Moderate Alzheimer's Disease Research Articles

Impact of Independent Review on Potential MMSE Score Inflation at Screening in AD trials

AbstractBackgroundThe Mini‐Mental State Examination (MMSE) is widely used as a screening tool in Alzheimer’s Disease (AD) clinical trials. Screening score inflation is documented in clinical trials of depression and anxiety. We investigated whether score distributions on several multi‐site multinational AD trials showed truncated scores around MMSE inclusion criteria cut‐off, and whether Independent Review (IRev), where site assessments are reviewed by independent clinicians, is an effective methodology to mitigate inclusion bias.MethodMMSE screening score distributions from several clinical trials of Early Symptomatic and Mild to Moderate AD were examined. To assess the impact of IRev on screening score distribution, we compared two studies with similar inclusion criteria (Early AD, MMSE ≥ 22; CDR GS = 0.5 or 1) one with no IRev and one with IRev via audio recording.ResultMMSE screening frequency distributions showed a statistically significant difference between IRev and No‐IREV groups (p < 0.001). The distributions for the two groups were also compared using several score ranges around the threshold. Significant group differences were observed across the score ranges; 20‐24 (D = 0.099, p = 0.01), 19‐25 (D = 0.094, p = 0.002), and 18‐26 (D = 0.0987, p < 0001), suggesting a smaller inclusion bias around the threshold in the IRev group.ConclusionWe observed that screening score inflation occurs in AD trials and Independent Review may be an effective strategy to reduce the number of subjects inappropriately enrolled in the study. IRev should be applied to assessments that fall around the required scored for study participation.

Detection of subclinical epileptiform discharges in Alzheimer’s disease using long‐term out‐patient EEG monitoring

AbstractBackgroundIn patients with Alzheimer’s disease (AD) without clinical seizures, up to half have epileptiform discharges in long‐term in‐patient electroencephalography (EEG) recordings. Long‐term in‐patient monitoring is obtrusive, and expensive as compared to out‐patient monitoring. No studies have so far investigated if long‐term out‐patient EEG monitoring is able to identify epileptiform discharges in AD. To investigate if epileptiform discharges as measured with ear‐EEG are more common in patients with AD compared to healthy elderly controls (HC). To understand the association with AD, we investigated the variability across multiple recordings.MethodIn this longitudinal observational study, 24 patients with mild to moderate AD and 15 age‐matched HC were included in the analysis. Patients with AD underwent up to three ear‐EEG recordings, each lasting up to two days, within 6 months. The first recording was defined as the baseline recording.ResultAt baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p‐value = 0.073). The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77‐5.01, p<0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear‐EEG recordings.ConclusionLong‐term ear‐EEG monitoring detects epileptiform discharges in most patients with AD with a three‐fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD.

Impact of rater change on data variability in ADAS‐Cog and CDR assessments

AbstractBackgroundThe past decade has seen numerous research trial failures in Alzheimer’s Disease. The CDR and ADAS‐Cog are the two most frequently used primary outcome measures of memory and cognition in clinical trials of Alzheimer’s Disease (AD). Given the high number of failed AD trials in recent years, data reliability of these measures is paramount. In an effort to minimize data variability and increase data quality, study designs often require the same rater assesses the subject/caregiver at each study visit. However, the impact of rater change on data reliability of these measures is largely unknown. This analysis investigates the impact of rater change on data variability in these measures.MethodData from 13 multinational clinical trials of early symptomatic and mild to moderate AD were analyzed. ADAS‐Cog and CDR assessments conducted by site raters were arranged according to visit sequence and divided into two groups: Rater Change (different raters administered subject’s consecutive visits) and No Rater Change (same rater administered consecutive visits). Visit‐to‐visit absolute score changes for CDR‐SB and ADAS‐Cog Total Score were calculated, and frequency distributions were evaluated.ResultWelch corrected, two sample t‐tests were conducted to compare score changes between rater change groups. For CDR, the Rater Change group showed a higher mean visit‐to‐visit score change (mean = 1.26, SD = 1.32) compared to the No Rater Change (mean = 1.02, SD = 1.13) group. The Rater Change group also showed a higher mean score change on ADAS‐Cog (mean = 4.44, SD: 3.77 and mean ‐ 4.06, SD = 3.50, for Rater Change and No Rater Change Groups, respectively). These group differences reached significance for both ADAS‐Cog (t = ‐7.2925, df = 9769.1, p < .001) and CDR (t = ‐11.228, df = 6122.7, p < .001).ConclusionThe analysis indicates significantly different score changes when there is a rater change between visits than not for both CDR and ADAS‐Cog assessments. These findings highlight the importance of rater consistency in reducing variability in an effort to improve data quality in AD trials.

