Disease Assessment Scale-Cognitive Subscale Research Articles

Use of Bacopa monnieri in the Treatment of Dementia Due to Alzheimer Disease: Systematic Review of Randomized Controlled Trials.

BackgroundBacopa monnieri, a herb that has been used for many centuries in India, has shown neuroprotective effects in animal and in vitro studies; human studies on patients with Alzheimer disease have been inconclusive.ObjectiveThe primary objective of this review was to determine the clinical efficacy and safety of B. monnieri in persons with mild, moderate, or severe dementia, or mild cognitive impairment, due to Alzheimer disease.MethodsWe searched PubMed, Embase, Cochrane Library, clinical trial registries (World Health Organization, Australia-New Zealand, United States, and South Africa), the metaRegister of Controlled Trials, and CINAHL. We intended to include all randomized and quasi-randomized controlled trials that compared B. monnieri, its extract or active ingredients (at any dosage), with a placebo or a cholinesterase inhibitor among adults with dementia due to Alzheimer disease and in those with mild cognitive impairment due to Alzheimer disease.ResultsOur comprehensive search yielded 5 eligible studies. A total of 3 studies used B. monnieri in combination with herbal extracts while the remaining 2 used B. monnieri extracts only. Two studies compared B. monnieri with donepezil while the others used a placebo as the control. There was considerable variation in the B. monnieri dose used (ranging between 125 mg to 500 mg twice daily) and heterogeneity in treatment duration, follow-up, and outcomes. The major outcomes were Mini-Mental State Examination scores reported in 3 trials, Cognitive subscale scores of the Alzheimer’s Disease Assessment Scale in 1 study, and a battery of cognitive tests in 2 studies. Using the Cochrane risk-of-bias tool, overall, we judged all 5 studies to be at high risk of bias. While all studies reported a statistically significant difference between B. monnieri and the comparator in at least one outcome, we rated the overall quality of evidence for the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, Postgraduate Institute Memory Scale, Mini-Mental State Examination, and Wechsler Memory Scale to be very low due to downgrading by 2 levels for high risk of bias and 1 more level for impreciseness due to small sample sizes and wide CIs.ConclusionsThere was no difference between B. monnieri and the placebo or donepezil in the treatment of Alzheimer disease based on very low certainty evidence. No major safety issues were reported in the included trials. Future randomized controlled trials should aim to recruit more participants and report clinically meaningful outcomes.Trial RegistrationPROSPERO CRD42020169421; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=169421

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments

BackgroundGuanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s disease.Methods/designNorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed.DiscussionThere is strong evidence for early noradrenergic dysfunction in Alzheimer’s disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.Trial registrationClinicalTrials.govNCT03116126. Registered on 14 April 2017EudraCT: 2016-002598-36

Brain MRI Biomarkers to Predict Cognitive Decline in Older People with Alzheimer's Disease.

Structural magnetic resonance imaging markers predicting symptomatic progression at the individual level can be highly beneficial for early intervention and treatment planning for Alzheimer's disease (AD). However, the correlation between baseline MRI findings and AD progression has not been fully established. To explore the correlation between baseline MRI findings and AD progression. Brain volumetric measures were applied to differentiate the patients at risk of fast deterioration in AD. We included 194 AD patients with a 24-month follow-up: 65 slow decliners, 63 normal decliners, and 66 fast decliners categorized by changes in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). ANOVA analyses were used to identify baseline brain atrophy between groups. Logistic regressions were further performed to explore the relative merits of AD resemblance structural atrophy index (AD-RAI) and individual regional volumetric measures in prediction of disease progression. Atrophy in the temporal and insular lobes was associated with fast cognitive decline over 24 months. Smaller volumes of temporal and insular lobes in the left but not the right brain were associated with fast cognitive decline. Baseline AD-RAI predicted fast versus slow progression of cognitive decline (odds ratio 3.025 (95% CI: 1.064-8.600), high versus low, AUC 0.771). Moreover, AD-RAI was significantly lower among slow decliners when compared with normal decliners (p = 0.039). AD-RAI on MRI showed potential in identifying clinical AD patients at risk of accelerated cognitive decline.

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia.

Cerebral small vessel disease is a progressivedisease of the brain'sdeep perforating blood vessels.It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is anestablished treatment for stroke prevention, we sought to determinewhether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease. To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database. SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compareantithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or comparedifferent antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapyor combination therapy), anticoagulants or a combination. Two review authors independently screened all the titlesidentified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses. We included threeRCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate(2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk(HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia. We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition tostandard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneityacross the trials and the certainty of the evidence was generally poor.

