Functional Activities Questionnaire Scores Research Articles

Effects of Multicomponent Exercise on Community-Dwelling Older Adults With Mild Cognitive Impairment.

To explore the effects of a group-based multicomponent exercise program on general cognitive functioning, depression, and social functioning in community-dwelling older adults with mild cognitive impairment (MCI) and whether the effects can be maintained. Fifty older adults with MCI were conveniently recruited from two communities in the study area and randomly assigned to the intervention group or control group. The intervention group received three sessions of 60-minute, multicomponent exercise per week for 3 months, plus MCI-related health education. The control group only received MCI-related health education. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Beijing Version (MoCA-BJ) were used to assess general cognitive function. The Functional Activities Questionnaire (FAQ) and Geriatric Depression Scale (GDS-30) were used to evaluate participants' social function and depression, respectively. Participants' exercise intensity was assessed using the Category Ratio Scale. After the 3-month intervention, there were significant improvements in general cognitive function (p = 0.046), attention (p = 0.009), delayed recall (p = 0.015), and social function (p = 0.011) in the intervention group compared with the control group. However, after 3-month postintervention follow up, no significant differences in MMSE, MoCA-BJ, GDS-30, and FAQ scores were noted between groups. The 3-month multicomponent exercise program improved general cognitive function and social functioning in community-dwelling older adults with MCI. However, there was no evidence that these benefits lasted for another 3 months after stopping the exercise program. [Research in Gerontological Nursing, 17(2), 65-79.].

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-β load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-β+ mild cognitive impairment and 54 amyloid-β+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (β = 0.43, P = 0.03) and V-VI (β = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (β = 0.43, P = 0.02) and V-VI (β = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (β = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (β = 1.69, P < 0.0001), the Everyday Cognition (β = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (β = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

Comparing Symmetric Dimethylarginine and Amyloid-β42 as Predictors of Alzheimer's Disease Development.

Physicians may soon be able to diagnose Alzheimer's disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-β42 (Aβ42). Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and biomarker concentrations were obtained from the Alzheimer's Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Aβ42 (p = 0.65) and symmetric dimethylarginine (p = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aβ42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p < 0.05) that generally decreased in time. There were no significant associations between Aβ42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Correlations were smaller between Aβ42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found.

The Digital Clock Drawing Test and Delayed Recall Predict Informant‐Rated Functional Impairment in Individuals with Cognitive Impairment

AbstractBackgroundNearly 6.7 million people aged 65 and older in the US are living with Alzheimer’s disease (AD). Early detection of dementia presents a difficult challenge, as the earliest signs of cognitive decline often go undetected. Thus, more sensitive and clinically meaningful cognitive screening tools are needed. Evaluating the patient’s dependence in activities of daily living is critical to detect progression toward dementia. The Linus Health DCTclock™ employs AI‐enabled analyses of the clock drawing process to evaluate cognitive and motor function. We evaluated the utility of four DCTclock composite scales including Spatial Reasoning, Drawing Efficiency, Information Processing, and Motor Skills, 22 DCTclock subscales, and the 3‐word Delayed Recall score from the Digital Clock and Recall (DCR™) to predict the informant‐rated functional activities questionnaire (FAQ) score in older adults ranging from cognitively unimpaired to individuals with mild cognitive impairment (MCI) and AD‐related dementia (ADRD).Method939 participants in a multisite study (age mean±SD = 72.1±6.7; 57.1% female; years of education mean±SD = 15.4±2.7; primary language English), classified as cognitively unimpaired (n = 406), MCI (n = 293), or ADRD (n = 238) were included. We conducted cross‐validated regularized logistic regressions with FAQ score ≥6 or ≥9 (mild or moderate functional impairment, respectively) as dependent variable and DCTclock composite scales, subscales, and Delayed Recall score as predictors, in addition to age, sex, and education.ResultCombination of DCTclock subscales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.79 and 0.81, respectively. DCTclock composite scales predicted FAQ≥ 6 and ≥9 with AUCs = 0.75 and 0.77, respectively. Combination of DCTclock composite scales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively. DCTclock subscales by themselves predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively.ConclusionThe DCR, a brief digital cognitive assessment with automatic scoring that can be completed in primary‐care settings, can infer the effect of cognitive impairment on a patient’s functional activity with great accuracy and within a few minutes. This makes the DCR an empowering tool for primary‐care providers in practical evaluation of patients with cognitive impairment.