Categorical reasoning in Alzheimer’s disease: What is preserved?

AbstractBackgroundSemantic knowledge impairment appears to be a robust early indicator of Alzheimer’s disease (AD) pathology. The disruption of semantic cognition has been detected in preclinical AD. We investigate the ability of patients with mild to moderate AD to categorize items belonging to two semantic domains critical in daily life, living kinds and artefacts.MethodThe categorial reasoning competence of 12 patients with AD and 16 age‐matched normal controls, in the semantic domains of living kinds and man‐made objects are compared by means of an unconstrained pile‐sorting experiment. The participants are left to decide how to lump a list of items, hence, to select organizational schemes of their choosing. Unconstrained pile‐sorting has the potential to better reveal the most salient concepts and principles that orient the classificatory decisions of the participants.ResultThe experimental findings highlight both preserved and disrupted abilities. Important structural principles organizing knowledge in both semantic categories seem to remain well preserved and to still drive patients’ core reasoning. Patients and controls do differ in the specific contents of their piles, even though the number of piles generated by each group does not diverge. Patients with AD were less systematic in their categorization strategies than control participants. The performance of patients displays evidence of a broad weakening of conceptual associations at levels of categorizations requiring finer details.ConclusionEarly deviations in cognitive performance of individuals with AD from cognitively normal adults might only appear when careful analyses of contents are conducted. To our knowledge, it is the first study to use this task as developed in cognitive anthropology to investigate semantic knowledge in AD. We propose that the detection of early deviations in performance of patients with AD might be enhanced by the combination of detailed analysis of contents and a quantitative approach.

A Randomized, Double‐blind, Sham‐controlled, Adaptive‐Design Pivotal Trial of Sensory Stimulation in Subjects with Alzheimer’s Disease

AbstractBackgroundIn three prospective clinical trials (Overture: NCT03556280, Etude: NCT03661034, Flicker: NCT03543878) non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation diminished Alzheimer’s disease (AD) symptoms, including a reduction in decline in cognitive and functional symptoms. These trials initiated the design of the Cognito Therapeutics sponsored Hope pivotal trial which examines the safety and efficacy of Cognito Therapeutics’ Sensory Stimulation System.MethodThe US‐based multicenter Hope trial will randomize (1:1) approximately 500 subjects aged 50 and older diagnosed with mild to moderate AD (MMSE 15‐26) and will stratify them to active and sham in a blinded manner across MMSE score ranges: 15‐20 and 21‐26. Subjects in both study arms will self‐administer therapy via the Sensory Stimulation System for 60 minutes daily for 12 months. An interim analysis will employ the promising zone methodology, allowing the sample size to be adjusted if the effect is trending toward success, but additional subjects are needed to maintain greater than 80% power.ResultThe primary outcome measure will be the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS‐ADL) test. Changes in function and cognition will be evaluated using a combined statistical test for ADCS‐ADL and the Mini Mental State Exam (MMSE). The key secondary outcome is change in cognition using the MMSE. Other clinical efficacy assessments include instrumental activities of daily living (IADL), Zarit Burden Index (ZBI), the Clinical Dementia Rating Scale (CDR) and The Neuropsychiatric Inventory anxiety subscale (NPI – Anxiety). Key biomarker assessments include whole brain, white matter, and hippocampal volume and occipital cortical thickness. Sleep fragmentation will be assessed in a subgroup of subjects using actigraphy. Exploratory measures will include additional brain structural change, plasma biomarkers, EEG assessed coherence, and at‐home tablet‐based tasks. Safety will be evaluated via routine clinical laboratory assessments, review of adverse events, concurrent medication use, physical and neurological exams, vital signs, MRI, and a suicidality scale.ConclusionThe Hope pivotal trial is designed to demonstrate the efficacy and safety of daily in‐home gamma sensory stimulation in AD patients to support a regulatory filing with the FDA.