Cannabinoid extract in microdoses ameliorates mnemonic and nonmnemonic Alzheimer’s disease symptoms: a case report

BackgroundCannabinoid-based therapy has been shown to be promising and is emerging as crucial for the treatment of cognitive deficits, mental illnesses, and many diseases considered incurable. There is a need to find an appropriate therapy for Alzheimer’s disease, and cannabinoid-based therapy appears to be a feasible possibility.Case presentationThis report addresses the beneficial effect of cannabinoids in microdoses on improving memory and brain functions of a patient with mild-stage Alzheimer’s disease. The patient is a 75-year-old white man presenting with main symptoms of memory deficit, spatial and temporal disorientation, and limited daily activity. The experimental therapeutic intervention was carried out for 22 months with microdoses of a cannabis extract containing cannabinoids. Clinical evaluations using Mini-Mental State Examination and Alzheimer’s Disease Assessment Scale-Cognitive Subscale were performed.ConclusionsHere we provide original evidence that cannabinoid microdosing could be effective as an Alzheimer’s disease treatment while preventing major side effects. This is an important step toward dissociating cannabinoids’ health-improving effects from potential narcotic-related limitations.

Normative Data of Mini-Mental State Examination, Montreal Cognitive Assessment, and Alzheimer’s Disease Assessment Scale-Cognitive Subscale of Community-Dwelling Older Adults in Taiwan

Introduction: Appropriate tools and references are essential for evaluating individuals’ cognitive levels. This study validated the Taiwan version of the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog) and provided normative data for the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and ADAS-cog in community-dwelling older adults. Methods: MMSE, MoCA, and ADAS-cog were administered to 150 nondemented healthy adults aged 55–85 years during 2018–2020 as part of the Northeastern Taiwan Community Medicine Research Cohort. ADAS-cog was translated from the original English version to traditional Chinese with cultural and language considerations in Taiwan. Cronbach’s alpha (α) tested the reliability of ADAS-cog, and Pearson correlations examined its external validity using MMSE and MoCA as comparisons. Normative data were generated and stratified by age and education, and the one-way analysis of variance compared scores between age and education groups. Another 20 hospital-acquired participants with cognitive impairment joined the 150 healthy participants. Comparisons in the Clinical Dementia Rating (CDR) tiers tested the discriminability of the tests for different cognitive levels. The area under the receiver operating characteristic curve (AUROC) analyzed the power of ADAS-cog in predicting CDR 0.5 from CDR 0. Results: The Taiwan version of ADAS-cog had fair reliability between items (α = 0.727) and good correlations to MMSE (r = −0.673, p < 0.001) and MoCA (r = −0.746, p < 0.001). The normative data of MMSE, MoCA, and ADAS-cog showed ladder changes with age (p = 0.006, 0.001, and 0.437) and education (p < 0.001, <0.001, and <0.001) in the 150 nondemented older adults. Next, in the 170 mixed participants from the communities and the hospital, MMSE, MoCA, and ADAS-cog scores were well differentiable between CDR 0, 0.5, and 1. In addition, ADAS-cog discriminated CDR 0.5 from 0 by an AUROC of 0.827 (p < 0.001). Discussion/Conclusion: The three structured cognitive tests consistently reflect cognitive levels of healthy older adults. The Taiwan version of ADAS-cog is compatible with MMSE and MoCA to distinguish people with mildly impaired from normal cognition. In addition, this study derived MMSE, MoCA, and ADAS-cog norms tailored to demographic factors. The findings highlight the need for stratification of age and education rather than applying a fixed cutoff for defining normal and abnormal cognition.

Spatio-temporal Tensor Multi-Task Learning for Predicting Alzheimer's Disease in a Longitudinal study.

The utilisation of machine learning techniques to predict Alzheimer's Disease (AD) progression will substantially assist researchers and clinicians in establishing effective AD prevention and treatment strategies. In this research, we present a novel Multi-Task Learning (MTL) model for modelling AD progression based on tensor formation from spatio-temporal similarity measures of brain biomarkers. In this model, each patient sample's prediction in the tensor is assigned to a task, with each task sharing a set of latent factors acquired via tensor decomposition. To further improve the performance of the model, we present a novel regularisation term which utilises the convex combination of disease progression to modify longitudinal stability and ensure that two regression models have a minimal variation at successive time points. The model can be utilised to effectively predict AD progression with magnetic resonance imaging (MRI) data and cognitive scores of AD patients at various stages. We conducted extensive experiments to evaluate the performance for the proposed model and algorithm utilising data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Compared to single-task and state-of-the-art multi-task regression techniques, our proposed method has greater accuracy and stability for predicting AD progress in terms of root mean square error, with an average reduction of 2.60 compared to single-task regression methods and 1.17 compared to multi-task regression methods in the Mini-Mental State Examination (MMSE) questionnaire; with an average reduction of 5.08 compared to single-task regression methods and 2.71 compared to multi-task regression methods in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog).

