Disease Assessment Scale-Cognitive Subscale Research Articles

Therapeutic Inhalation of Hydrogen Gas for Alzheimer's Disease Patients and Subsequent Long-Term Follow-Up as a Disease-Modifying Treatment: An Open Label Pilot Study.

(1) Background: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (-4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.

Cognitive and behavioral abnormalities in individuals with Alzheimer’s disease, mild cognitive impairment, and subjective memory complaints

AbstractIn this study, we investigated the ability of commonly used neuropsychological tests to detect cognitive and functional decline across the Alzheimer’s disease (AD) continuum. Moreover, as preclinical AD is a key area of investigation, we focused on the ability of neuropsychological tests to distinguish the early stages of the disease, such as individuals with Subjective Memory Complaints (SMC). This study included 595 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset who were cognitively normal (CN), SMC, mild cognitive impairment (MCI; early or late stage), or AD. Our cognitive measures included the Rey Auditory Verbal Learning Test (RAVLT), the Everyday Cognition Questionnaire (ECog), the Functional Abilities Questionnaire (FAQ), the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), the Montreal Cognitive Assessment scale (MoCA), and the Trail Making test (TMT-B). Overall, our results indicated that the ADAS-13, RAVLT (learning), FAQ, ECog, and MoCA were all predictive of the AD progression continuum. However, TMT-B and the RAVLT (immediate and forgetting) were not significant predictors of the AD continuum. Indeed, contrary to our expectations ECog self-report (partner and patient) were the two strongest predictors in the model to detect the progression from CN to AD. Accordingly, we suggest using the ECog (both versions), RAVLT (learning), ADAS-13, and the MoCA to screen all stages of the AD continuum. In conclusion, we infer that these tests could help clinicians effectively detect the early stages of the disease (e.g., SMC) and distinguish the different stages of AD.

Plasma tau and neurofilament light chain as biomarkers of Alzheimer's disease and their relation to cognitive functions.

Alzheimer's disease (AD) dementia is the most frequent cause of neurodegenerative dementia. The cognitive and behavioral symptoms associated with this disorder often have overlapping characteristics, potentially resulting in delayed diagnosis or misdiagnosis. This study aimed to assess the level of peripheral blood neurofilament light chain (NfL) and total tau (t-tau) protein in AD patients and investigate their relationship with cognitive impairment. The study included 80 participants of both sexes between the ages of 60 to 85 years. The participants were divided into two groups, consisting of 40 individuals in the control group (mean age 75±6.6 years) who had no cognitive or functional impairments and 40 AD patients (mean age 74.98±5.03 years). This study utilized the DSM-5 diagnostic criteria for major or mild neurocognitive disorder attributed to Alzheimer's disease (AD). The clinical and biochemical features of all participants were documented, and the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-cog) scores were evaluated. Sandwich ELISA was employed to determine serum NfL and t-tau protein levels. The median serum NfL and t-tau protein levels in AD patients were significantly higher than those of the controls (47.84 pg/ml versus 17.66 pg/ml and 12.05 pg/ml versus 11.13 pg/ml, respectively). Age was positively correlated with NfL, t-tau levels, and ADAS-cog. Although elevated NfL and t-tau protein levels may play a role in disease progression, their diagnostic value for AD was limited.

Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer’s dementia: a randomized controlled trial