MRI CHANGES FOLLOWING TREATMENT OF GLP‐1 ANALOGUE, LIRAGLUTIDE IN ALZHEIMER’S DISEASE

AbstractBackgroundPreclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12‐month, multi‐centre, randomised, double‐blind, placebo‐controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK.MethodAs a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysisResultMRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide‐treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo.ConclusionIn the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP‐1 analogues in the treatment of Alzheimer’s disease

Relationship among cerebral Aβ burden, cognitive function and diabetes

AbstractBackgroundDiabetes mellitus (DM) increases the risk of brain atrophy and dementia. We aimed to reveal whether DM could affect cognitive function and the pattern of amyloid retention in cognitively impaired patients. Also we tried to show whether the existence of DM could cause subcortical structural abnormalities with cognitive dysfunction.MethodWe included consecutive 56 controls and 145 cognitively impaired people (CI, 50 MCI and 95 mild to moderate Alzheimer’s disease (AD) patients). All participants of this cross‐sectional study underwent blood tests, detailed neuropsychological evaluations, 3D T1‐weighted MRI at 3‐Tesla and 18F‐FBB‐PET. We estimated the cerebral Aβ burden quantitatively using volume‐of‐interest analysis and segmented the volumes of six subcortical structures, using FMRIBs integrated registration and segmentation tool Multiple linear regression analysis adjusted for age and gender was performed to evaluate the relationship among cerebral Aβ burden, cognitive function and diabetes.ResultAll subcortical structures, except for the globus pallidus, were smaller in CI compared with controls on adjusting for age and gender. CI with DM was associated with the lower volumes of caudate nucleus and putamen than CI without DM patients. Although there was no significant difference of MMSE score within two groups, the performance of frontal‐executive and memory functions was negatively correlated with subcortical structural volume loss in CI with DM. There was no difference between cerebral Aβ burden using composite SUVR and MMSE score in CI patients. However we found higher amyloid retention in CI with DM patients.ConclusionThe co‐morbidity of DM in AD patients might cause more specific subcortical volume loss beyond diffuse cerebral atrophy and the resultant cortical‐subcortical dysfunction could make cognitive dysfunction worse, especially frontal‐executive and memory functions. Also, CI with DM patients showed higher cerebral amyloid retention, which might be the accelerating factor of cognitive deterioration.

Effect of Internet‐based vs in‐person cognitive interventions on patients with mild to moderate Alzheimer’s disease: A randomized, cross‐over, open‐label trial

AbstractBackgroundWe aimed to investigate the effect of Internet‐based and in‐person cognitive interventions on cognition, mood, and activities of daily living (ADL) on patients with mild to moderate Alzheimer’s disease (AD) and examine whether Internet‐based intervention is as effective as the in‐person intervention.MethodWe recruited 52 patients with probable mild AD, of whom 42 completed the trial. We randomly divided participants into intervention and control groups at a 1:1 ratio and statistically compared the neuropsychological test results of the two groups. In addition, patients in the intervention group were randomly assigned to a four‐week Internet‐based or in‐person intervention, with subsequent crossover to the other group for four weeks. We statistically analyzed and compared the neuropsychological test scores between Internet‐based and in‐person interventions.ResultCompared with the control group, the intervention group (Internet‐based and in‐person) showed significantly improved profile in cognition (P<0.001), depression (P<0.001), anxiety (P<0.001) and ADL (P<0.001). In addition, the effect of the Internet‐based intervention on cognition (P = 0.918) and depression (P = 0.282) was not significantly different from that of the in‐person intervention. However, in the Beck Anxiety Inventory (P = 0.009) and Seoul Instrumental Activity of Daily Living (P = 0.023), in‐person intervention was more effective than Internet‐based intervention.ConclusionThis study suggests that both types of cognitive intervention (in‐person and Internet‐based) may be viable supplementary treatments along with approved pharmacological therapy. In terms of cognition and depression, the effect of Internet‐based interventions may not be significantly different from that of in‐person interventions.

