Clinical Dementia Rating Global Score Research Articles

Machine Learning Model for Mild Cognitive Impairment Stage Based on Gait and MRI Images.

In patients with mild cognitive impairment (MCI), a lower level of cognitive function is associated with a higher likelihood of progression to dementia. In addition, gait disturbances and structural changes on brain MRI scans reflect cognitive levels. Therefore, we aimed to classify MCI based on cognitive level using gait parameters and brain MRI data. Eighty patients diagnosed with MCI from three dementia centres in Gangwon-do, Korea, were recruited for this study. We defined MCI as a Clinical Dementia Rating global score of ≥0.5, with a memory domain score of ≥0.5. Patients were classified as early-stage or late-stage MCI based on their mini-mental status examination (MMSE) z-scores. We trained a machine learning model using gait and MRI data parameters. The convolutional neural network (CNN) resulted in the best classifier performance in separating late-stage MCI from early-stage MCI; its performance was maximised when feature patterns that included multimodal features (GAIT + white matter dataset) were used. The single support time was the strongest predictor. Machine learning that incorporated gait and white matter parameters achieved the highest accuracy in distinguishing between late-stage MCI and early-stage MCI.

The risk of developing dementia in the COVID-19 pandemic; a cohort study.

The effects of the COVID-19 pandemic on cognitive decline are not fully understood. Higher social activity and relationships have been associated with decreased risk of dementia. We hypothesised that risk of transition to dementia would increase after the start of the first national lockdown. We obtained data from the Brains for Dementia (BDR) cohort, which has collected roughly annual data on 3726 older adults with and without dementia since 2008. Data continued to be collected during the lockdowns, although by telephone and/or video call instead of in person. Individuals diagnosed with dementia at study entry were excluded from this study as were individuals with only one visit. Cognitive status was classified using the Clinical Dementia Rating (CDR) global score. Poisson regression with cubic splines to account for differences in age was used to compare the incidence of dementia before and after March 1st 2020. Out of 2242 individuals, 208 individuals developed dementia before and 50 developed dementia after 01/03/20. The incidence rate ratio of developing dementia after 01/03/20 was 0.847 (0.538-1.335) p=0.570. In our secondary analysis we found that the positive association between mild cognitive impairment (MCI) and dementia incidence decreased after 1/3/20 (interaction effect p=0.031). The incidence of dementia as defined using the CDR global score did not change significantly after the first lockdown began, but we found evidence that lockdown decreased the positive association between MCI and dementia incidence. This may reflect that individuals were progressing to dementia more rapidly and thus missing the MCI stage or that assessing patients over the phone made diagnosing MCI more challenging.

Medical help-seeking intentions among patients with early Alzheimer's disease.

Limited information is available on the active process of seeking medical help in patients with Alzheimer's disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors. A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer's Association criteria), a Mini-Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. A multivariate logistic regression analysis was conducted. A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex (p = 0.003), fewer years of education (p = 0.005), a low awareness of diagnosis (p = 0.005), and a low emotional consequence of the condition (p = 0.016). Understanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition.

Risk of neuropsychiatric symptoms among people who develop cognitive impairment with and without a history of post‐traumatic stress disorder