Computerized Games versus Crosswords Training in Mild Cognitive Impairment: The COG‐IT trial

AbstractBackgroundMild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear.MethodIn a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer’s Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.ResultAmong 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p &lt; .05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p = .02 [cortical thickness]).ConclusionHome‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI.

Disrupted Balance of Gray Matter Volume and Directed Functional Connectivity in Mild Cognitive Impairment and Alzheimer's Disease.

Alterations in functional connectivity have been demonstrated in Alzheimer's disease (AD), an age-progressive neurodegenerative disorder that affects cognitive function; however, directional information flow has never been analyzed. This study aimed to determine changes in resting-state directional functional connectivity measured using a novel approach, granger causality density (GCD), in patients with AD, and mild cognitive impairment (MCI) and explore novel neuroimaging biomarkers for cognitive decline detection. In this study, structural MRI, resting-state functional magnetic resonance imaging, and neuropsychological data of 48 Alzheimer's Disease Neuroimaging Initiative participants were analyzed, comprising 16 patients with AD, 16 with MCI, and 16 normal controls. Volume-based morphometry (VBM) and GCD were used to calculate the voxel-based gray matter (GM) volumes and directed functional connectivity of the brain. We made full use of voxel-based between-group comparisons of VBM and GCD values to identify specific regions with significant alterations. In addition, Pearson's correlation analysis was conducted between directed functional connectivity and several clinical variables. Furthermore, receiver operating characteristic (ROC) analysis related to classification was performed in combination with VBM and GCD. In patients with cognitive decline, abnormal VBM and GCD (involving inflow and outflow of GCD) were noted in default mode network (DMN)-related areas and the cerebellum. GCD in the DMN midline core system, hippocampus, and cerebellum was closely correlated with the Mini- Mental State Examination and Functional Activities Questionnaire scores. In the ROC analysis combining VBM with GCD, the neuroimaging biomarker in the cerebellum was optimal for the early detection of MCI, whereas the precuneus was the best in predicting cognitive decline progression and AD diagnosis. Changes in GM volume and directed functional connectivity may reflect the mechanism of cognitive decline. This discovery could improve our understanding of the pathology of AD and MCI and provide available neuroimaging markers for the early detection, progression, and diagnosis of AD and MCI.

Regional cerebral tau predicts decline in everyday functioning across the Alzheimer’s disease spectrum

BackgroundEmerging difficulty performing cognitively complex everyday tasks, or ‘instrumental activities of daily living’ (IADL) may be an early clinical sign of Alzheimer’s disease (AD). We aimed to investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum.MethodsWe included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer’s Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-β.ResultsGreater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-β; amyloid-β itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-β, were present only in the symptomatic group.ConclusionsThe rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-β, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease.

Computerized Cognitive Training in Mild Cognitive Impairment: Findings in African Americans and Caucasians

BackgroundAfrican Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear.MethodsWe used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study.ResultsA total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants’ FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes.ConclusionsOur preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.)

Feasibility and Effects of Cognitive Training with the COGNIPLAT Game Platform in Elderly with Mild Cognitive Impairment: Pilot Randomized Controlled Trial.

