Longitudinal Cognitive Function Research Articles

Psychological resilience is protective against cognitive deterioration in motor neuron diseases

Objectives Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs. Methods 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann–Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients. Results MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally. Conclusions PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions.

Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Is the change in longitudinal cognitive function in older adults with diabetes affected by trajectory classes of depressive symptoms?

This study aims to identify classes based on the trajectory of depressive symptoms and to examine the impact of trajectory classes of depressive symptoms on longitudinal changes in cognitive function in older adults with diabetes. This is a secondary data analysis of 572 older adults with diabetes using data from the 5th (2014) to 8th (2020) wave of the Korean longitudinal study of aging. Analysis of latent class growth and the effect of trajectories of depressive symptoms on cognitive function was examined using a latent growth curve model. This analysis has been found to be functional in change trajectories and in describing the direction of the trajectory. The trajectory of depressive symptoms was classified into four classes: low-stable (36.89%), high-decreasing (20.28%), low-increasing (18.71%), and high-persistent (24.13%). Compared with the high-persistent class, higher initial levels of cognitive function were observed in the high-decreasing and low-stable classes. Compared with the high-persistent class, a slower rate of cognitive decline was observed in the low-stable class (B=0.410, p=.021). Continuous monitoring of depressive symptoms and early management of depressive symptoms for community-dwelling older adults with diabetes can help prevent the cognitive decline and delay the deterioration of cognitive function.

Different effect of hypo- and hypermetabolism on cognition in dementia with Lewy bodies: are they coupled or independent?

Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid β (Aβ)42, the Aβ42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. After adjusting for confounders, lower Aβ42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aβ42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Transcriptional risk score in Alzheimer’s disease: from pathology to cognition

AbstractBackgroundTranscriptional risk scores (TRS), a summation of polarized expression levels of functional genes, have been proposed for disease risk assessment using transcriptome profiles. Our previously developed blood‐based TRS showed associations with diagnosis and neuroimaging biomarkers for Alzheimer’s disease (AD). Here, we developed brain‐based TRS models and calculated TRS using brain tissue‐based transcriptome profiles.MethodWe integrated AD genome‐wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization and then calculated individual TRS by summing the polarized z‐scores over the target genes. We used brain transcriptome data from the Religious Orders Study and Rush Memory and Aging Project cohort (ROSMAP; N = 634) as a discovery set and the Mount Sinai Brain Bank cohort (MSBB; N = 244) as a replication set. We performed association analysis of TRS with AD diagnosis, amyloidopathy, tauopathy, and cross‐sectional and longitudinal cognitive function. We compared AD classification performance of TRS with polygenic risk scores (PRS) using a machine learning approach (Fig. 1).ResultHigher TRS values were significantly associated with AD compared to cognitively normal controls (Table 1). Higher TRS values were also related with amyloidopathy, tauopathy, poor cognitive performance, and faster cognitive decline. The AD classification performance of PRS was increased with the inclusion of TRS up to 12% with the area under the curve value of 0.842 (Fig. 2). These findings were replicated in the replication dataset.ConclusionOur results showed that brain‐based TRS is associated with AD pathology and clinical course. Furthermore, TRS improves the AD classification performance of PRS. Along with static PRS, dynamic TRS based on transcriptional expression levels at a given time could be a potential disease‐stage specific AD biomarker.

