physical health, emotional and mental health, and social health).Conclusion: This study identified domains of QoL that are impacted by providing informal care to people living with dementia, offering a conceptual framework for instrument validation and development as well as guidance for service provision. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway.Objective: To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients.Methods: We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible articles which involved 738 patients and 665 healthy controls.Results: Our results revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = -0.520, 95% CI: -0.738; -0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood.Conclusion: AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD. [ABSTRACT FROM AUTHOR]

Background: Studies related to clinical quality indicators (CQIs) in dementia have focused on hospitalizations, medication management, and safety. Less attention has been paid to indicators related to primary and secondary care.Objective: To evaluate the incidence of primary and secondary care CQIs for Australians with dementia using government-subsidized aged care. The examined CQIs were: comprehensive medication reviews, 75+ health assessments, comprehensive geriatric assessments, chronic disease management plans, general practitioner (GP) mental health treatment plans, and psychiatrist attendances.Methods: Retrospective cohort study (2011-2016) of 255,458 individuals. National trend analyses estimated incidence rates and 95% confidence intervals (CI) using Poisson or negative binomial regression. Associations were assessed using backward stepwise multivariate Poisson or negative binomial regression model, as appropriate. Funnel plots examined geographic and permanent residential aged care (PRAC) facility variation.Results: CQI incidence increased in all CQIs but medication reviews. For the overall cohort, 75+ health assessments increased from 1.07/1000 person-days to 1.16/1000 person-days (adjusted incidence rate ratio (aIRR) = 1.03, 95% CI 1.02-1.03).Comprehensive geriatric assessments increased from 0.24 to 0.37/1000 person-days (aIRR = 1.12, 95% CI 1.10-1.14). GP mental health treatment plans increased from 0.04 to 0.07/1000 person-days (aIRR = 1.13, 95% CI 1.12-1.15). Psychiatric attendances increased from 0.09 to 0.11/1000 person-days (aIRR = 1.05, 95% CI 1.03-1.07). Being female, older, having fewer comorbidities, and living outside a major city were associated with lower likelihood of using the services. Large geographical and PRAC facility variation was observed (0-92%).Conclusion: Better use of primary and secondary care services to address needs of individuals with dementia is urgently needed. [ABSTRACT FROM AUTHOR]

Background: The prevalence of mild cognitive impairment (MCI) continues to increase due to population aging. Exercise has been a supporting health strategy that may elicit beneficial effects on cognitive function and prevent dementia.Objective: This study aimed to examine the effects of aerobic, resistance, and multimodal exercise training on cognition in adults aged > 60 years with MCI.Methods: We searched the Cochrane Library, PubMed, and Embase databases and ClinicalTrials.gov (https://clinicaltrials.gov) up to November 2021, with no language restrictions. We included all published randomized controlled trials (RCTs) comparing the effect of exercise programs on cognitive function with any other active intervention or no intervention in participants with MCI aged > 60 years.Results: Twelve RCTs were included in this review. Meta-analysis results revealed significant improvements in resistance training on measures of executive function (p < 0.05) and attention (p < 0.05); no significant differences were observed between aerobic exercise and controls on any of the cognitive comparisons.Conclusion: Exercise training had a small beneficial effect on executive function and attention in older adults with MCI. Larger studies are required to examine the effects of exercise and the possible moderators. [ABSTRACT FROM AUTHOR]

Background: As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer's disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results.Objective: This study aimed to evaluate the association between metformin and the risk of developing AD.Methods: We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models.Results: After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88-1.56, p = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24-2.37, p = 0.001).Conclusion: The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan.Objective: To establish a large cohort for use in clinical trials and research in Japan.Methods: This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment [MCI], and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression.Results: There were 1450 registered patients (649 men, 801 women; mean age, 77.92±6.70 years; mean Mini-Mental State Examination [MMSE] score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio [OR] = 11.085, 95% confidence interval [CI]:1.619-75.913, p = 0.014), low MMSE score (OR = 0.835, 95% CI: 0.761-0.917, p < 0.001), high Geriatric Depression Scale score (OR = 1.093, 95% CI: 1.005-1.189, p = 0.038), and low body mass index (OR = 0.895, 95% CI: 0.829-0.967, p = 0.005) at enrollment were significant factors for conversion.Conclusion: The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently. [ABSTRACT FROM AUTHOR]