AbstractBackgroundMost research studying the link between PTSD and cognitive impairment focuses on PTSD as a risk factor for developing Alzheimer’s disease; however, few studies focus on the impact cognitive impairment has on neuropsychiatric symptoms among people with a history of PTSD. Symptoms associated with cognitive decline may increase or cause the relapse of recurrent intrusive memories, dreams, or flashbacks of traumatic events among individuals with a history of PTSD. Additionally, cognitive impairment may lead to a delayed onset, worsening, or recurrence of PTSD‐related neuropsychiatric symptoms among people with PTSD. We aimed to prospectively assess the change in neuropsychiatric symptoms among people who develop cognitive impairment and have a history of PTSD.MethodData were obtained from the National Alzheimer’s Coordinating Center (NACC). Eligibility criteria included participants who were cognitively unimpaired and had non‐missing assessment of PTSD at initial visit, and who had at least one follow‐up visit with cognitive impairment. Information from the Uniform Data Set (UDS) health history and clinical diagnosis forms at the initial visit was used to separate participants with a history of (PTSD+) and participants without a history of (PTSD‐). Demographics, clinical symptoms, and mean NPI‐Q severity scores at the first UDS visit vs first visit with a Clinical Dementia Rating global score (CDR‐GS) of 0.5 were compared between groups.ResultThe final analytic sample included 18 PTSD+ participants and 585 PTSD‐ participants. While both groups experienced significantly higher mean NPI‐Q severity scores between baseline and the first visit with CDR‐GS = 0.5, there was not a significant difference between the groups (p = 0.79). Additionally, both groups exhibited significantly increased rates of change in NPI‐Q severity scores, but this rate was not statistically different between the groups (p = 0.73).ConclusionIn this sample, we found no differences in NPI‐Q scores. The small sample size of PTSD+ participants as well as the mild nature of participants’ cognitive impairment might account for these null findings, as it might be too mild to impact PTSD symptoms; as such, future research examining these symptoms in larger and more diverse samples is warranted.

Evaluating the global cortical Centiloid value for predicting functional decline

AbstractBackgroundPrevious results on amyloid‐PET imaging for predicting functional decline are conflicting. Given that the Centiloid approach (CL) may serve for inclusion in anti‐amyloid trials, we investigated the extent to which CL may predict functional decline in the AMYPAD‐Prognostic and Natural History Study (PNHS), including 1094 participants.MethodWe analyzed, cross‐sectionally and longitudinally, the associations between CL and global and sum‐of‐boxes (SOB) Clinical Dementia Rating (CDR), and Instrumental Activity of Daily Living (IADL) scores. Mean follow‐up duration ranged from 2.7‐3.0 years (±1.1‐1.6) depending on the functional score. Longitudinal CDR‐SOB and IADL changes were modeled using linear mixed‐effects models with random intercepts and slopes, covarying age and sex, stratified by CDR global score. Analyses included comparisons between three CL groups (Aβ‐: CL<12; grey‐zone: CL = 12‐50; Aβ+: CL>50) and correlation between the baseline CL and the time for progression on the CDR global score.ResultThe baseline CL was significantly higher in CDR = 0 (Mdn = 6.6) than in CDR = 0.5 participants (Mdn = 17.2; p<.001). Baseline CDR‐SOB was significantly higher in Aβ+ (M = 0.48) than in Aβ‐ (M = 0.12) and grey‐zone participants (M = 0.13, p‐values <.001). Baseline IADL was (marginally) significantly lower in Aβ+ (Mdn = 81.3) than in Aβ‐ (Mdn = 82.8, p = .02) and grey‐zone participants (Mdn = 83.5, p = .08, Table 1). Baseline CL significantly predicted subsequent changes in CDR‐SOB and IADL, both in CDR = 0 and CDR = 0.5 participants, but only in the CL>50 groups (βCL12‐50 = 0.03, p = .32,βCL>50 = 0.14, p<.001 for CDR‐SOB in CDR = 0 participants;βCL12‐50 = 0.19, p = .31,βCL>50 = 1.04, p = .01 for CDR‐SOB in CDR = 0.5 participants;βCL12‐50 = ‐0.002, p = .99, βCL>50 = ‐1.00, p = .08 for IADL in CDR = 0 participants; Fig.1). The participants who progressed from global CDR = 0 to CDR = 0.5 (N = 90) had a higher baseline CL (Mdn = 15.16) than stable participants (Mdn = 5.95, p = .002). However, the baseline CL was not associated with a shorter time of clinical progression (rs= ‐.02, p = .8; Fig.2).ConclusionCross‐sectionally, amyloid burden expressed in CL units was associated with functional outcomes. A baseline CL>50 predicted subsequent functional decline in CDR‐SOB and IADL scores in clinically normal and mildly clinically impaired participants. At lower CL values, no functional decline was observed during a three‐year follow‐up. Clinically normal individuals with increasing global CDR scores had higher baseline CL values, but these values were not associated with faster clinical progression.