BackgroundThis phase II proof-of-concept study assessed the efficacy and safety of BI 425809, a novel selective glycine transporter-1 inhibitor, for the treatment of cognitive impairment associated with probable Alzheimer’s disease dementia.MethodsThis 12-week, multicenter, double-blind, placebo-controlled, parallel-group study randomized (1:1:1:1:1) patients with mild-to-moderate probable Alzheimer’s disease dementia to BI 425809 2, 5, 10, and 25 mg or placebo once daily. The primary efficacy endpoint was the change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11-item total score after 12 weeks of treatment. Safety was also assessed.ResultsSix hundred and ten male and female patients were randomized to BI 425809 2 mg (n = 123), 5 mg (n = 122), 10 mg (n = 122), and 25 mg (n = 123) or placebo (n = 120). Approximately 47% (n = 286) were male; the mean (standard deviation) age was 72.9 (7.7) years. Treatment compliance was above 97% for all dose groups. The Mini-Mental State Examination category on the median score was < 22 in 47% (n = 287) of patients and ≥ 22 in 53% (n = 322) of patients. No significant, non-flat dose–response relationship was detected for the primary endpoint (adjusted p-value > 0.76 for all models). BI 425809 was generally well-tolerated. Overall, 47.9% (n = 292) of patients reported at least one adverse event during the trial; the frequency of patients with investigator-defined drug-related adverse events was similar in all treatment groups, ranging from 15.4 to 19.5% across the BI 425809 treatment groups and 15.8% for placebo.ConclusionsNo clinically meaningful changes from baseline were observed following treatment with BI 425809 in patients with mild-to-moderate probable Alzheimer’s disease dementia.Trial registrationClinicalTrials.gov NCT02788513 (1346-0023). Registered on June 2, 2016. EU Clinical Trials Register 2015-005438-24. Registered on May 6, 2016

State, trait, and accumulated features of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) in mild Alzheimer's disease.

The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). A latent state-trait model with autoregressive effects was used to determine how much of the ADAS-Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS-Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion-specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Although the ADAS-Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion-specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS-Cog item measures. Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS-Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state-trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion-specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually.

A Single-Blind Randomized Control Trial on the Effectiveness of Adjunct Cognitive Stimulation Therapy on Cognitive Outcomes in Dementia.

Dementia is characterized by neurocognitive decline which interferes with daily function and independence. Cognitive stimulation therapy (CST) is an evidence-based cognitive psychosocial intervention for people with dementia. A prospective interventional study of single-blind RCT design conducted in the Department of Neurology at ABVIMS and Dr RML Hospital amongst patients with DSM-V major neurocognitive disorder aged more than 50 years. Participants were randomized to CST and control groups using a block-randomized design. The control group participants received treatment as usual while the CST group delivered 45-min virtual group CST sessions for a total of 14 sessions over seven weeks. All participants in both groups were assessed at baseline and eight weeks using the Montreal Cognitive Assessment Scale (MoCA), Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), neuropsychiatric inventory, instrumental activities of daily living, and Zarit Burden Interview for Caregiver Burden (ZBI) by a rater blind to group randomization. Total MoCA scores improved significantly in the CST group, compared to the control group which showed a statistically significant decrease. The mean total ADAS-Cog score in the CST group improved significantly compared to controls. The Lawton Instrumental Activities of Daily Living Scale showed a statistically significant change in the control group compared to the intervention group. From the comparison of the mean total neuropsychiatric inventory scale, it was observed that there was a statistically significant decrease in the severity of Behavioural and Psychological Symptoms of Dementia (BPSD) symptoms in the CST group. The mean total ZBI score decreased significantly in the CST group favoring less caregiver burden. This study proved that CST has a significant impact on cognitive outcomes in dementia and it also proved its effectiveness in controlling the BPSD outcomes and caregiver burden in dementia.

Explainable Tensor Multi-Task Ensemble Learning Based on Brain Structure Variation for Alzheimer’s Disease Dynamic Prediction