Background: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking.Objective: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimer's disease (AD).Methods: Memory clinic patients without dementia (N = 558; mean age = 66; up to 3 years of follow-up; n = 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were retrospectively applied: 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF Aβ42/tau-ratio indicative of AD.Results: The four definitions overlapped considerably, classified 35-58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39-46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy.Conclusion: he operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Memory tests using controlled encoding and cued recall paradigm (CECR) have been shown to identify prodromal Alzheimer's disease (AD), but information about the effectiveness of CECR compared to other memory tests in predicting clinical progression is missing.Objective: The aim was to examine the predictive ability of a memory test based on the CECR paradigm in comparison to other memory/non-memory tests for conversion to dementia in patients with amnestic mild cognitive impairment (aMCI).Methods: 270 aMCI patients from the clinical-based Czech Brain Aging Study underwent a comprehensive neuropsychological assessment including the Enhanced Cued Recall test (ECR), a memory test with CECR, two verbal memory tests without controlled encoding: the Auditory Verbal Learning Test (AVLT) and Logical memory test (LM), a visuospatial memory test: the Rey-Osterrieth Complex Figure test, and cognitive testing based on the Uniform Data Set battery. The patients were followed prospectively. Conversion to dementia as a function of cognitive performance was examined using Cox proportional hazard models.Results: 144 (53%) patients converted to dementia. Most converters (89%) developed dementia due to AD or mixed (AD and vascular) dementia. Comparing the four memory tests, the delayed recall scores on AVLT and LM best predicted conversion to dementia. Adjusted hazard ratios (HR) of immediate recall scores on ECR, AVLT, and LM were similar to the HR of categorical verbal fluency.Conclusion: Using the CECR memory paradigm in assessment of aMCI patients has no superiority over verbal and non-verbal memory tests without cued recall in predicting conversion to dementia. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS) due to underlying neurodegenerative pathology. Some studies using electroencephalography (EEG) have shown increased epileptiform and epileptic activity in AD.Objective: This review and meta-analyses aims to synthesize the existing evidence for quantitative abnormalities of cortical excitability in AD and their relationship with clinical symptoms.Methods: We systematically searched and reviewed publications that quantitatively assessed cortical excitability, using transcranial magnetic stimulation (TMS) resting motor threshold (rMT), active motor threshold (aMT), motor evoked potential (MEP) or directly from the cortex using TMS-EEG via TMS-evoked potential (TEP). We meta-analyzed studies that assessed rMT and aMT using random effects model.Results: We identified 895 publications out of which 37 were included in the qualitative review and 30 studies using rMT or aMT were included in the meta-analyses. The AD group had reduced rMT (Hedges' g = -0.99, 95% CI [-1.29, -0.68], p < 0.00001) and aMT (Hedges' g = -0.87, 95% CI [-1.50, -0.24], p < 0.00001) as compared with control groups, indicative of higher cortical excitability. Qualitative review found some evidence of increased MEP amplitude, whereas findings related to TEP were inconsistent. There was some evidence supporting an inverse association between cortical excitability and global cognition. No publications reported on the relationship between cortical excitability and NPS.Conclusion: There is strong evidence of increased motor cortex excitability in AD and some evidence of an inverse association between excitability and cognition. Future studies should assess cortical excitability from non-motor areas using TMS-EEG and examine its relationship with cognition and NPS. [ABSTRACT FROM AUTHOR]