OP142 Progression Analysis Versus Traditional Methods To Quantify Slowing Of Disease Progression In Alzheimer’s Disease

IntroductionNew statistical methodology, known as progression models for repeated measures (PMRM), can estimate the slowing of progression (percentage slowing or time delay) of Alzheimer’s disease from trial data on disease-modifying therapies. We compared the PMRM methodology with mixed models for repeated measures (MMRM) and Cox time-to-event analysis on simulated trial data with respect to their power and interpretability of estimates.MethodsTwo novel models were included: PMRM (estimating slowing of progression and allowing different rates across visits) and proportional-slowing PMRM. Clinical Dementia Rating (CDR) Sum of Boxes score and progression to dementia as assessed by CDR global score were the primary outcomes for MMRM/PMRM and the Cox model, respectively. Subject-level placebo arm trajectories were jointly simulated based on estimated CDR mean trajectories and joint temporal correlation structure of 538 amyloid-positive patients with mild cognitive impairment who met typical disease-modifying trial inclusion criteria from the Alzheimer’s Disease Neuroimaging Initiative study. Active arm trajectories were simulated to show an average 20 percent slowing of disease progression, compared with placebo, at each visit. We conducted 1,000 simulations across multiple scenarios, varying the number of patients per arm (200 to 700) and clinical trial duration (18 to 36 months).ResultsThe power of PMRM models was greater than that of MMRM, and much greater than that of the Cox model whose power never exceeded 45 percent. PMRM models accurately estimated the underlying treatment effect (median 20% slowed progression, which translated to a delay in progression of 5 and 7 months at trial durations of 24 and 36 months, respectively), unlike quantifications of the MMRM (median estimated 25% reduction in decline), and the Cox model (median estimated hazard ratio of 0.9).ConclusionsFor disease-modifying therapies, PMRM estimates may have a more intuitive clinical interpretation in terms of delayed progression than MMRM or Cox models and enable a description of the amount of time spent in less severe disease stages. Among all the methods studied, PMRM offered the best combination of interpretability and power.

Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in Mild Cognitive Impairment

AbstractBackgroundBoth the loss of awareness for cognitive decline (a.k.a anosognosia) and neuropsychiatric symptoms (NPS) are commonly seen in patients with Alzheimer’s disease (AD) dementia, even in the prodromal stages. Anosognosia and NPS may negatively affect caregiver burden and patient’s activities of daily living. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross‐sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI).MethodWe included 310 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with a baseline Clinical Dementia Rating global score of 0.5. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study‐partners at baseline and annually over a mean of 4 years (SD = 3). Anosognosia was defined as the study‐partner having an ECog score ≥2.5/4 and the participant having an ECog score ≤2.5/4 on their baseline measure and their last observation and without having more than 2 consecutive deviating observations during the follow‐up period. The 12 study‐partner‐rated Neuropsychiatric Inventory items determined the presence or absence of specific NPS (see Table 1). The Mini‐Mental State Examination (MMSE), an assessment used to screen for cognitive impairment, was administered annually. Survival analyses were performed to analyze the rate of appearance of NPS over time in individuals with and without anosognosia.ResultSixty participants displayed anosognosia, while 250 did not. At baseline, groups had similar lengths of follow‐up. Participants with anosognosia had lower MMSE scores and a higher proportion of amyloid positivity (see Table 1). At baseline, the frequency of agitation and disinhibition was higher in the anosognosia group. Survival analyses showed earlier onset of all NPS in the anosognosia group (see Figure 1). Specifically, aberrant motor behavior, irritability, disinhibition, apathy, agitation, and hallucinations were highly significant.ConclusionLoss of awareness for cognitive decline is associated with greater frequency and faster onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process, a finding that needs to be addressed further in future studies.

B - 25 Examining Mini-Mental State Examination (MMSE) Performance by Primary and Testing Language.