Machine learning approaches for predicting Alzheimer's disease (AD) progression can substantially assist researchers and clinicians in developing effective AD preventive and treatment strategies. This study proposes a novel machine learning algorithm to predict the AD progression utilising a multi-task ensemble learning approach. Specifically, we present a novel tensor multi-task learning (MTL) algorithm based on similarity measurement of spatio-temporal variability of brain biomarkers to model AD progression. In this model, the prediction of each patient sample in the tensor is set as one task, where all tasks share a set of latent factors obtained through tensor decomposition. Furthermore, as subjects have continuous records of brain biomarker testing, the model is extended to ensemble the subjects' temporally continuous prediction results utilising a gradient boosting kernel to find more accurate predictions. We have conducted extensive experiments utilising data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to evaluate the performance of the proposed algorithm and model. Results demonstrate that the proposed model have superior accuracy and stability in predicting AD progression compared to benchmarks and state-of-the-art multi-task regression methods in terms of the Mini Mental State Examination (MMSE) questionnaire and The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) cognitive scores. Brain biomarker correlation information can be utilised to identify variations in individual brain structures and the model can be utilised to effectively predict the progression of AD with magnetic resonance imaging (MRI) data and cognitive scores of AD patients at different stages.

Associations of MRI-visible perivascular spaces with longitudinal cognitive decline across the Alzheimer’s disease spectrum

ObjectiveTo investigate the characteristics and associations of MRI-visible perivascular spaces (PVS) with clinical progression and longitudinal cognitive decline across the Alzheimer’s disease spectrum.MethodsWe included 1429 participants (641 [44.86%] female) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. PVS number and grade in the centrum semiovale (CSO-PVS), basal ganglia (BG-PVS), and hippocampus (HP-PVS) were compared among the control (CN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups. PVS were tested as predictors of diagnostic progression (i.e., CN to MCI/AD or MCI to AD) and longitudinal changes in the 13-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 13), Mini-Mental State Examination (MMSE), memory (ADNI-MEM), and executive function (ADNI-EF) using multiple linear regression, linear mixed-effects, and Cox proportional hazards modeling.ResultsCompared with CN subjects, MCI and AD subjects had more CSO-PVS, both in number (p < 0.001) and grade (p < 0.001). However, there was no significant difference in BG-PVS and HP-PVS across the AD spectrum (p > 0.05). Individuals with moderate and frequent/severe CSO-PVS had a higher diagnostic conversion risk than individuals with no/mild CSO-PVS (log-rank p < 0.001 for all) in the combined CN and MCI group. Further Cox regression analyses revealed that moderate and frequent/severe CSO-PVS were associated with a higher risk of diagnostic conversion (HR = 2.007, 95% CI = 1.382–2.914, p < 0.001; HR = 2.676, 95% CI = 1.830–3.911, p < 0.001, respectively). A higher CSO-PVS number was associated with baseline cognitive performance and longitudinal cognitive decline in all cognitive tests (p < 0.05 for all).ConclusionsCSO-PVS were more common in MCI and AD and were associated with cognitive decline across the AD spectrum.

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

High tau PET binding reveals a constellation of beta‐amyloid positivity and fast cognitive decline

AbstractBackgroundBeta‐amyloid Positron Emission Tomography (PET) efficiently detects beta‐amyloid plaques supporting the presence of a pathophysiological landmark of Alzheimer’s disease (AD) continuum, but lacks specificity regarding the prediction of future cognitive status. The increasing validation of tau PET tracers raises questions about whether a tau PET biomarker could predict clinically relevant cognitive decline and its potentially beneficial role in the assessment of individuals who belong to the AD continuum.MethodWe identified 335 subjects [cognitive normal (CN; n=217), mild cognitive impairment (MCI; n=99), dementia (n=19)] with baseline beta‐amyloid and tau PET scans that have completed a follow‐up of at least two years, from the Alzheimer’s Disease Neuroimaging Initiative dataset. First, we assessed the accuracy of tau PET to discriminate the MCI patients that will convert to AD. Based on Alzheimer’s Disease Assessment Scale–Cognitive Subscale, we used linear mixed‐effects models to define the annual rate of cognitive change of all individuals and Gaussian mixture modelling to cluster them as either fast or slow decliners. Next, group comparisons and the accuracy of tau PET to discriminate between them were tested. Finally, the association between baseline tau PET SUVR and cognitive rate of change was assessed with linear modelsResultThe individuals with beta‐amyloid positivity and fast cognitive decline showed the highest tau PET binding values independently of baseline cognitive status, compared to the other groups (beta‐amyloid negative with fast or slow decline and beta‐amyloid positive with slow decline). Baseline tau PET binding could determine fast decliners with a beta‐amyloid positive scan with an accuracy of 85% (composite temporal region of interest). Similarly, tau PET binding accuracy was high in determining MCI patients that would be both beta‐amyloid positive and show progress in their diagnosis. Linear models showed that baseline tau PET binding is related to the annual rate of cognitive decline in beta‐amyloid positive individuals.ConclusionHigh baseline tau load is coupled with both beta‐amyloid pathology and an accelerated profile of cognitive decline. Tau PET imaging could offer substantial advantages over beta‐amyloid PET imaging since it provides important information about both the underlying pathophysiology and the prognosis of the disease.