Background: Probiotics have been reported to ameliorate cognitive impairment.Objective: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI).Methods: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition.Results: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation.Conclusion: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic evidence suggests that physical activity benefits cognition, but results from randomized trials in sedentary individuals are limited and inconsistent.Objective: To evaluate the effects of physical activity on cognition among sedentary older adults.Objective: A systematic literature search for eligible studies published up to January 1, 2021, was performed on six international (PubMed, Cochrane Library, Web of Science, Sinomed, FMRS, and OVID) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and VIP). We estimated the effect of physical activity on the cognition of sedentary elderly by standardized mean differences (SMD) and 95% confidence intervals (CI) using a random-effects model. We evaluated publication bias using funnel plots and heterogeneity using I2 statistics. Subgroup analyses were conducted by baseline cognition, intervention duration, activity type, and country.Results: Seven randomized controlled trials (RCTs) comprising 321 (experimental group, 164; control group, 157) sedentary older adults were included in the meta-analysis. Physical activity significantly improved cognition in sedentary elderly adults compared with controls (SMD: 0.50, 95% CI:0.09-0.92). Subgroup analyses showed significant effects of baseline cognition impairment (SMD: 9.80, 95% CI: 5.81-13.80), intervention duration > 12 weeks (SMD: 2.85, 95% CI: 0.73-4.96), aerobic exercise (SMD: 0.74, CI: 0.19-1.29), and countries other than the United States (SMD: 10.50, 95% CI: 7.08-13.92).Conclusion: Physical activity might have a general positive effect on the cognition of sedentary older adults. Intervention > 12 weeks and aerobic exercise can effectively delay their cognitive decline; however, more rigorous RCTs are needed to support our findings. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) increases the risk of future dementia and Alzheimer's disease (AD). However, it is unclear whether this is true for mild TBI (mTBI).Objective: To explore the association between mTBI and subsequent risk of developing AD.Method: We systematically searched four electronic databases from January 1954 to April 2020. We included studies reporting primary data and where mTBI preceded AD by≥5 years. We meta-analyzed included studies for both high quality studies and studies with a follow up of > 10 years.Result: We included 5 of the 10,435 results found. Meta-analysis found a history of mTBI increased risk of AD (pooled relative risk = 1.18, 95% CI 1.11-1.25, N = 3,149,740). The sensitivity analysis including only studies in which mTBI preceded AD by > 10 years, excluded two very large studies and resulted in wider confidence intervals (RR = 2.02, 95% CI 0.66-6.21, N = 2307).Conclusion: There is an increased risk of AD following mTBI. Our findings of increased risk even with mTBI means it cannot be assumed that mild head injuries from sports are harmless. The sensitivity analysis suggests that we cannot exclude reverse causation, and longer follow up times are needed. Implementation of policy to reduce mTBIs, including in children and sportsmen, are urgently needed. Further research is needed on the effect of frequency and age at injury of mTBIs. [ABSTRACT FROM AUTHOR]

Background: Visual short-term memory (VSTMT) and visual attention (VAT) exhibit decline in the Alzheimer's disease (AD) continuum; however, network disruption in preclinical stages is scarcely explored.Objective: To advance our knowledge about brain networks in AD and discover connectivity alterations during VSTMT and VAT.Methods: Twelve participants with AD, 23 with mild cognitive impairment (MCI), 17 with subjective cognitive decline (SCD), and 21 healthy controls (HC) were examined using a neuropsychological battery at baseline and follow-up (three years). At baseline, the subjects were examined using high density electroencephalography while performing a VSTMT and VAT. For exploring network organization, we constructed weighted undirected networks and examined clustering coefficient, strength, and betweenness centrality from occipito-parietal regions.Results: One-way ANOVA and pair-wise t-test comparisons showed statistically significant differences in HC compared to SCD (t (36) = 2.43, p = 0.026), MCI (t (42) = 2.34, p = 0.024), and AD group (t (31) = 3.58, p = 0.001) in Clustering Coefficient. Also with regards to Strength, higher values for HC compared to SCD (t (36) = 2.45, p = 0.019), MCI (t (42) = 2.41, p = 0.020), and AD group (t (31) = 3.58, p = 0.001) were found. Follow-up neuropsychological assessment revealed converge of 65% of the SCD group to MCI. Moreover, SCD who were converted to MCI showed significant lower values in all network metrics compared to the SCD that remained stable.Conclusion: The present findings reveal that SCD exhibits network disorganization during visual encoding and retrieval with intermediate values between MCI and HC. [ABSTRACT FROM AUTHOR]