The effect of structured education and phone follow-up on moderate stage Alzheimer's disease caregiving: Outcomes for patient and caregivers.

To determine the effectiveness of a caregiver education (needs tailored) and telephone follow-up intervention for caregivers of people with moderate stage Alzheimer's disease on caregiver burden, caregiving impact on life, and patients' neuropsychiatric symptoms, dependence on activities of daily living. This quasi-experimental study sampled caregivers of people with moderate stage Alzheimer's. Caregivers in the intervention group received education and telephone follow-up over 12 weeks, while the control group received routine care. Caregivers were assessed for burden, changes in life, and patients for neuropsychiatric symptoms, and dependence on daily living activities. The caregiver burden, life changes, distress, and patients' neuropsychiatric symptom scores showed apparent trend toward betterment, but no statistically significant differences were found in study outcomes between the two groups (P > .05). The caregiver need-based, structured education and telephone follow-up intervention was not empirically effective. With the promising effect from this study, managing behavioral symptoms with need-based, structured, and skill-oriented training has the potential to alleviate the burden on caregivers.

A Comparative Analysis on Alzheimer’s Medication

Alzheimer's disease (AD) is a neurodegenerative disorder in which brain cells, or neurons, slowly degenerate and die resulting in a gradual cognitive decline. AD does not have a known cure; this requires effective strategies to manage symptoms and slow its progression of this disease. This review paper delves into treatments, for Alzheimers disease (AD) such as cholinesterase inhibitors, NMDA antagonists and immunotherapies. The focus will be on exploring their effectiveness in early and mild to AD cases well as examining any potential side effects. This paper highlights the importance of treatment plans that take into account the nature of AD and emphasizes the significance of addressing both the underlying pathology and symptoms. After conducting an analysis on clinical trials, the conclusion is that cholinesterase inhibitor therapy stands out as the approach, for managing mild to moderate AD based on comprehensive clinical trial results and a comparative analysis.

Effect of Personalized Blue-Enriched White Light Intervention on Rest-Activity and Light Exposure Rhythms in Mild and Moderate Alzheimer's Disease.

We aimed to examine the effectiveness of personalized light intervention using a blue-enriched light-emitting-diodes device on rest-activity rhythm (RAR) and light exposure rhythm (LER) in patients with mild and moderate Alzheimer's disease (AD). AD patients with poor sleep quality and/or insomnia symptoms were assigned into either an experimental group (EG) or control group (CG) in a single-blind design. Personalized light intervention was given at 9-10 h after individual dim light melatonin onset, lasting for 1 h every day for two weeks in the EG (77.36±5.79 years, n=14) and CG (78.10±7.98 years, n=10). Each patient of CG wore blue-attenuating sunglasses during the intervention. Actigraphy recording at home for 5 days was done at baseline (T0), immediate postintervention (T1), and at four weeks after intervention (T2). The variables of RAR and LER were derived using nonparametric analysis. We found a significant time effect on the intradaily variability (IV) of RAR at T2 with respect to T0 (p=0.039), indicating reduced IV of RAR at four weeks after personalized light intervention regardless of blue-enriched light intervention. There was a time effect on the IV of LER at T1 with respect to T0 (p=0.052), indicating a reduced tendency in the IV of LER immediately after intervention. Our personalized light intervention, regardless of blue-enriched light source, could be useful in alleviating fragmentation of RAR and LER in AD patients.

Relationship Between Non-Cognitive Intrinsic Capacity and Activities of Daily Living According to Alzheimer's Disease Stage.