This study examines the effectiveness of a new multi-domain multimodal cognitive training game platform, COGNIPLAT, in improving cognitive performance in elderly with mild cognitive impairment (MCI). The platform combines standard serious games and cognitive stimulation leveraging virtual and augmented reality technologies. A double-arm, evaluator-blinded randomized controlled trial was conducted with 21 elderly participants in the MCI spectrum, with 11 in the intervention group (INT) and 10 in the control group (CTL). Feasibility was assessed in terms of adherence, effective learning, and perceived usefulness. The INT attended 24 training sessions, 60 minutes long, twice a week, whereas the CTL engaged in normal daily activities and usual care. Results showed that the INT had a statistically significant change in the Montreal Cognitive Assessment score, stages List B Recall, Short-term delayed Recall, and Long-term delayed Recall of the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test-A and B test scores, Digit Span Test (DST) Forward Span, and Functional Activities Questionnaire score. A trend level difference was also found for the RAVLT Recognition and the DST Backward Span. No significant differences were found for the CTL in any of the metrics. The completion rate of the INT was 91%, and the attendance rate was 100% for participants who completed the follow-up segment of the study. The engagement level was high, and effective learning was observed between the participants. The perceived usability and usefulness of the game platform was assessed as high. This study provides evidence of a positive effect of a multi-domain multimodal-based cognitive training program in elderly with MCI, with broader benefits on cognition by inducing more cooperative transfer effects over different domains.

Ecological validity of cognitive fluctuations in dementia with Lewy bodies.

Cognitive fluctuations are a core clinical feature of dementia with Lewy bodies (DLB), but their contribution to the everyday functioning difficulties evident DLB are not well understood. The current study evaluated whether intraindividual variability across a battery of neurocognitive tests (intraindividual variability-dispersion) and daily cognitive fluctuations as measured by informant report are associated with worse daily functioning in DLB. The study sample included 97 participants with consensus-defined DLB from the National Alzheimer's Coordinating Center (NACC). Intraindividual variability-dispersion was measured using the coefficient of variation, which divides the standard deviation of an individual's performance scores across 12 normed neurocognitive indices from the NACC neuropsychological battery by that individual's performance mean. Informants reported on daily cognitive fluctuations using the Mayo Fluctuations Scale (MFS) and on daily functioning using the functional activities questionnaire (FAQ). Logistic regression identified a large univariate association of intraindividual variability-dispersion and presence of daily cognitive fluctuations on the MFS (Odds Ratio = 73.27, 95% Confidence Interval = 1.38, 3,895.05). Multiple linear regression demonstrated that higher intraindividual variability-dispersion and presence of daily cognitive fluctuations as assessed by the MFS were significantly and independently related to worse daily functioning (FAQ scores). Among those with DLB, informant-rated daily cognitive fluctuations and cognitive fluctuations measured in the clinic (as indexed by intraindividual variability-dispersion across a battery of tests) were independently associated with poorer everyday functioning. These data demonstrate ecological validity in measures of cognitive fluctuations in DLB.

Integrative analysis of multi-omics and imaging data with incorporation of biological information via structural Bayesian factor analysis.

With the rapid development of modern technologies, massive data are available for the systematic study of Alzheimer's disease (AD). Though many existing AD studies mainly focus on single-modality omics data, multi-omics datasets can provide a more comprehensive understanding of AD. To bridge this gap, we proposed a novel structural Bayesian factor analysis framework (SBFA) to extract the information shared by multi-omics data through the aggregation of genotyping data, gene expression data, neuroimaging phenotypes and prior biological network knowledge. Our approach can extract common information shared by different modalities and encourage biologically related features to be selected, guiding future AD research in a biologically meaningful way. Our SBFA model decomposes the mean parameters of the data into a sparse factor loading matrix and a factor matrix, where the factor matrix represents the common information extracted from multi-omics and imaging data. Our framework is designed to incorporate prior biological network information. Our simulation study demonstrated that our proposed SBFA framework could achieve the best performance compared with the other state-of-the-art factor-analysis-based integrative analysis methods. We apply our proposed SBFA model together with several state-of-the-art factor analysis models to extract the latent common information from genotyping, gene expression and brain imaging data simultaneously from the ADNI biobank database. The latent information is then used to predict the functional activities questionnaire score, an important measurement for diagnosis of AD quantifying subjects' abilities in daily life. Our SBFA model shows the best prediction performance compared with the other factor analysis models. Code are publicly available at https://github.com/JingxuanBao/SBFA. qlong@upenn.edu.

Decreased myelin proteins in brain donors exposed to football-related repetitive head impacts.