Previous research has identified that MMSE scores vary by education raising concern that examinees with lower educational level may be inaccurately identified as cognitively impaired. Most studies, however, used the English MMSE and may not generalize to Spanish speakers. We compared MMSE scores in primary Spanish-speakers tested in English (S-E) with primary Spanish-speakers tested in Spanish (S-S). This project involved secondary analysis of de-identified National Alzheimer's Coordinating Center data. Cases with visit one MMSE data and demographics were included if the primary language was Spanish yielding a sample of S-S (n = 1514) and S-E (n = 346) participants. Coarsened exact matching derived a subset of S-E and S-S participants matched on age, education, and Clinical Dementia Rating global score (n = 630). In the overall sample, groups were not different in age, but education was lower in S-S (M = 9.2; SD = 5.1) than S-E (M = 12.9; SD = 5.1; p < 0.001) participants. MMSE scores were lower in S-S (M = 22.4, SD = 7.1) than S-E participants (M = 23.7, SD = 6.2; p = 0.002). More S-S participants (45%) had an abnormal (< 24) MMSE compared to S-E participants (38%; p = 0.02). In the matched sample, MMSE scores were not significantly different between S-S (M = 24.4; SD = 6.0) and S-E (M = 23.9; SD = 6.1; p = 0.30) participants, and rates of abnormal MMSE scores were not significantly different between S-S (32%) and S-E (37%; p = 0.16) participants. Overall sample MMSE scores differed by test administration language groups, but group differences were not observed in the matched subset. Consistent with other research, educational level is associated with MMSE scores in Spanish-speakers regardless of test administration language.

B - 26 Examining Montreal Cognitive Assessment (MoCA) Performance by Primary and Testing Language.

The MoCA has been translated into almost 100 languages including a Spanish version used in multiple validation studies. Research considering primary language and language of test administration is limited. We compared MoCA scores of primary Spanish speakers tested in English (S-E) with those of primary Spanish speakers tested in Spanish (S-S). This project involved secondary analysis of deidentified National Alzheimer's Coordinating Center data. Cases with first visit MoCA data, demographics, and primary language of Spanish were included resulting in a final sample (N = 395) of S-S (n = 265) and S-E (n = 130) participants. Coarsened exact matching was used to derive a sample subset matched on age, education, and Clinical Dementia Rating global score (n = 160). Participants were compared on demographics and MoCA. In the final sample, S-S and S-E participants were not different in age, but educational level was lower in S-S (M = 10.0; SD = 5.3) than S-E (M = 14.6; SD = 3.9; p < 0.001) participants. MoCA scores were lower in S-S (M = 19.1, SD = 6.2) than S-E participants (M = 21.2, SD = 6.1; p = 0.002). A larger proportion of the S-S group (79%) had an abnormal MoCA compared to the S-E group (67%; p = 0.021). In the matched sample, MoCA scores were not significantly different between S-S (M = 21.2; SD = 4.8) and S-E (M = 21.2; SD = 5.3; p = 0.95) participants; rates of abnormal MoCA scores were not significantly different between S-S (73%) and S-E (66%; p = 0.39) participants. Relationships between primary language, test administration language, and MoCA score were reduced in groups matched on education. Future research should explore additional education and language interactions among bilingual older adults.