Few studies have examined the relationship between non-cognitive factors and activities of daily living (ADL) according to Alzheimer's disease (AD) stage. We aimed to identify the differences in non-cognitive factors according to AD stages and their involvement in basic and instrumental ADL performance by using intrinsic capacity (IC) in groups with cognition ranging from normal to moderate or severe AD. We enrolled 6397 patients aged≥65 years who visited our memory clinic. Non-cognitive IC was assessed using the locomotion, sensory, vitality, and psychological domains. Multiple logistic regression was performed to identify how non-cognitive IC declines over the AD course and examine the correlation between non-cognitive IC and basic and instrumental ADL performance. Non-cognitive IC declined from the initial AD stage and was significantly correlated with both basic and instrumental ADL performance from the aMCI stage through all AD stages. In particular, the relationship between IC and basic ADL was stronger in mild and moderate to severe AD than in the aMCI stage. On the other hand, the relationship between IC and instrumental ADL was stronger in aMCI than in later AD stages. The results show non-cognitive factors, which decline from the aMCI stage, are correlated with ADL performance from the aMCI stage to almost all AD stages. Considering that the relationship strength varied by ADL type and AD stage, an approach tailored to ADL type and AD stage targeting multiple risk factors is likely needed for effectively preventing ADL performance declines.

Cost of Patients with Alzheimer's Disease in Spain According to Disease Severity.

Alzheimer's disease (AD) has been associated with great healthcare and non-healthcare resource consumption. The aim of this study was to estimate the burden of AD in Spain according to disease severity from a societal perspective. A self-administered questionnaire was designed by the researchers and completed by the informal caregivers of patients with AD, reporting data on themselves as caregivers and on the AD patients for whom they care. The patients' sociodemographic and clinical data, their healthcare and non-healthcare resource consumption in the previous 12 months, and the impact of the disease on labor productivity were compiled. Data collected on informal caregivers included sociodemographic data and the impact of caring for a person with AD on their quality of life and labor productivity. Costs were estimated by multiplying the number of consumed resources by their unit prices. The cost of informal care was assessed using the proxy good method, and labor productivity losses were estimated using the human capital method. Costs were estimated by disease severity and are presented per patient per year in 2021 euros (€). The study sample comprised 171 patients with AD aged 79.1 ± 7.4 years; 68.8% were female, time from diagnosis was 5.8 ± 4.1 years, diagnosis delay was 1.8 ± 2.3 years, and the mean Cumulative Illness Rating Scale-Geriatric (CIRS-G) total was score 8.2 ± 6.0. According to disease severity, 14% had mild cognitive impairment or mild AD, 43.9% moderate AD, and 42.1% severe AD. The average annual cost per patient was €42,336.4 in the most conservative scenario. The greatest proportion of this cost was attributed to direct non-healthcare costs (86%, €36,364.8), followed by direct healthcare costs (8.6%, €3647.1), social care costs (4.6%, €1957.1), and labor productivity losses (less than 1%, €367.4). Informal care was the highest cost item, representing 80% of direct non-healthcare costs and 69% of the total cost. The total direct non-healthcare cost and total cost were significantly higher in moderate to severe disease severities, compared to milder disease severity. AD poses a substantial burden on informal caregivers, the national healthcare system, and society at large. Early diagnosis and treatment to prevent disease progression could reduce this economic impact.

Potential cardioprotective effects of acetylcholinesterase inhibitors in patients with Alzheimer's disease