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% (n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease (r = -0.23 and -0.20, respectively, Ps < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease (n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy (P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football (n = 78), those who played 11 or more years (n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older (n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings.

Editors' Note: Cognitive-Driven Activities of Daily Living Impairment as a Predictor for Dementia in Parkinson Disease: A Longitudinal Cohort Study.

In “Cognitive-Driven Activities of Daily Living Impairment as a Predictor for Dementia in Parkinson Disease: A Longitudinal Cohort Study,” Becker et al. report that while 40% of 268 patients with Parkinson disease (PD) had mild cognitive impairment (MCI) at baseline, of 164 patients who completed follow-up after 3.78 ± 0.84 years, 33% had MCI and 10% had dementia. Patients in this study were evaluated using the Functional Activities Questionnaire (FAQ) to differentiate cognitive and motor contributions to impairment in performance of instrumental activities of daily living (IADL). Kasten questions how the results of the FAQ compared with results of the Montreal Cognitive Assessment (MoCA) and whether these scores could be used interchangeably. Dr. Kasten also cites a prior study that found that the Unified Parkinson Disease Rating Scale was moderately correlated with the MoCA. Becker reports there was a weak to moderate correlation between FAQ and MoCA scores at both baseline and follow-up. However, although there is some overlap between these assessments, Becker does not believe they should be used interchangeably because MoCA measures general cognition while the FAQ measures cognitive contributions to IADL impairment. This exchange highlights important methodological considerations when screening for cognitive decline in PD. In “Cognitive-Driven Activities of Daily Living Impairment as a Predictor for Dementia in Parkinson Disease: A Longitudinal Cohort Study,” Becker et al. report that while 40% of 268 patients with Parkinson disease (PD) had mild cognitive impairment (MCI) at baseline, of 164 patients who completed follow-up after 3.78 ± 0.84 years, 33% had MCI and 10% had dementia. Patients in this study were evaluated using the Functional Activities Questionnaire (FAQ) to differentiate cognitive and motor contributions to impairment in performance of instrumental activities of daily living (IADL). Kasten questions how the results of the FAQ compared with results of the Montreal Cognitive Assessment (MoCA) and whether these scores could be used interchangeably. Dr. Kasten also cites a prior study that found that the Unified Parkinson Disease Rating Scale was moderately correlated with the MoCA. Becker reports there was a weak to moderate correlation between FAQ and MoCA scores at both baseline and follow-up. However, although there is some overlap between these assessments, Becker does not believe they should be used interchangeably because MoCA measures general cognition while the FAQ measures cognitive contributions to IADL impairment. This exchange highlights important methodological considerations when screening for cognitive decline in PD.

Causal Inference in Unrepresentative Databases: An Analysis of Vitamin E Supplementation in the National Alzheimer’s Coordinating Center Uniform Dataset

AbstractBackgroundSelf‐selection into research studies can lead to samples that are unrepresentative of the target population. For example, the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set is often used to identify risk factors of Alzheimer’s disease and overrepresents highly educated and non‐Hispanic White participants, relative to the US population. Sampling weights that are related to the self‐selection of enrolling in the NACC database can be used to estimate causal effects in the US population of older adults. We applied this strategy to estimate the effect of vitamin E supplementation on functional activities using NACC data and estimated sampling weights as proof of concept. A meta‐analysis found mixed evidence about the effect of vitamin E on functional outcomes in cognitively normal older adults (Browne et al. 2019).MethodsWe used baseline data for NACC participants who enrolled from 2005‐2021, were cognitively normal, and 65 or older. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA‐funded ADCs. We estimated the probability of self‐selection into NACC relative to a nationally representative survey. We used the corresponding sampling weights to estimate weighted propensity scores and weighted propensity‐adjusted estimates of the effect of vitamin E supplementation on the Functional Activities Questionnaire (FAQ) and compared the results to unweighted models.ResultsAfter excluding 809 participants missing the FAQ, there were 14,358 participants. When incorporating sampling weights to obtain inference about the US population, we estimated that participants who take vitamin E supplements have a 0.29 point lower (95% CI: ‐0.54, ‐0.04) FAQ score, on average, compared to participants who do not. When failing to account for sampling bias and omitting sampling weights, we estimated that they have a 0.01 point lower (95% CI: ‐0.11, 0.09) FAQ score, on average (see figure).ConclusionWhen accounting for sampling bias we estimated that participants who take vitamin E supplements perform better on the FAQ compared to those who do not, but this effect was attenuated when failing to account for sampling weights. Incorporating estimated sampling weights allows for better isolation of causal effects in the population of interest.