Background: Neuropsychological assessment is still the basis for the first evaluation of patients with cognitive complaints. The Free and Cued Selective Reminding Test (FCSRT) generates several indices that could have different accuracy in the differential diagnosis between Alzheimer's disease (AD) and other disorders.Objective: In a consecutive series of naturalistic patients, the accuracy of the FCSRT indices in differentiating patients with either mild cognitive impairment (MCI) due to AD or AD dementia from other competing conditions was evaluated.Methods: We evaluated the accuracy of the seven FCSRT indices in differentiating patients with AD from other competing conditions in 434 consecutive outpatients, either at the MCI or at the early dementia stage. We analyzed these data through the receiver operating characteristics curve, and we then generated the odds-ratio map of the two indices with the best discriminative value between pairs of disorders.Results: The immediate and the delayed free total recall, the immediate total recall, and the index of sensitivity of cueing were the most useful indices and allowed to distinguish AD from dementia with Lewy bodies and psychiatric conditions with very high accuracy. Accuracy was instead moderate in distinguishing AD from behavioral variant frontotemporal dementia, vascular cognitive impairment, and other conditions.Conclusion: By using odd-ratio maps and comparison-customized cut-off scores, we confirmed that the FCSRT represents a useful tool to characterize the memory performance of patients with MCI and thus to assist the clinician in the diagnosis process, though with different accuracy values depending on the clinical hypothesis. [ABSTRACT FROM AUTHOR]

Background: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults.Objective: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians' awareness of hearing loss and improve access to timely hearing care.Methods: Patients referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology.Results: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology.Conclusion: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia. [ABSTRACT FROM AUTHOR]

Background: Dementia is the decline in cognitive function sufficient to impair one's accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents.Objective: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia.Methods: An online anonymous cross-sectional questionnaire was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions.Results: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females = 69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions.Conclusion: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support. [ABSTRACT FROM AUTHOR]

Background: Serum non-high-density lipoprotein-cholesterol (non-HDL-C) levels may be associated with cognitive function.Objective: The objective of this study was to evaluate the association between non-HDL-C and cognitive function among American elders.Methods: We used data from the 2011 to 2014 U.S. National Health and Nutrition Examination Survey (NHANES). A total of 3,001 participants aged over 60 years were enrolled in our analysis. The cognitive function was evaluated with the word learning subtest from the Consortium to Establish a Registry for Alzheimer's disease (CERAD W-L), the Animal Fluency Test (AFT), and the digit symbol substitution test (DSST). We also created a composite cognitive z-score to represent a global cognition. We applied multivariate linear regression analyses to estimate the associations between non-HDL-C levels and all domains of cognitive function. Further, the generalized additive model and the smooth curve were conducted to investigate the dose-response relationship between non-HDL-C and global cognition.Results: Serum non-HDL-C was positively associated with global cognition (β= 0.20, 95% CI: 0.11, 0.28), AFT score (β= 0.54, 95% CI: 0.33, 0.76), and DSST score (β= 1.13, 95% CI: 0.56, 1.69) after fully adjusted. While non-HDL-C was not related to CERAD W-L score. In addition, an inverted U-shape curve was observed in the dose-response relationship between non-HDL-C and global cognition (p for non-linearity < 0.001).Conclusion: Serum non-HDL-C is positively and nonlinearly associated with cognitive function among American older adults. Maintaining serum cholesterol levels at an appropriate range may be helpful to the cognitive health of the elderly. [ABSTRACT FROM AUTHOR]

Background: Recent Alzheimer's disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations.Objective: Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations.Methods: We developed the Alzheimer's Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer's Disease Genetics Consortium and other consortia. Genetic associations were systematically extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories.Results: ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings.Conclusion: ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer's disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention.Objective: We aim to explore the difference in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition.Methods: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition.Results: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores.Conclusion: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals. [ABSTRACT FROM AUTHOR]

Background: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning.Objective: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD).Methods: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. Quantitative meta-analysis was conducted where studies reported sufficient data for pooling.Results: Thirty studies met all inclusion criteria (people with AD (n = 26), FTD (n = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = -0.07; 95% CI -0.14 to 0.00; p = 0.045). Most studies that stratified their sample reported that younger AD onset (usually < 65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive.Conclusion: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias. [ABSTRACT FROM AUTHOR]