Evaluation of the Electronic Clinical Dementia Rating for Dementia Screening

The Clinical Dementia Rating (CDR) is a well-validated instrument widely used to detect and stage dementia due to Alzheimer disease. The digital Electronic Clinical Dementia Rating (eCDR) can be remotely self-administered and automatically scored, with potential to facilitate efficient dementia screening and staging. To evaluate the association of the eCDR with the CDR and other in-clinic assessments for screening older adults for cognitive impairment. This multisite, cross-sectional study used baseline data from a longitudinal, observational study from 2020 to 2023, including up to 3 years of follow-up. Participants were enrolled from 3 Alzheimer Disease Research Centers and the Brain Health Registry. Participants (aged ≥55 years, with a study partner, and no acute or unstable major medical conditions) were recruited during in-clinic visits or by automated emails. Participants completed the Uniform Data Set Version 3 (UDS; including the CDR) in supervised clinical research settings, and then completed the eCDR remotely, online and unsupervised, using their own device. The primary outcomes were eCDR scores (item; categorical box and global; continuous box and global), CDR scores (item; categorical box and global), and UDS assessment scores. Associations were evaluated using linear and logistic regressions. A total of 3565 participants were contacted, and 288 were enrolled. Among 173 participants with item-level data (mean [SD] age, 70.84 [7.65] years; 76 women [43.9%]), eCDR to CDR concordance was 90% or higher for 33 items (63%) and 70% to 89% for 13 items (25%). Box (domain) level concordance ranged from 80% (memory) to 99% (personal care). The global score concordance rate was 81%. κ statistics were fair to moderate. Among 206 participants with box and global scores (mean [SD] age, 71.34 [7.68] years; 95 women [46.1%]), eCDR continuous global score was associated with CDR global (categorical) score with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.70-0.87). Correlations between eCDR and in-clinic UDS assessments were similar to those between CDR sum of box scores and the same in-clinic assessments. These findings suggest that the eCDR is valid and has potential use for screening and assessment of older adults for cognitive and functional decline related to Alzheimer disease. Instrument optimization and validation in diverse cohorts in remote settings are crucial for evaluating scalability and eCDR utility in clinical research, trials, and health care settings.

Relationship of Neural Correlates of Gait Characteristics and Cognitive Dysfunction in Patients with Mild Cognitive Impairment.

Background: Some patients with mild cognitive impairment (MCI) experience gait disturbances. However, there are few reports on the relationship between gait disturbance and cognitive function in patients with MCI. Therefore, we investigated the neural correlates of gait characteristics related to cognitive dysfunction. Methods: Eighty patients diagnosed with MCI from three dementia centers in Gangwon-do, Korea, were recruited for this study. We defined MCI as a Clinical Dementia Rating global score of 0.5 or higher, with a memory domain score of 0.5 or greater. The patients were classified as having either higher or lower MMSE and the groups were based on their Mini Mental Status Examination z-scores. Multiple logistic regression analysis was performed to examine the association between the gait characteristics and cognitive impairment. Analyses included variables such as age, sex, years of education, number of comorbidities, body mass index, and height. Results: Gait velocity, step count, step length, heel-to-heel base support, swing and stance phase duration, and support time were associated with cognitive function. A decrease in gray matter volume in the right pericalcarine area was associated with gait characteristics related to cognitive dysfunction. An increase in the curvature of gray matter in the right entorhinal, right lateral orbitofrontal, right cuneus, and right and left pars opercularis areas was also associated with gait characteristics related to cognitive dysfunction. Conclusion: Since gait impairment is an important factor in determining activities of daily living in patients with mild cognitive impairment, the evaluation of gait and cognitive functions in patients with mild cognitive impairment is important.

Exploring the relationship between patient-relevant outcomes and Alzheimer's disease progression assessed using the clinical dementia rating scale: a systematic literature review.

People with Alzheimer's disease (AD) have difficulties in performing activities of daily living (ADLs) as the disease progresses, commonly experience neuropsychiatric symptoms (NPS), and often have comorbidities such as cardiovascular disease. These factors all contribute to a requirement for care and considerable healthcare costs in AD. The Clinical Dementia Rating (CDR) scale is a widely used measure of dementia staging, but the correlations between scores on this scale and patient-/care partner-relevant outcomes have not been characterized fully. We conducted a systematic literature review to address this evidence gap. Embase, MEDLINE, and the Cochrane Library were searched September 13, 2022, to identify published studies (no restriction by date or country) in populations with mild cognitive impairment due to AD or AD dementia. Studies of interest reported data on the relationships between CDR Global or CDR-Sum of Boxes (CDR-SB) scores and outcomes including NPS, comorbidities, ADLs, nursing home placement, healthcare costs, and resource use. Overall, 58 studies met the inclusion criteria (42 focusing on comorbidities, 14 on ADLs or dependence, five on nursing home placement, and six on economic outcomes). CDR/CDR-SB scores were correlated with the frequency of multiple NPS and with total scores on the Neuropsychiatric Inventory. For cardiovascular comorbidities, no single risk factor was consistently linked to AD progression. Increasing CDR/CDR-SB scores were correlated with decline in multiple different measures of ADLs and were also associated with nursing home placement and increasing costs of care. NPS, ADLs, and costs of care are clearly linked to AD progression, as measured using CDR Global or CDR-SB scores, from the earliest stages of disease. This indicates that scores derived from the CDR are a meaningful way to describe the severity and burden of AD for patients and care partners across disease stages.