Cerebrospinal fluid levels of growth associated protein 43 (GAP‐43) are associated with Alzheimer’s disease biomarkers, cognition, and functional changes

AbstractBackgroundGrowth‐associated protein 43 (GAP‐43) is a presynaptic protein involved in synaptic plasticity implicated in Alzheimer’s disease (AD). This study investigates cerebrospinal fluid (CSF) levels of GAP‐43 in relation to AD fluid biomarkers and clinical outcomes. To determine how associations change across disease states, interactions with cognitive and amyloid status are examined.MethodVanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±7 years, 37% mild cognitive impairment (MCI)) underwent fasting lumbar puncture, 3T brain MRI, neuropsychological assessment, and informant‐reported functional activities questionnaire (FAQ). CSF GAP‐43, b‐amyloid1‐42 (Ab1‐42), tau, and phosphorylated‐tau (p‐tau) were analyzed in batch. An AD‐signature imaging composite was calculated by summing cortical thickness measurements from brain regions commonly affected by AD (Schwarz et al., 2016). Linear mixed effects models cross‐sectionally related GAP‐43 to CSF AD biomarkers, structural neuroimaging, cognitive, and FAQ variables adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow‐up models assessed GAP‐43 x cognitive status (normal cognition (NC), MCI) and GAP‐43 x amyloid positivity interactions on outcomes.ResultIn main effect models, higher CSF GAP‐43 was associated with higher CSF tau (p&lt;0.0001) and CSF p‐tau (p&lt;0.0001); worse semantic fluency (p&lt;0.02), visuospatial (p&lt;0.007) and episodic memory performances (p=0.06); and worse FAQ scores (p=0.003). Remaining models were null (p‐values&gt;0.23). GAP‐43 interacted with cognitive status on all CSF biomarkers, AD‐signature composite cortical thickness, visuospatial, executive functioning, and memory performances, and FAQ score (p‐values&lt;0.06). CSF GAP‐43 interacted with amyloid positivity on CSF tau and CSF p‐tau, and memory composite score (p‐values&lt;0.03). Stratified results suggested most associations were slightly stronger in participants with MCI (p‐values&lt;0.02) versus NC and in amyloid positive (p‐values&lt;0.02) versus negative participants.ConclusionWe found higher CSF GAP‐43 levels were associated with tau and p‐tau pathology, AD‐related neurodegeneration on MRI, and worse cognitive and functional scores. Results were more prominent in individuals at increased risk for AD‐type dementia (i.e., participants who were amyloid positive or have MCI). These findings extend prior work by highlighting the importance of synaptic dysfunction in the AD clinical syndrome.

Computerized Games versus Crosswords Training in Mild Cognitive Impairment

BackgroundMild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in patients with MCI is unclear.MethodsIn a two-site, single-blinded, 78-week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles, followed by six booster sessions. In mixed-model analyses, the primary outcome was change from baseline in the 11-item Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) score, a 70 point scale in which higher scores indicate greater cognitive impairment at 78 weeks, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score, University of California San Diego Performance-Based Skills Assessment (functional outcome) score, and Functional Activities Questionnaire (functional outcome) score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.ResultsAmong 107 participants (n=51 [games]; n=56 [crosswords]), ADAS-Cog score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, −1.44; 95% confidence interval [CI], −2.83 to −0.06; P=0.04). From baseline to week 78, mean ADAS-Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, −2.45; SE, 0.89; 95% CI, −4.21 to −0.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, −1.08; 95% CI, −1.97 to −0.18). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI, 0.51 to 67.63 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04 [cortical thickness]).ConclusionsHome-based computerized training with crosswords demonstrated superior efficacy to games for the primary outcome of baseline-adjusted change in ADAS-Cog score over 78 weeks. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.)