Abstract Background In patients with mild to moderate Alzheimer's disease (AD), acetylcholinesterase inhibitors (AChE-I) are commonly employed to improve cognitive function. They increase the amount of acetylcholine (ACh) in the neuronal synapses, but bradycardia, cardiac electrical conduction blocks and hypotension due to muscarinic M2 receptor stimulation are potential side effects. However, whether these "side effects" could play a potential protective effect on cardiovascular (CV) events is not yet well defined. Purpuses To evaluate potential beneficial cardiac effects of AChE-Is in patients with AD, in terms of reduction of major adverse cardiovascular events (MACEs). Methods We conducted a retrospective, monocentric, observational cohort study in patients referred to our hospital. Two groups were considered: the interventional group included AD patients treated with AChE-I. The control group enrolled a cohort of subjects matched for age and comorbidities, recruited between caregivers of intervention group subjects that were cognitively unimpaired and not taking AchE-I. The primary endpoint was a composite of hospitalization for heart failure (HF), non-fatal acute myocardial infarction (AMI), myocardial revascularization, hospitalization for cardiovascular (CV) causes, cardiovascular mortality and occurrence of stroke and/or TIA during total 5 year follow-up period (MACEs). Secondary endpoints were each individual component of the primary end point, total deaths, non-cardiovascular death and incidence of pacemaker implant. Results 221 AD patients treated with AChE-I (91 with Donepezil, 130 with Rivastigmine) were included in intervention group and 221 non-AD patients in control group. Groups were homogeneous in terms of age, gender and main cardiovascular risk factors, except for family history of cardiovascular diseases (CVD), which was more frequent in control group. During a median follow-up of 3.1 years the primary endpoint occurred in 24 patients in intervention group (2.1 per 100 patient-years) compared to 56 patients in the control group (5.0 per 100 patient-years). Therefore, AChE-I therapy resulted a protective factor from primary endpoint (HR 0.48, 95% CI 0.24-0.95; p= 0.036). Even not significant, the difference was mainly driven by myocardial revascularization (3.2% in intervention group vs 6.8% in controls) and hospitalization for heart failure (4.5% in intervention group vs 14.5% in controls). Non-CVD mortality was significantly higher in treatment group (13,6% in intervention group vs 2,7% in controls). No significant difference was observed between groups in terms of other secondary outcomes. Conclusions Among patients with AD, use of AChE-I may be protective for CV outcomes, especially reducing HF hospitalisation and myocardial revascularization.Kaplan-Meier of cumulative MACEsNumber of Event/Years

Development and Psychometric Validation of the 27 Item Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD-27).

Caring for an individual with Alzheimer's disease (AD) is an allencompassing challenge that affects daily life. Assessment of the care partner experience is needed to support the development and evaluation of successful interventions for people with AD and their care partners. We developed the 27-item Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD-27) to assess the impact of informal caregiving in the context of AD. We assessed the psychometric validity of the ZCI-AD-27 in a population of care partners for individuals with moderate AD, and established thresholds for meaningful score change. Secondary data were obtained from informal care partners of participants in a clinical trial (NCT01677754). Psychometric analyses were conducted to assess validity, reliability, and responsiveness of the ZCI-AD-27. Anchor-based and distribution-based methods were performed to determine clinically meaningful score change. The ZCI-AD-27 had a 12-domain factor structure, including a second-order domain termed Humanistic impact that included four key domains (Physical, Emotional, Social, and Daily life) as confirmed by confirmatory factor analysis with the adequate fit. Internal consistency (Cronbach's alpha ranging from 0.66 to 0.93 for domains), convergent validity, and discriminant validity indicated the good performance of the ZCI-AD-27. Known-groups validity analyses showed a greater impact on care partners with increasing disease severity. Responsiveness results demonstrated that the ZCI-AD- 27 is sensitive to change over time and meaningful change analyses indicated a range of meaningful score changes in this population. The ZCI-AD-27 is a comprehensive, psychometrically valid measure to assess the impact of caring for individuals with moderate AD.

Drug Repositioning of Pioglitazone in Management and Improving the Cognitive Function among the Patients With Mild to Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Disease-modifying agents like Pioglitazone have shown promising effects on neuroinflammation and homeostasis of amyloid plaques, but there is a lack of research papers providing conclusive evidence. This study is aimed to determine the safety and efficacy of Pioglitazone in improving cognitive function in patients with mild-moderate Alzheimer's disease (AD). Trials published in the last 12 years were identified from PubMed, Scopus, Cochrane Central, and other trial registries. Five hundred twenty-five records were obtained, from which five studies were included for quantitative analysis. Studies comparing Pioglitazone with a suitable placebo or other oral hypoglycemic agent were considered for review. Data was extracted using a pretested form, which was followed by a risk of bias assessment (ROB) with Cochrane's ROB assessment tool. This meta-analysis included studies where Pioglitazone (15-30 mg) was compared to other oral hypoglycemic agents, placebo, or diabetic diet for a minimum duration of 6 months. Pioglitazone did not show a statistically significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores [mean difference (MD): -1.16; 95% confidence interval (CI): -4.14-1.81]. By conducting sensitivity analysis with the removal of one study, significant efficacy was obtained [MD: -2.75; 95% CI: -4.84--0.66]. The Wechsler Memory Scale-Revised logical memory I (WMS-R) scores had a significant improvement in the Pioglitazone group [MD: 2.02; 95% CI: 0.09-3.95]. Pioglitazone is a safe medication that has a promising effect in slowing the advancement of AD.