Background: Cerebral white matter lesions (WML) are related to a higher risk of vascular and Alzheimer's dementia. Moreover, oligomerized amyloid-β (OAβ) can be measured from blood for dementia screening.Objective: We aimed to investigate the relationship of plasma OAβ levels with clinical and radiological variables in a health screening population.Methods: WML, other volumetric parameters of magnetic resonance images, cognitive assessment, and plasma OAβ level were evaluated.Results: Ninety-two participants were analyzed. The majority of participants' clinical dementia rating was 0 or 0.5 (96.7%). White matter hyperintensities (WMH) increased with age, but OAβ levels did not (r2 = 0.19, p < 0.001, r2 = 0.03, p = 0.10, respectively). No volumetric data, including cortical thickness/hippocampal volume, showed any significant correlation with OAβ. Log-WMH volume was positively correlated with OAβ (r = 0.24, p = 0.02), and this association was significant in the periventricular area. White matter signal abnormalities from 3D-T1 images were also correlated with the OAβ in the periventricular area (p = 0.039). Multivariate linear regression showed that log-WMH values were independently associated with OAβ (B = 0.879 (95% confidence interval 0.098 -1.660, p = 0.028)). Higher tertiles of WMH showed higher OAβ levels than lower tertiles showed (p = 0.044). Using a cutoff of 0.78 ng/mL, the high OAβ group had a larger WMH volume, especially in the periventricular area, than the low OAβ group (p = 0.036).Conclusion: Both WML and plasma OAβ levels can be early markers for neurodegeneration in the healthcare population. The lesions, especially in the periventricular area, might be related to amyloid pathogenesis, which strengthens the importance of WML in the predementia stage. [ABSTRACT FROM AUTHOR]

Background: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia.Objective: To evaluate the therapeutic effect of makeup therapy.Methods: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n = 16) or skin care plus makeup therapy (makeup therapy group, n = 18) once every 2 weeks for 3 months were assessed.Results: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients (*p < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression (*p < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43, *p < 0.05).Conclusion: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software. [ABSTRACT FROM AUTHOR]

Background: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes.Objective: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61).Methods: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs.Results: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC.Conclusion: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients.Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients.Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification.Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort.Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain. [ABSTRACT FROM AUTHOR]

Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material.Objective: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date.Methods: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control.Results: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects.Conclusion: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD. [ABSTRACT FROM AUTHOR]

Background: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results.Objective: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1.Methods: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period.Results: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences.Conclusion: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view. [ABSTRACT FROM AUTHOR]

Background: The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.Objective: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences.Methods: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting.Results: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Compensatory aids can help mitigate the impact of progressive cognitive impairment on daily living.Objective: We evaluate whether the learning and sustained use of an Electronic Memory and Management Aid (EMMA) application can be augmented through a partnership with real-time, activity-aware transition-based prompting delivered by a smart home.Methods: Thirty-two adults who met criteria for amnestic mild cognitive impairment (aMCI) were randomized to learn to use the EMMA app on its own (N = 17) or when partnered with smart home prompting (N = 15). The four-week, five-session manualized EMMA training was conducted individually in participant homes by trained clinicians. Monthly questionnaires were completed by phone with trained personnel blind to study hypotheses. EMMA data metrics were collected continuously for four months. For the partnered condition, activity-aware prompting was on during training and post-training months 1 and 3, and off during post-training month 2.Results: The analyzed aMCI sample included 15 EMMA-only and 14 partnered. Compared to the EMMA-only condition, by week four of training, participants in the partnered condition were engaging with EMMA more times daily and using more basic and advanced features. These advantages were maintained throughout the post-training phase with less loss of EMMA app use over time. There was little differential impact of the intervention on self-report primary (everyday functioning, quality of life) and secondary (coping, satisfaction with life) outcomes.Conclusion: Activity-aware prompting technology enhanced acquisition, habit formation and long-term use of a digital device by individuals with aMCI. (ClinicalTrials.gov NCT03453554). [ABSTRACT FROM AUTHOR]