Effect of Electroacupuncture Stimulation at Acupoints of the Heart Meridian on Cognitive Function in Vascular Dementia Patients

Background: This study aims to investigate the therapeutic effect of electroacupuncture stimulation at acupoints of the heart meridian on vascular dementia (VD). Methods: A total of 120 VD patients were enrolled and randomly divided into two groups: The observation group, in which patients were treated with electroacupuncture stimulation; The control group, in which the patients were treated with oral medicine. Cognitive function was assessed by using the Mini-mental State Examination (MMSE), Activity of Daily Living (ADL) and functional activities questionnaire (FAQ). Results: The total effective rate was 75% in the observation group and 73.33% in the control group, and the difference between these two groups was not statistically significant (P &gt;0.05). After treatment, the MMSE, ADL and FAQ scores in these two groups significantly improved, when compared to scores before treatment (P &lt;0.01). After treatment, the differences in MMSE, ADL and FAQ scores between these two groups were not statistically significant (P &gt;0.05). Conclusion: Electroacupuncture stimulation at acupoints of the heart meridian has a definite effect in improving the cognitive function of VD patients.

Divergence Between Informant and Self-Ratings of Activities of Daily Living Impairments in Parkinson's Disease.

ObjectiveTo examine the agreement between self- and informant-reported activities of daily living (ADL) deficits in Parkinson’s Disease (PD) patients, and to examine factors influencing ADL ratings.BackgroundIn PD, the loss of functional independence is an important outcome of disease progression. The valid assessment of ADL function in PD is essential, but it is unclear to what extent informants’ and patients’ perceptions of their daily functions concur, and how other factors may influence both ratings.MethodsData of 150 PD patients who underwent cognitive and motor testing, as well as their informants were analyzed. The 10-item Functional Activities Questionnaire (FAQ), completed separately by patients (FAQ-S) and their informants (FAQ-I), assessed ADL function. Weighted κ statistics summarized level of agreement, and a discrepancy score (FAQ-I – FAQ-S) quantified agreement. Correlation analyses between FAQ total scores, patient and informant characteristics, and cognitive scores were conducted, with post hoc regressions to determine the associations between both FAQ scores and cognition, independent of patient characteristics.ResultsThe sample included 87 patients with normal cognition, 50 with mild cognitive impairment, and 13 with dementia. Overall, there was fair to moderate agreement between patients and informants on individual FAQ items (0.27 ≤ κ ≤ 0.61, p < 0.004), with greater discrepancies with increasing cognitive impairment. Patients’ age, motor severity, non-motor burden, and depression also affected both ratings (0.27 ≤ r ≤ 0.50, p < 0.001), with motor severity showing the greatest influence on both ratings. Both the FAQ-I and FAQ-S were correlated with almost all cognitive domains. Post hoc regression analyses controlling for patient characteristics showed that the attention domain was a significant predictor of both the FAQ-S and FAQ-I scores, and memory was also a significant predictor of the FAQ-I score. Only 29.3% of patients agreed perfectly with informants on the FAQ total score, with informants most commonly rating ADL impairments as more severe than patients.ConclusionsPatient and informant ratings of ADL function using FAQ items showed moderate agreement, with only few items reaching substantial agreement. Ratings of both were associated with patient cognitive status, but also other characteristics. In addition to patient and informant reports, objective measures are needed to accurately classify ADL deficits in PD.