Inter-Hospital Advanced and Mild Alzheimer's Disease Classification Based on Electroencephalogram Measurements via Classical Machine Learning Algorithms.

In pursuit of diagnostic tools capable of targeting distinct stages of Alzheimer's disease (AD), this study explores the potential of electroencephalography (EEG) combined with machine learning (ML) algorithms to identify patients with mild or moderate AD (ADM) and advanced AD (ADA). This study aims to assess the classification accuracy of six classical ML algorithms using a dataset of 668 patients from multiple hospitals. The dataset comprised measurements obtained from 668 patients, distributed among control, ADM, and ADA groups, collected from five distinct hospitals between 2011 and 2022. For classification purposes, six classical ML algorithms were employed: support vector machine, Bayesian linear discriminant analysis, decision tree, Gaussian Naïve Bayes, K-nearest neighbor and random forest. The RF algorithm exhibited outstanding performance, achieving a remarkable balanced accuracy of 93.55% for ADA classification and 93.25% for ADM classification. The consistent reliability in distinguishing ADA and ADM patients underscores the potential of the EEG-based approach for AD diagnosis. By leveraging a dataset sourced from multiple hospitals and encompassing a substantial patient cohort, coupled with the straightforwardness of the implemented models, it is feasible to attain notably robust results in AD classification.

Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: a phase I/II clinical trial

BackgroundThere have been no effective treatments for slowing or reversing Alzheimer’s disease (AD) until now. Growing preclinical evidence, including this study, suggests that mesenchymal stem cells-secreted exosomes (MSCs-Exos) have the...

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on global cognitive function of elderly in mild to moderate Alzheimer's disease: a systematic review and meta-analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a non-invasive brain stimulation technique used to improve cognitive deficits in patients with Alzheimer's disease (AD). This systematic review and meta-analysis aimed to evaluate the efficacy of HF-rTMS in improving global cognitive function rehabilitation in elderly patients with mild to moderate AD. A detailed literature search of publications using ten databases (Chinese: Wanfang, VIP Periodical, SinoMed, the Chinese National Knowledge Infrastructure; English: PubMed, Embase, OVID, Web of Science, Cochrane Library, and EBSCOhost) was performed to identify English and Chinese language articles published up to December 2022. We only included randomized controlled trials (RCTs) that evaluate the effect of HF-rTMS on elderly patients with mild to moderate AD. The retrieved studies were carefully reviewed, extracted data, and assessed quality. Seventeen studies, including 1161 elderly patients with mild to moderate AD, were included in this meta-analysis. Compared to the control group, HF-rTMS could increase MMSE (mean difference [MD] = 3.64; 95%CI 1.86-5.42; P < 0.0001), MoCA (MD = 3.69; 95%CI 1.84-5.54; P < 0.0001), P300 amplitude (MD = 1.09; 95%CI 0.45-1.72; P = 0.0008), and total effective rate scores (MD = 3.64; 95% CI 2.14-6.18; P < 0.00001) while decreasing ADAS-Cog (MD = - 3.53; 95%CI - 4.91- - 2.15; P < 0.00001) and P300 latency scores (MD = - 38.32; 95%CI - 72.40- - 4.24; P = 0.03). Our study showed that HF-rTMS could improve the global cognitive function of elderly patients with mild to moderate AD. HF-rTMS can improve global cognitive function in elderly patients with mild to moderate AD, which is an effective and safe rehabilitation treatment tool for AD patients.

Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.