Comparison of Plasma‐based Biomarkers and Cognitive Assessments in predicting progression of MCI to Dementia

AbstractBackgroundWe evaluated the predictive value of phospho‐tau181 (ptau181) and neurofilament light (NfL) in predicting disease progression from amnestic mild cognitive impairment stage (aMCI) to Dementia in models including demographic data and neuropsychological test results.MethodParticipants were 248 Cognitively Normal (CN), 325 MCI, and 91 individuals with dementia due to AD confirmed with amyloid PET from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had at least one follow‐up visit, and measures of plasma biomarkers (ptau181 and NfL) were included. We examined the separate and joint predictive value of baseline plasma biomarkers and neuropsychological tests (RAVLT: Rey Auditory Verbal Learning Test; ADAS‐Cog: Alzheimer’s Disease Assessment Scale–Cognitive Subscale; TRA‐B: Trail Making Test – Part B; FAQ: Functional Activity Questionnaire) in estimating disease progression from MCI to Dementia. Random Forests machine learning models were used for the classification. Data from CN and AD participants were used for training the models and trained models were used in MCI group to identify those more likely to progress to Dementia. Predictive performances of these models were assessed using longitudinal outcomes at 2 years.ResultParticipants were on average 71.9 yr. old (SD=6.9) and 49.6% female (Table 1). Addition of plasma biomarkers to the model with demographics and APOE4 (base model) improved predictive performance of models in prediction of conversion from MCI to dementia at 2 years (Sensitivity=53.7%, Specificity=81.5%, AUC=0.68). Models that included cognitive tests in addition to the measures in the base model had higher performance in comparison with that only included biomarkers (Sensitivity=55.6%, Specificity=91.5%, AUC=0.74). Best predictive performance was achieved when cognitive scores and plasma biomarkers were both included in the models (Sensitivity=63.0%, Specificity=91.5%, AUC=0.77, Table 2). In the MCI‐subgroup who were amyloid positive (Aβ+) at baseline, similar pattern of results was observed (Table 3).ConclusionIn persons with MCI, plasma biomarkers of ptau181and NFL can improve our ability to predict disease progression. Concurrent use of plasma biomarkers and cognitive scores improve this predictive ability. This work needs to be extended to various samples and a broader set of plasma biomarkers and neuropsychological tests.

The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer’s Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

BackgroundScreening procedures for early Alzheimer’s disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain.ObjectivesCross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and β-amyloid (Aβ) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD.DesignSecondary analyses of cross-sectional and longitudinal clinical trial data.SettingMulti-center international clinical trials.ParticipantsIndividuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aβ positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331).MeasurementsCross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aβ positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL).ResultsLower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aβ positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel).ConclusionsCutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aβ positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.