Research on predicting the risk of mild cognitive impairment in the elderly based on the joint model

Objective: To construct and compare the dynamic prediction models of the risk of mild cognitive impairment (MCI) in the elderly based on six different cognitive function scales. Methods: Based on longitudinal data from the Alzheimer's Disease Neuroimaging Initiative from 2005 to 2020, Mini-mental state examination (MMSE), functional activities questionnaire (FAQ), Alzheimer's disease assessment scale-cognitive (ADAS-Cog) 11, ADAS-Cog13, ADAS delayed word recall (ADASQ4), and Rey auditory verbal learning test (RAVLT)_immediate were used as longitudinal cognitive function evaluation indicators to assess the longitudinal changes in cognitive function. The joint model was used to analyze association between indicators variation trajectory and survival outcome MCI, and construct the risk prediction model of MCI in the elderly, the linear mixed model was constructed the longitudinal sub-model which described the evolution of a repeated measure over time, a proportional hazards model was constructed the survival sub-model, and the two sub-models were connected through the correlation parameter (α). The areas under the receiver operator characteristic curve (AUC) were used to evaluate the predictive efficacy of the model in the follow-up period of (t, t+Δt). The starting point t was selected at the 30th, 42nd, and 54th month, and the Δt was selected as 15 and 21 months. Based on the prediction model, an example of the research object was selected for dynamic individual predictions of the risk of MCI. Results: Finally, 544 older adults (aged 60 years and above) with normal baseline cognitive status were included, of which 119 cases (21.9%) had MCI during the follow-up process were regarded as the case group, and 425 cases remained normal as the control group. The joint model suggests that the longitudinal trajectories of the six evaluation indicators are all related to the risk of MCI (P<0.001). The risk of MCI decreased by 32.3% (HR=0.677, 95%CI: 0.541-0.846) and 10.8% (HR=0.892, 95%CI: 0.865-0.919) for each one-point increase of MMSE and RAVLT_immediate longitudinal scores. The risk of MCI increased by 53.2% (HR=1.532, 95%CI: 1.393-1.686), 36.2% (HR=1.362, 95%CI: 1.268-1.462), 23.2% (HR=1.232, 95%CI: 1.181-1.285), and 85.1% (HR=1.851, 95%CI:1.629-2.104) for each one-point increase of FAQ, ADAS-Cog11, ADAS-Cog13, and ADASQ4 longitudinal scores. AUC results show that RAVLT_immediate (0.760 2) and ADASQ4 (0.755 8) have higher average prediction efficiency, followed by ADAS-Cog13 (0.743 7), ADAS-Cog11 (0.715 3), FAQ (0.700 8) and MMSE (0.629 5). ADASQ4 joint model was used to provide a dynamic individual prediction of the risk of MCI. The average probability of MCI after five years of follow-up and ten years of follow-up in the example individuals were 8% and 40%, respectively. Conclusions: The RAVLT_immediate and ADASQ4 scales, which are only for memory tests, have high accuracy in predicting the risk of MCI. Using the RAVLT_immediate and ADASQ4 scales as longitudinal cognitive function evaluation indicators to construct a joint model, the results can provide a basis for realizing MCI risk prediction for the elderly.

Coupling analysis between functional and structural brain networks in Alzheimer's disease.

The coupling between functional and structural brain networks is difficult to clarify due to the complicated alterations in gray matter and white matter for the development of Alzheimer's disease (AD). A cohort of 112 participants [normal control group (NC, 62 cases), mild cognitive impairment group (MCI, 31 cases) and AD group (19 cases)], was recruited in our study. The brain networks of rsfMRI functional connectivity (rsfMRI-FC) and diffusion tensor imaging structural connectivity (DTI-SC) across the three groups were constructed, and their correlations were evaluated by Pearson's correlation analyses and multiple comparison with Bonferroni correction. Furthermore, the correlations between rsfMRI-SC/DTI-FC coupling and four neuropsychological scores of mini-mental state examination (MMSE), clinical dementia rating-sum of boxes (CDR-SB), functional activities questionnaire (FAQ) and montreal cognitive assessment (MoCA) were inferred by partial correlation analyses, respectively. The results demonstrated that there existed significant correlation between rsfMRI-FC and DTI-SC (p < 0.05), and the coupling of rsfMRI-FC/DTI-SC showed negative correlation with MMSE score (p < 0.05), positive correlations with CDR-SB and FAQ scores (p < 0.05), and no correlation with MoCA score (p > 0.05). It was concluded that there existed FC/SC coupling and varied network characteristics for rsfMRI and DTI, and this would provide the clues to understand the underlying mechanisms of cognitive deficits of AD.