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis

BackgroundDysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments...

Levetiracetam in Alzheimer's Disease: Do Epileptologists Already Have the Cure?

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial Vossel K, Ranasinghe KG, Beagle AJ, et al. JAMA Neurol. 2021;78(11):1345-1354. doi:10.1001/jamaneurol.2021.3310.Importance:Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).Objective:To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participants:The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.Interventions:Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measures:The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale—Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.Results:Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, .07 points; 95% CI, −.18 to .32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, .2–14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = .11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevance:In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Selective Serotonin Reuptake Inhibitor-Treatment Does Not Show Beneficial Effects on Cognition or Amyloid Burden in Cognitively Impaired and Cognitively Normal Subjects.

Preclinical studies indicate that selective serotonin reuptake inhibitors (SSRI) have beneficial effects on Alzheimer-related pathologies. Therefore, the aim of this study was to evaluate the influence of SSRI-treatment on amyloid burden in 18F-Florbetapir-positron emission tomography (PET) and on cognition in cognitively normal and cognitively impaired subjects. We included n = 755 cognitively impaired and n = 394 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that underwent at least one 18F-Florbetapir-PET. Standardized uptake ratios (SUVR) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS) scores as well as follow-up results were compared between subgroups with a history of SSRI-treatment (SSRI+) and without SSRI-treatment (SSRI-) as well as in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. 18F-Florbetapir-PET did not show significant differences of SUVR between the SSRI+ and SSRI- groups in both, cognitively impaired and cognitively normal participants. There were no differences in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. However, SUVR showed a dose-dependent inverse correlation to the duration of medication in cognitively normal and in cognitively impaired patients. SRRI-treatment did not show an effect on ADAS scores. Furthermore, there was no effect on follow-up SUVR or on follow-up ADAS scores. Overall, SSRI-treatment did not show beneficial effects on amyloid load nor on cognition.

A Stacking Framework for Multi-Classification of Alzheimer's Disease Using Neuroimaging and Clinical Features.

Alzheimer's disease (AD) is a severe health problem. Challenges still remain in early diagnosis. The objective of this study was to build a Stacking framework for multi-classification of AD by a combination of neuroimaging and clinical features to improve the performance. The data we used were from the Alzheimer's Disease Neuroimaging Initiative database with a total of 493 subjects, including 125 normal control (NC), 121 early mild cognitive impairment, 109 late mild cognitive impairment (LMCI), and 138 AD. We selected structural magnetic resonance imaging (sMRI) feature by voting strategy. The imaging feature, demographic information, Mini-Mental State Examination, and Alzheimer's Disease Assessment Scale-Cognitive Subscale were combined together as classification features. We proposed a two-layer Stacking ensemble framework to classify four types of people. The first layer represented support vector machine, random forest, adaptive boosting, and gradient boosting decision tree; the second layer was a logistic regression classifier. Additionally, we analyzed performance of only sMRI feature and combined features and compared the proposed model with four base classifiers. The Stacking model combined with sMRI and non-imaging features outshined four base classifiers with an average accuracy of 86.96%. Compared with using sMRI data alone, sMRI combined with non-imaging features significantly improved diagnostic accuracy, especially in NC versus LMCI. The Stacking framework we used can improve performance in diagnosis of AD using combined features.

The Patient Voice: Exploring Treatment Preferences in Participants with Mild Cognitive Concerns to Inform Regulatory Decision Making.