Plasma adiponectin levels predict cognitive decline and cortical thinning in mild cognitive impairment with beta-amyloid pathology

BackgroundBlood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer’s disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aβ) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aβ on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aβ conditions (Aβ [+] and Aβ [−]) in individuals with mild cognitive impairment (MCI).MethodsOf 156 participants with MCI from the longitudinal cohort study of Alzheimer’s Disease Neuroimaging Initiative (ADNI), 31 were Aβ (−) and 125 were Aβ (+) as determined by CSF analysis. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aβ conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined.ResultsOf the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aβ (+) and (−) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aβ (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aβ (+) condition (beta = − 0.004, p = 0.012 for the right side; beta = − 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aβ (−) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aβ status.ConclusionPlasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aβ (+) MCI.

Sex differences in Alzheimer’s disease: plasma MMP-9 and markers of disease severity

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women’s elevated susceptibility to AD.

The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning.

Accumulating evidence suggests that α-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether α-synuclein level in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also explored whether this relationship was mediated by proinflammatory cytokines TNF-α and IL-6, along with sIL-6R and vascular endothelial growth factor (VEGF). Using a cross-sectional Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 148) sample, we examined the relationship between α-synuclein and participants' performance on Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 13) at baseline. Mediation analyses were utilized, adjusting for age, education, APOEe4, and Geriatric Depression Scale scores. All biological markers were measured in CSF. Participants in the current sample were 58.3% males, 41.7% females, and Caucasian (95.5%); their average education and age were 15.5 (standard deviation [SD] = 2.97) and 74.4 (SD = 7.51) years, respectively. Higher accumulation of α-synuclein was associated with poorer MMSE scores (β = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (β = 0.27, SE = 2.15, p = .025) and IL-6r (β = 0.22, SE = 1.66, p < .026). In addition, α-synuclein was associated with poorer performance on the ADAS-Cog 13 (β = 0.34, p = .005) and mediated by VEGF (β = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. α-Synuclein may serve as an additional biomarker for determining poor cognitive functioning. VEGF and IL-6 soluble receptors were significant mediators of the relationship between α-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.

Cross-sectional association of metrics derived from continuous glucose monitoring with cognitive performance in older adults with type 2 diabetes.

To examine the association between continuous glucose monitoring (CGM)-derived metrics and cognitive performance in older adults with type 2 diabetes (T2D). A total of 100 outpatients with T2D aged 70 years or older were analysed. Participants underwent CGM for 14 days. As CGM-derived metrics, mean sensor glucose (SG), glucose coefficient of variation (CV), time in range (TIR; 70-180 mg/dl), time above range (TAR; > 180 mg/dl) and time below range (TBR; < 70 mg/dl), were calculated. Participants underwent cognitive tests, including the Japanese version of the Montreal Cognitive Assessment (MoCA-J), a delayed word-recall test from the Alzheimer's Disease Assessment Scale-cognitive subscale, a digit symbol substitution test, a letter word fluency test, a trail-making test (TMT) and digit span test (DSP). In multiple regression analyses adjusted for confounders, a higher mean SG was associated with a lower performance in MoCA-J and TMT part B (TMT-B) (P < .05). A higher TAR was associated with a lower performance in TMT-B and DSP-backward (P < .05). By contrast, a higher TIR was associated with better function in TMT-B and DSP-backward (P < .05). Furthermore, CV and TBR were not associated with any cognitive function. Hyperglycaemia metrics and TIR derived from CGM are associated with cognitive functions, especially with executive function and working memory, in older adults with T2D.

Abnormal regional homogeneity in right caudate as a potential neuroimaging biomarker for mild cognitive impairment: A resting-state fMRI study and support vector machine analysis.