Blood-Derived Progenitor Cells Are Depleted in Older Adults with Cognitive Impairment: A Role for Vascular Resilience?

Depletion of blood-derived progenitor cells, including so called "early endothelial progenitor cells", has been observed in individuals with early stage Alzheimer's disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro. Neuropsychological testing was administered to all participants. Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults.

Statistical harmonization of everyday functioning and dementia-related behavioral measures across nine surveys and trials.

Efforts to harmonize measures of everyday function and dementia-related behaviors are needed to synthesize across studies in dementia research. There have been some psychometric attempts to harmonize everyday function for secondary analysis, but far less for dementia-related behaviors. Statistical co-calibration was performed to generate factor scores representing everyday function and dementia-related behaviors for participants with dementia. We evaluated convergent criterion validity of factor scores and mapped the scores onto established clinical instruments. Factor analyses of included items fit well to available data. Harmonized factors showed expected associations with the Global Clinical Dementia Rating (CDR) score, with greater impairment (higher Global CDR score) corresponding to higher (more severe) levels on factor scores. We used large, well-characterized samples to derive harmonized factors representing everyday functions and dementia-related behaviors. These harmonized factors can be used to tackle questions about dementia phenotypes which require either large samples or unique subpopulations.

The association of gabapentin use and change of cognitive and functional status in older adults with normal cognition

AbstractBackgroundAlthough gabapentin has been increasingly prescribed to older adults, the relationship between gabapentin and cognition/functional status is not well studied. Therefore, we aimed to examine the association of gabapentin use and cognitive/functional change in older adults.MethodsA retrospective cohort study was conducted using National Alzheimer’s Coordinating Center Uniform Data Set (2005‐March 2021). Gabapentin new users with normal cognition at the visit of gabapentin initiation (i.e., index visit) were included. New‐users were matched on year of first enrollment and time of gabapentin initiation since enrollment to randomly select nonusers with replacement. The decline of cognitive/functional status, including Clinical Dementia Rating global score (CDRGLOB), Clinical Dementia Rating sum of boxes (CDRSUM), Mini‐Mental State Examination (MMSE), sum of Functional Activities Questionnaire (FAQ), and mean of FAQ, was assessed from index to index+1 and index+2 visits. The criteria of cognitive/functional status decline were any increase of CDRGLOB, 1 point increase of CDRSUM, 1 point decrease of MMSE, 3 point increase of sum of FAQ, and 0.3 point increase of mean of FAQ. To mitigate confounding and selection bias, stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights were used. Generalized estimating equations with an exchangeable working correlation structure were used to account for within‐participant correlations and obtain robust standard errors.ResultsWe included 496 new‐users (mean age [SD]: 78.0 [7.1]; male 35.9%) and 4,464 nonusers (77.4 [7.1]; 35.1%) with normal cognition at index. Among the participants who had information of seizure history (57.1% of new‐users and 58.0% of nonusers), 2.2% and 1.6% of new‐users and nonusers, respectively, reported having seizure history, indicating that gabapentin is widely prescribed off‐label in older adults. Gabapentin use was significantly associated with cognitive/functional status decline with outcomes, including CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.57 [1.08, 2.31]); CDRSUM at index+1 visit (1.89 [1.16, 3.06]) and at index+2 visit (1.66 [1.05, 2.63]); and mean of FAQ at index+2 visit (2.23 [1.22, 4.07]) (Figure 1).ConclusionsGabapentin use was significantly associated with decline in cognitive and functional status among older adults with initially normal cognition. Further studies are needed to examine the association.