ObjectiveWe aimed to assess the feasibility of developing a discrete-choice experiment survey to elicit preferences for a treatment to delay cognitive decline among people with a clinical syndrome consistent with early Alzheimer’s disease, including the development of self-reported screening criteria to recruit the sample.MethodsUsing input from qualitative interviews, we developed a discrete-choice experiment survey containing a multifaceted beneficial treatment attribute related to slowing cognitive decline for respondents with self-reported cognitive concerns. In two rounds of in-person pretest interviews, we tested and revised the survey text and discrete-choice experiment questions, including examples, language, and levels associated with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, along with a set of de novo self-reported questions for identifying respondents who had neither too mild nor too advanced cognitive decline. Self-reported memory and thinking problems were compared with symptoms from studies of patients with early Alzheimer’s disease (e.g., mild cognitive impairment, mild Alzheimer’s disease) to determine whether those studies’ recruited patients were similar to our anticipated target population. Round 1 pretest interviews resulted in significant simplifications in the survey instrument, revisions to the inclusion and exclusion criteria, and revisions to the screening process. In round 2 of the pretest interviews, the ability of participants to provide consistent responses to the self-reported screening questions was further assessed. In addition, to evaluate participants’ ability to understand and independently complete the discrete-choice experiment survey, two interviewers independently evaluated each participant’s ability to make trade-offs in the discrete-choice experiment questions and to understand the content of the survey.ResultsRound 1 (15 pretest interviews) identified challenges with the survey instrument related to the complexity of the choice questions. The screening process did not screen out seven respondents with more advanced cognitive decline, as determined qualitatively by the interviewers and by these participants’ inability to complete the survey. The survey instrument and screening criteria were revised, and an initial online screener was added to the screening process before round 2 pretests. In round 2 pretests, 12 participants reported cognitive problems similar to the target population for the survey but were judged able to understand and independently complete the discrete-choice experiment survey.ConclusionsWe developed self-reported screening criteria that identified a sample of individuals with memory and thinking concerns who were similar to individuals with clinical symptoms of early Alzheimer’s disease and who were able to independently complete a simplified discrete-choice experiment survey. Quantitative patient preference studies provide important information on patients’ willingness to trade off treatment benefits/risks. Adapting the technique for patients with cognitive decline requires careful testing and adjustments to survey instruments. This work suggests it is the severity of cognitive impairment, rather than its presence, that determines the ability to complete a simplified discrete-choice experiment survey.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-022-00576-w.

Test–retest reliabilities and minimal detectable changes of 5 versions of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale in people with dementia

Purpose To compare the test–retest reliability and minimal detectable change (MDC) of the commonly used versions of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (the ADAS-Cog-11 (11 items), ADAS-Cog-3 (three items), ADAS-Cog-5-Subset (five items), ADAS-Cog-6-Subset (six items), and ADAS-Rasch (11 items)) in people with dementia. Materials and methods A repeated-assessments design (2 weeks apart) was used to examine the ADAS-Cog-11, ADAS-Cog-3, ADAS-Cog-5-Subset, ADAS-Cog-6-Subset, and ADAS-Rasch. Participants with dementia were recruited from one hospital, one elder care center, and two day-care centers using convenience sampling. Results Fifty-two participants finished the assessments twice in two weeks. All versions showed high intraclass correlation coefficients (ICCs) (0.82–0.96), minimal standardized response means (–0.07 to 0.08) and low to acceptable MDC% (9.2–28.6%). The ADAS-Rasch had the highest ICC (0.96) and the lowest MDC%. The ADAS-Cog-3 had an ICC lower than 0.90 (0.82) and the highest MDC% (28.6%). Conclusions The ADAS-Rasch seems to be the most reliable version of the ADAS-Cog for group- and individual-level comparisons. The ADAS-Cog-3 may be a better choice for researchers for group-level comparisons because it requires fewer items to achieve acceptable reliability. The ADAS-Cog-11, ADAS-Cog-5-Subset, ADAS-Cog-6-Subset, and ADAS-Rasch could be considered for clinical usage for individual-level comparisons. Implications for rehabilitation The ADAS-Rasch is the most reliable version of the ADAS-Cog for group- and individual-level comparisons due to its excellent test–retest reliability, lowest random measurement error and absence of a practice effect. The ADAS-Cog-5-Subset and ADAS-Cog-6-Subset might be good substitutes for the ADAS-Rasch in clinical settings because of their comparable reliability features and superior administration efficiency.