ObjectiveMild cognitive impairment (MCI) is a heterogeneous syndrome characterized by cognitive impairment on neurocognitive tests but accompanied by relatively intact daily activities. Due to high variation and no objective methods for diagnosing and treating MCI, guidance on neuroimaging is needed. The study has explored the neuroimaging biomarkers using the support vector machine (SVM) method to predict MCI.MethodsIn total, 53 patients with MCI and 68 healthy controls were involved in scanning resting-state functional magnetic resonance imaging (rs-fMRI). Neurocognitive testing and Structured Clinical Interview, such as Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) test, Activity of Daily Living (ADL) Scale, Hachinski Ischemic Score (HIS), Clinical Dementia Rating (CDR), Montreal Cognitive Assessment (MoCA), and Hamilton Rating Scale for Depression (HRSD), were utilized to assess participants' cognitive state. Neuroimaging data were analyzed with the regional homogeneity (ReHo) and SVM methods.ResultsCompared with healthy comparisons (HCs), ReHo of patients with MCI was decreased in the right caudate. In addition, the SVM classification achieved an overall accuracy of 68.6%, sensitivity of 62.26%, and specificity of 58.82%.ConclusionThe results suggest that abnormal neural activity in the right cerebrum may play a vital role in the pathophysiological process of MCI. Moreover, the ReHo in the right caudate may serve as a neuroimaging biomarker for MCI, which can provide objective guidance on diagnosing and managing MCI in the future.

Efficacy and safety of 3-n-butylphthalide for the treatment of cognitive impairment: A systematic review and meta-analysis.

BackgroundCurrent evidence for the efficacy of pharmacological treatment in improving cognitive function is absent. Recent studies have reported that 3‐n‐butylphthalide (NBP) has a positive effect on improving cognitive impairment; however, its clinical efficacy and safety is unclear. Therefore, we conducted a meta‐analysis to assess its efficacy and safety for cognitive impairment.MethodsWe systematically searched the PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases, and two reviewers independently screened and extracted the data from included studies. We synthesized the data using the Review Manager Software version 5.3.ResultsWe included six randomized clinical trials (RCTs), encompassing 851 patients with cognitive impairment. The results showed that NBP improved cognitive impairment. Specifically, the clinical efficacy was better than that in the control group, with better performance in improving the Mini‐Mental State Examination and the Montreal Cognitive Assessment scores, while decreasing the Alzheimer's Disease Assessment Scale‐Cognitive subscale and the Clinician's Interview‐Based Impression of Change plus caregiver input scores. There was no significant difference in the incidence of adverse events between both groups.ConclusionThe NBP is effective and safe in improving cognitive impairment; however, more high‐quality RCTs are needed to confirm these findings.

Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: An instrumental variable meta-analysis.

Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline. Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD. A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.

Effects of magnesium valproate adjuvant therapy on patients with dementia: A systematic review and meta-analysis.

Background:Current research has found contradictory results on the treatment of magnesium valproate (VPM) in patients with dementia (PwD).Objectives:Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.Purpose:Current research has found contradictory results on the treatment of VPM in PwD. Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.Methods:MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI), and Wan Fang databases were researched to gather relevant data on magnesium valproate assistant therapy for patients with dementia (PwD) by using medical subject headings and term words.Results:After the final screening, 22 RCT studies (a total of 1899 participants) were included in this meta-analysis, which compared VPM adjuvant treatment with antidementia or psychotropic drug monotherapy. Significant differences were found in the scores on mini-mental state examination (P = .028), Alzheimer disease assessment scale cognitive subscale (P < .05), Bech-Rafaelsen Mania Rating Scale (P < .05), behavioral pathology in Alzheimer disease rating scale (P = .001), activities of daily living (P < .05), and Pittsburgh Sleep Quality Index (P < .05). Besides, the levels of inflammatory factors including IL-1β, IL-6, and TNF-α were significantly lower than those in the monotherapy group (P < .05). While there was no increase in the incidence of adverse events (P = .383), VPM as an assistant therapy is generally well tolerated in PwD.Conclusion:By meta-analysis, evidence was found to support VPM additional used for the treatment of cognitive function, psychiatric symptoms, or disease improvement in PwD. VPM may be a potential drug to aid in the treatment of dementia patients. However, there was lack of enough evidence to classification of dementia severity in our inclusion study. More research is still needed, including clinical trials evaluating VPM as a complementary therapy.