ACT‐AD: Fosgonimeton in mild‐to‐moderate Alzheimer’s disease – first results of a randomized, placebo‐controlled, 26‐week Phase 2 proof‐of‐concept trial

AbstractBackgroundFosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer’s disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects.MethodACT‐AD is a Phase 2, 26‐week, randomized, double‐blind, placebo‐controlled, parallel group trial in patients with a clinical diagnosis of mild to moderate AD. Patients enrolled were aged 55‐85 years, had a mini‐mental state examination (MMSE) score of 14‐24, a Clinical Dementia Rating global score of 1 or 2 at screening, a syndromal clinical diagnosis of probable AD according to McKhann et al. (Alzheimers Dement. 2011), and were treatment‐naïve or receiving stable acetylcholinesterase inhibitor therapy. Patients were randomized (1:1:1) to placebo or fosgonimeton at doses of 40 or 70 mg, administered subcutaneously once daily. The trial is powered for the primary endpoint, change in ERP P300 latency. Secondary endpoints include ADAS‐Cog11, ADCS‐CGIC and ADCS‐ADL23. The relationship of ERP P300 latency with cognition, memory and executive function, as well as pharmacokinetics, and safety will also be analyzed.ResultIn total, 77 patients with mild to moderate AD were randomized, with a mean (SD) age of 71.4 (7.3) years, 50.6% female, and mean (SD) baseline MMSE score of 19.5 (3.1). ApoE4 carriers made up 56% of the population, with 42% as noncarriers and 2% unknown.ConclusionThe double‐blind period of ACT‐AD is ongoing and estimated to complete in May 2022, with results available in June 2022. First analyses will be presented at the annual 2022 AAIC congress.This study is sponsored by Athira Pharma, registered at Clinicaltrials.gov: NCT04491006, and supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268.

SAGE‐718 in Patients With Mild Cognitive Impairment or Mild Dementia due to Alzheimer’s Disease: Results From the Phase 2 LUMINARY Study

AbstractBackgroundCognitive impairment has a deleterious impact on patients with AD and their caregivers; new therapies are needed. SAGE‐718, a novel N‐methyl‐D‐aspartate receptor positive allosteric modulator, is being investigated for the treatment of cognitive impairment in patients with neurodegenerative diseases such as Alzheimer’s disease (AD). The LUMINARY Study is designed to evaluate the safety/tolerability of SAGE‐718 and its effects on cognitive symptoms in patients with AD.MethodLUMINARY (NCT04602624) is an open‐label, Phase 2 study evaluating SAGE‐718 (3mg QD for 14 days) in patients with AD. Patients (aged 50‐80 years) with Montreal Cognitive Assessment (MoCA) scores of 15‐24 were included. Treatment‐emergent adverse event (TEAE) incidence through Day 28 (primary endpoint), other safety outcomes (secondary endpoints), and cognitive and functional assessments were analyzed.ResultTwenty‐six patients (69.2% female; mean age 67 years), with a mean±SD MoCA of 20.7±2.61 were enrolled. Most patients (23/26) had a global Clinical Dementia Rating score of 0.5. Eight TEAEs were reported in 7 (26.9%) patients; all were mild/moderate; 6 were treatment related. No serious adverse events or deaths were reported. At Day 14, improvements from baseline were observed on multiple tests of executive functioning (Digit Symbol Substitution, Multitasking, One Touch Stockings, Spatial Working Memory, and 2‐Back tests) and learning and memory (Pattern Recognition Memory and Verbal Recognition Memory tests). Statistically significant MoCA improvement (+2.3 points vs baseline) was observed at Day 28. No changes in attention/psychomotor speed were observed. Functional assessments also captured notable improvement in some patients (Clinical Global Impressions Scales and Amsterdam Instrumental Activities of Daily Living Questionnaire), particularly on items measuring aspects of complex/higher order activities.ConclusionIn this study, SAGE‐718 was generally well tolerated and associated with cognitive and functional improvements in patients with AD. These results support further investigation of SAGE‐718 for the treatment of cognitive impairment associated with AD and other neurodegenerative diseases.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

Awareness of Diagnosis in Persons with Early-Stage Alzheimer's Disease: An Observational Study in Spain.