Background: The Pentagon Drawing Test (PDT) is a common assessment for visuospatial function. Evaluating the PDT by artificial intelligence can improve efficiency and reliability in the big data era. This study aimed to develop a deep learning (DL) framework for automatic scoring of the PDT based on image data.Methods: A total of 823 PDT photos were retrospectively collected and preprocessed into black-and-white, square-shape images. Stratified fivefold cross-validation was applied for training and testing. Two strategies based on convolutional neural networks were compared. The first strategy was to perform an image classification task using supervised transfer learning. The second strategy was designed with an object detection model for recognizing the geometric shapes in the figure, followed by a predetermined algorithm to score based on their classes and positions.Results: On average, the first framework demonstrated 62%accuracy, 62%recall, 65%precision, 63%specificity, and 0.72 area under the receiver operating characteristic curve. This performance was substantially outperformed by the second framework, with averages of 94%, 95%, 93%, 93%, and 0.95, respectively.Conclusion: An image-based DL framework based on the object detection approach may be clinically applicable for automatic scoring of the PDT with high efficiency and reliability. With a limited sample size, transfer learning should be used with caution if the new images are distinct from the previous training data. Partitioning the problem-solving workflow into multiple simple tasks should facilitate model selection, improve performance, and allow comprehensible logic of the DL framework. [ABSTRACT FROM AUTHOR]

Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Autobiographical memory (AM) is a personal form of memory that becomes impaired in the early, clinical stages of Alzheimer's disease (AD). In the "preclinical" phase of AD, neuropathological hallmarks are present (especially in a brain network underpinning AM), but performance on standardized neuropsychological tests is normal. Even so, some patients have subjective cognitive decline (SCD).Objective: The aim was to 1) investigate AM performance on two tests with different approaches in SCD, and in prodromal and mild AD, and 2) examine the association between the AM tests.Methods: We included 17 SCD patients with heightened risk of AD, 17 amnestic mild cognitive impairment (aMCI) patients, 17 patients with mild dementia due to AD, and 30 healthy controls. Patients were diagnosed according to international criteria, and all participants had MMSE scores≥24. AM was assessed using the Columbia Autobiographical Memory Interview-Short Form (CAMI-SF) and the Three Events Test. These tests measure the production of contextual details.Results: Significant group effects were found for the Three Events Test and the CAMI-SF. All patient groups produced significantly fewer contextual details than the controls on the Three Events Test. On CAMI-SF, the aMCI and mild AD groups were able to answer fewer questions or gave significantly less detailed answers than the other groups. The SCD patients performed below the controls on CAMI-SF, but the difference was not significant.Conclusion: AM may be impaired in very early AD, even in the phases where standardized episodic memory tests show no decline. [ABSTRACT FROM AUTHOR]

Background: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain.Objective: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women.Method: Women (N = 2,142) from the Women's Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant's addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates.Result: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10-1.52) or superior attention (OR = 1.30; 95% CI = 1.10-1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17-1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67-0.97).Conclusion: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains. [ABSTRACT FROM AUTHOR]

Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics.Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort.Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests.Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal.Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research. [ABSTRACT FROM AUTHOR]

Background: With the rapid development of neurobiology and neuroimaging technologies, mounting evidence shows that Alzheimer's disease (AD) is caused by the build-up of two abnormal proteins, amyloid-β plaques (A) and neurofibrillary tangles (T). Over time, these AD-related neuropathological burdens begin to spread throughout the brain, which results in the characteristic progression of symptoms in AD.Objective: Although tremendous efforts have been made to link biological indicators to the progression of AD, limited attention has been paid to investigate the multi-factorial role of socioeconomic status (SES) in the prevalence or incidence of AD. There is high demand to explore the synergetic effect of sex and SES factors in moderating the neurodegeneration process caused by the accumulation of A and T biomarkers.Methods: We carry out a meta-data analysis on the longitudinal neuroimaging data, clinical outcomes, genotypes, and demographic data in Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu).Results: Our major findings include 1) education and occupation show resilience effects at the angular gyrus, superior parietal lobule, lateral occipital-temporal sulcus, and posterior transverse collateral sulcus where we found significant slowdown of neurodegeneration due to higher education level or more advanced occupation rank; 2) A and T biomarkers manifest different spatial patterns of brain resilience; 3) BDNF (brain-derived neurotrophic factor) single nucleotide polymorphism (SNP) rs10835211 shows strong association to the identified resilience effect; 4) the identified resilience effect is associated with the clinical manifestation in memory, learning, and organization performance.Conclusion: Several brain regions manifest resilience from SES to A and T biomarkers. BDNF SNPs have a potential association with the resilience effect from SES. In addition, cognitive measures of learning and memory demonstrate the resilience effect. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer's disease (AD).Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging.Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed.Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, SE = 0.061, p = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, SE = 0.037, p = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PiB-PET and AV45-PET), but decreased hippocampus and entorhinal cortex volumes (p < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ42 (beta = 0.056, SE = 0.026, p = 0.036).Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI. [ABSTRACT FROM AUTHOR]