Effects of multisite anodal transcranial direct current stimulation combined with cognitive stimulation in patients with Alzheimer's disease and its neurophysiological correlates: A double-blind randomized clinical trial

ObjectivesWe aimed to examine the effects of multisite anodal transcranial direct current stimulation (tDCS) combined with cognitive stimulation (CS) over 2 months on cognitive performance and brain activity, and the relationship between them, in patients with Alzheimer's disease (AD). MethodsPatients with AD were randomly assigned to an active tDCS+CS (n=18) or a sham tDCS+CS (n=18) group. Cognitive performance was assessed using the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) and brain activity using EEG (spectral power and coherence analysis) before and after the intervention. Multisite anodal tDCS (2 mA, 30 min) was applied over six brain regions [left and right dorsolateral prefrontal cortex (F3 and F4), Broca's area (F5), Wernicke's area (CP5), left and right somatosensory association cortex (P3 and P4)] for 24 sessions (three times a week). Both groups performed CS during tDCS. ResultsAnodal tDCS+CS delays cognitive decline (ADAS-cog change) to a greater extent than sham tDCS+CS (-3.4±1.1 vs. -1.7±0.4; p=.03). Bilateral EEG coherence at high and low frequencies was greater for the active tDCS+CS than sham+CS group for most electrode pairs assessed (p < .05). The post-intervention ADAS-cog change score was predictive for EEG coherence at different sites (R²=.59 to .68; p < .05) in the active but not in the sham tDCS+CS group. ConclusionAnodal tDCS+CS improved overall cognitive function and changed EEG brain activity compared to sham tDCS+CS. Changes in cognitive performance were associated with changes in EEG measures of brain activity. Anodal tDCS+CS appears to be a promising therapeutic strategy to modulate cortical activity and improve cognitive function in patients with AD.

Multi-site rTMS with cognitive training improves apathy in the long term in Alzheimer’s disease: A 4-year chart review

ObjectiveTo assess the long-term effects of multi-site repetitive transcranial magnetic stimulation combined with cognitive training (NeuroAD procedure) on cognitive symptoms and apathy in patients with Alzheimer's disease (AD) as part of a 4-year chart review. MethodsThe study included the 30 AD patients who underwent NeuroAD treatment between 2015 and 2019 at our center. The clinical evaluation was based on the Mini Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Apathy Inventory (AI). Assessment was performed before treatment (baseline), after an initial 6-week protocol of 30 sessions (M1.5), then 3 months (M3), 1 year (M12), and between 1.5 and 4 years (mean 28 months, M28) after treatment initiation. ResultsDuring the first year of follow-up, the AI score improved at all time points (M1.5, M3, M12, p < 0.0001), the ADAS-Cog score improved at the end of the initial procedure (M1.5, p = 0.003) then deteriorated (M12, p = 0.01), while the MMSE score did not change. At final assessment (M28), the AI score was still improved from baseline (p < 0.0001), while the MMSE and ADAS-Cog scores worsened (p < 0.0001). Regarding the ADAS-Cog score, the prolonged improvement at M12 or M28 was correlated with the initial improvement at M1.5. ConclusionThe NeuroAD procedure produced long-term improvement in apathy and more general cognitive improvement only in patients who responded well to the initial 6-week protocol. SignificanceOur results suggest long-term beneficial effects of the NeuroAD procedure on apathy, which need to be confirmed in controlled studies. The criteria for predicting a good outcome before starting the procedure remain to be defined.

Is the Alzheimer's Disease Assessment Scale-Cognitive Subscale Useful in Screening for Mild Cognitive Impairment and Alzheimer's Disease? A Systematic Review.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are screened to distinguish whether the cognitive decline in older adults is attributed to pathological causes rather than normal aging. The purpose of this review was to analyze the diagnostic performance of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in screening for MCI and AD. Electronic searches were performed on MEDLINE, EMBASE, CINAHL, and PsycArticles databases using the following keywords: dementia and ADAS-Cog. The Quality Assessment of Diagnostic Accuracy Studies-2 was used to check the risk of bias in the diagnostic studies. We reviewed 14 studies, including 3,875 patients who met the selection criteria. In 2,624 MCI patients from nine studies, the pooled sensitivity of ADAS-Cog was 0.80 (95% confidence interval [CI], 0.68-0.88), the pooled specificity was 0.84 (95% CI, 0.75-0.90), and the area under the curve of summary receiver-operating characteristic curves (SROC AUC) was 0.89 (SE = 0.03). In 2,517 AD patients from 10 studies, the pooled sensitivity and pooled specificity were 0.91 (95% CI, 0.86-0.95) and 0.93 (95% CI, 0.88-0.95), respectively, and the sROC AUC was 0.97 (SE = 0.01). Although sub-analyzed according to age and years of education, there was no significant difference in the predictive validity of the ADAS-Cog. The ADAS-Cog has high predictive validity as a screening tool in both MCI and AD and has better diagnostic performance in patients with AD. When early screening for AD is desired, ADAS-Cog is a first-stage screening tool that can be initially employed.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): ARandomized Double-Blind Delayed-Start Trial.

Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. Randomized double-blind placebo-controlled delayed-start study. Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n= 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6months, followed by a further 6months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). The primary outcome measure was occurrence of serious adverse events (SAEs) at 6months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference-4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD)-1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Efficacy of Traditional Chinese Veterinary Medicine in the Treatment of Cognitive Dysfunction: A Systematic Review and Meta-Analysis

The objective of this systematic review study was to assess the efficacy of traditional Chinese medicine (TCM) or traditional Chinese veterinary medicine (TCVM) in the treatment of cognitive dysfunction. The study considered the similarities in Alzheimer’s disease (AD) and canine cognitive dysfunction (CCD). The initial literature search resulted in 573 relevant clinical and nonclinical studies. Three categories of controlled clinical trials in AD patients were selected for review: placebo control (20), conventional medicine control (126), and integrated treatment (183). The studies were reviewed and those that met the inclusion criteria were selected for meta-analysis. The review found that 10 placebo-controlled studies, 38 conventional medicine-controlled studies, and 38 integrated studies were qualified for meta-analysis. In placebo-controlled studies, meta-analyses based on improvements in Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) found statistical significance in the MMSE (p=8.74×10-7), ADAS-cog (p=0.0085), and overall p-value (p=3.66×10-17), suggesting that the TCM treatments were significantly more effective than placebo. In conventional treatment-controlled studies, results from the meta-analyses also suggest that TCM treatments were significantly more effective than conventional treatments based on the overall p-value (p=1.67×10-23) and improvement in MMSE (p=0.0002). In the integrated treatment studies, the meta-analyses findings suggest that TCM-integrated treatments were significantly more effective than conventional treatments alone (overall p-value: p=1.82×10-48 and p=0.0050 in MMSE improvements). Based on this systematic review and considering the similarities in pathology in the human and canine, TCVM may be helpful to lessen suffering and improve the quality of life in patients with canine cognitive dysfunction.

Staging Disease Severity Using the Alzheimer's Disease Composite Score (ADCOMS): A Retrospective Data Analysis.

IntroductionThe Alzheimer’s disease (AD) composite score (ADCOMS) has been shown to be a more sensitive measure of cognitive change in early AD (i.e., mild cognitive impairment [MCI] and mild AD) than commonly used measures. This study derived ADCOMS value ranges associated with different disease severity stages across the predementia and AD continuum.MethodsData from patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative were assessed at baseline and month 24. Data were randomly split into derivation and validation samples. Receiver-operating characteristic (ROC) curves of ADCOMS values were generated in the derivation sample to assess the sensitivity and specificity of ADCOMS cutoff values compared with existing disease severity cutoff scores using the Clinical Dementia Rating (CDR) global, CDR Sum of Boxes, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Mini-Mental State Examination. Optimal ADCOMS cutoff values for each disease stage were compared between the derivation and the validation samples using a χ2 test. The diagnostic accuracy of the derived ADCOMS cutoff values was then assessed. The analyses were repeated for the subset with positive amyloid β confirmation (Aβ +).ResultsThe following ADCOMS value ranges for the total population and Aβ + population were < 0.11 indicative of normal cognition, 0.11 to < 0.31 indicative of MCI, 0.31 to 0.77 indicative of mild AD, and > 0.77 indicative of at least moderate AD. The reliability of these ADCOMS value ranges was supported by diagnostic accuracy tests and tests indicating no significant difference in the ROC curves between the derivation and validation samples.ConclusionADCOMS values ranges can be used to assess the severity of cognitive decline. The derived severity threshold score ranges for ADCOMS will enable its use as an endpoint in clinical trials assessing disease progression and clinical outcomes of disease-modifying therapies in persons with MCI or early AD, including patients with Aβ + confirmation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00326-y.

The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro

Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale—Cognitive Subscale behavioral test. Here, we explore a potential direct effect of Ator on Aβ42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on Aβ42 aggregation, as expected because of the presence of calcium ions. The effect was reversed when applying a CaCO3-based calcium ion scavenging method, which was validated by the aforementioned methods as well as thioflavin-T fluorescence assays and transmission electron microscopy. We found that the aggregation was inhibited significantly when the concentration of calcium-free Ator exceeded that of Aβ by at least a factor of 2. The 1H–15N heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the 16KLVF19 binding site on the Aβ peptide via its aromatic rings as well as hydroxyl and methyl groups. On the other hand, molecular dynamics simulations confirmed that the increasing concentration of Ator is necessary for the inhibition of the conformational transition of Aβ from an α-helix-dominant to a β-sheet-dominant structure.