IntroductionLimited information is available on people’s experiences of living with Alzheimer’s disease (AD) at earlier stages. This study assessed awareness of diagnosis among people with early-stage AD and its impact on different person-centered outcome measures.MethodsWe conducted an observational, cross-sectional study in 21 memory clinics in Spain. Persons aged 50–90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. The Representations and Adjustment to Dementia Index (RADIX) was used to assess participants’ beliefs about their condition and its consequences.ResultsA total of 149 persons with early-stage AD were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. Most participants (n = 84, 57.5%) used a descriptive term related to specific AD symptoms (e.g., memory difficulties) when asked what they called their condition. Participants aware of their diagnosis using the term AD (n = 66, 45.2%) were younger, had more depressive symptoms, and poorer life satisfaction and quality of life compared to those without awareness of their specific diagnosis. Practical and emotional consequences RADIX scores showed a significant negative correlation with Quality of Life in Alzheimer’s Disease score (rho = − 0.389 and − 0.413, respectively; p < 0.0001). Years of education was the only predictor of awareness of AD diagnosis [OR = 1.04 (95% CI 1.00–1.08); p = 0.029].ConclusionsAwareness of diagnosis was a common phenomenon in persons with early-stage AD negatively impacting their quality of life. Understanding illness representations in earlier stages may facilitate implementing optimized care that supports improved quality of life and well-being.

0271 Actigraphy Based Measures of Sleep Disruption and Circadian Rhythms in the WashU Biomarkers of Alzheimer’s Disease in Sleep and EEG (BASE) Cohort

Abstract Introduction Prospective studies of Alzheimer’s disease (AD) demonstrate sleep-wake disturbances may precede and accelerate with cognitive decline. Use of wrist-actigraphy in conjunction with overnight polysomnography (PSG) enables researchers to evaluate diverse characteristics of sleep and circadian rhythms. Though outcome measures from these devices have been implicated in the progression of AD, because of great individual differences, it is valuable to internally replicate within cohort. Here we demonstrate application of actigraphy in the context of healthy aging to identify patterns of activity that predict cognitive decline. Methods Participants were prospectively recruited at Washington University as part of the BASE study and wore an Actiwatch2 (Philips-Respironics) and cross-validated for sleep and wake using polysomnography. The watch was worn continuously for at least 5 consecutive nights to be included in the analysis (n = 68, age = 71.1 ± 4.5 years). Rest-activity rhythms were computed using compiled code from National Sleep Research Resource (actiCircadian) pipeline implemented in MATLAB R2021a (Mathworks). Clinical Dementia Rating (CDR) scales and cognitive tests were conducted on the first day of actigraphy recording. Results Individuals with cognitive impairment (CDR Global Score &amp;gt; 0) had increased wake after sleep onset (WASO) and reduced sleep efficiency compared with individuals with no impairment (CDR = 0). (unpaired ttest: p = 0.02 and p = 0.02). Participants with cognitive impairment had a trend toward reduced relative amplitude (RA) (p = 0.06). Reduced (worse) RA was correlated with worse performance on the Trail Making Task A (Pearson r: -0.37, p = 0.002). Higher (better) interdaily Stability (IS) was associated with better responses on subjective questionnaires including Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index (Pearson r: -0.24 p = 0.051; r: 0.242, p = 0.047, respectively). Conclusion Actigraphically-derived rest-activity metrics are correlated with cognitive status, cognitive test performance, and subjective sleep questionnaires. Support (If Any) NIH R01 AG059507, ARCS Foundation Scholar