Background: Mid-life hypertension is an established risk factor for cognitive impairment and dementia and related to greater brain atrophy and poorer cognitive performance. Previous studies often have small sample sizes from older populations that lack utilizing multiple measures to define hypertension such as blood pressure, self-report information, and medication use; furthermore, the impact of the duration of hypertension is less extensively studied.Objective: To investigate the relationship between hypertension defined using multiple measures and length of hypertension with brain measure and cognition.Methods: Using participants from the UK Biobank MRI visit with blood pressure measurements (n = 31,513), we examined the cross-sectional relationships between hypertension and duration of hypertension with brain volumes and cognitive tests using generalized linear models adjusted for confounding.Results: Compared with normotensives, hypertensive participants had smaller brain volumes, larger white matter hyperintensities (WMH), and poorer performance on cognitive tests. For total brain, total grey, and hippocampal volumes, those with greatest duration of hypertension had the smallest brain volumes and the largest WMH, ventricular cerebrospinal fluid volumes. For other subcortical and white matter microstructural regions, there was no clear relationship. There were no significant associations between duration of hypertension and cognitive tests.Conclusion: Our results show hypertension is associated with poorer brain and cognitive health however, the impact of duration since diagnosis warrants further investigation. This work adds further insights by using multiple measures defining hypertension and analysis on duration of hypertension which is a substantial advance on prior analyses-particularly those in UK Biobank which present otherwise similar analyses on smaller subsets. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) visual scales of brain atrophy are important for differential diagnosis of dementias in routine clinical practice. Atrophy patterns in early- and late-onset Alzheimer's disease (AD) can be different according to some studies.Objective: Our goal was to assess brain atrophy patterns in early- and late-onset AD using our recently developed simple MRI visual scales and evaluate their reliability.Methods: We used Hippocampo-horn percentage (Hip-hop) and Parietal Atrophy Score (PAS) to compare mediotemporal and parietal atrophy on brain MRI among 4 groups: 26 patients with early-onset AD, 21 younger cognitively normal persons, 32 patients with late-onset AD, and 36 older cognitively normal persons. Two raters scored all brain MRI to assess reliability of the Hip-hop and PAS. Brain MRIs were obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) database.Results: The patients with early-onset AD had significantly more pronounced mediotemporal and also parietal atrophy bilaterally compared to the controls (both p < 0.01). The patients with late-onset AD had significantly more pronounced only mediotemporal atrophy bilaterally compared to the controls (p < 0.000001), but parietal lobes were the same. Intra-rater and inter-rater reliability of both visual scales Hip-hop and PAS were almost perfect in all cases (weighted-kappa value ranged from 0.90 to 0.99).Conclusion: While mediotemporal atrophy detected using Hip-hop is universal across the whole AD age spectrum, parietal atrophy detected using PAS is worth rating only in early-onset AD. Hip-hop and PAS are very reliable MRI visual scales. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon.Objective: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition.Methods: Oligomerization of Aβ1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ1-42, Aβ1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia.Results: Whereas isoflurane and sevoflurane did not affect Aβ1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ1-42-induced spine density attenuation. In the presence of Aβ1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice.Conclusion: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ1-42 aggregation, LTP, and spine density. [ABSTRACT FROM AUTHOR]

Background: Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer's disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD.Objective: The present study investigated the association between SIRT1 and tau expression/tau localization in cells and in mice brains.Methods: Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains.Results: In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/- mice.Conclusion: SIRT1 may be a potential drug target for early intervention in AD. [ABSTRACT FROM AUTHOR]