16 Longitudinal Cognitive Functioning in Gulf War veterans with and without Gulf War Illness: Data Mining from the BBRAIN Repository

Objective:Veterans from the 1991 Gulf War (GW) experienced several neurotoxicant exposures, including chemical weapons, pesticide sprays and creams, oil well fires and pyridostigmine bromide anti-nerve gas pills during the war. Research has shown these exposures to affect cognition and mood. Moreover, MR diffusion imaging has shown microstructural changes in the white matter that may be related to psychomotor slowing. Over a third of all GW veterans suffer from a chronic multi-symptom disorder called Gulf War Illness (GWI). The Kansas Criteria for GWI consists of six distinct criteria including symptoms of fatigue/sleep problems, pain symptoms, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms. The Boston Gulf War Illness Consortium (GWIC) was a multi-site study designed to assess symptoms of GWI. After the conclusion of the GWIC study, the Boston Biorepository Recruitment and Integrative Network for Gulf War Illness (BBRAIN) was developed to harmonize retrospectively collected GW Veteran data while simultaneously collecting Time 2 data and samples from GW veterans who participated in the original study. This analysis includes the first 58 participants who have completed the GWIC study and the BBRAIN study.Participants and Methods:We conducted a longitudinal analysis of cognitive outcomes from the BBRAIN data repository. Verbal learning, memory, attention, and executive functioning were assessed using neuropsychological tests including the Continuous Performance Test (CPT3), Trail Making Test A, Delis-Kaplan Executive Function System (DKEFS), California Verbal Learning Test (CVLT-II). A total of 58 participants were re-evaluated from the original GWIC cohort with a total of 47 cases and 11 controls. Paired t-tests for the cognitive measures were completed separately for GWI cases and healthy GW veteran controls for each of the neuropsychological test measures. Average time between assessments was four years.Results:The overall sample was on average 56 years old, 84% male and 75% White. The average level of education was 15 years. GWI cases showed significantly more commission errors and slower reaction times on the CPT3 at Time 2 compared to Time 1 (p &lt; 0.05). Cases also showed a slowing in time to completion on Trails A at the second time point (p&lt;0.05). On the other hand, controls only showed significantly slower reaction times on the CPT3 at Time 2 (p&lt;0.05).Conclusions:These results showed that veterans with GWI are showing more decline over time in cognitive functioning particularly on psychomotor slowing and impulsivity than control veterans. It is important to document illness trajectories for veterans with GWI in order to devise strategies for interventions and treatments. The importance of studying longitudinal cohorts is to document changes in the same individuals over time. The next steps are to assess if this accelerated aging develops into neurodegenerative conditions by using brain imaging and other biomarkers in addition to cognitive evaluations. This could identify individuals who should be the focus of targeted treatment strategies while there is still time to intervene.

Oral health and risk of cognitive disorders in older adults: A biannual longitudinal follow-up cohort.

Oral health may be associated with cognitive disorders such as mild cognitive impairment or dementia. This study elucidates the effects of oral health conditions on the progression of cognitive disorders. Data were collected from 153 participants of the Korean Longitudinal Study on Cognitive Aging and Dementia cohort who completed the longitudinal dental examinations and cognitive function assessments using the three-wave biannual survey. We analysed the relationship between dental factors and the conversion of cognitive function. The ratio of maxillary removable partial denture use (p = .03) was high in the converter and mild cognitive impairment/dementia groups. The low-grade ratio of posterior masticatory performance increased in the converter and mild cognitive impairment/dementia groups (modified Eichner index 2, p = .04). The mild cognitive impairment/dementia group had a higher rate of complete mandibular denture use (p < .001). The converter and mild cognitive impairment/dementia groups had fewer remaining teeth (p < .05) or removable prostheses (p < .01) than the normal group. Masticatory performance is associated with the conversion of cognitive disorders. Our findings suggest that oral health management can help delay the progression of cognitive disorders.

Metabolically Healthy Overweight and Obesity, Transition to Metabolically Unhealthy Status and Cognitive Function: Results from the Framingham Offspring Study.

To evaluate the association between metabolically healthy overweight/obesity (MHO) status and longitudinal cognitive function while also considering the stability of the condition. In total, 2892 participants (mean age 60.7 (9.4) years) from Framingham Offspring Study completed health assessments every four years since 1971. Neuropsychological testing was repeated every four years starting from 1999 (Exam 7) to 2014 (Exam 9) (mean follow-up: 12.9 (3.5) years). Standardized neuropsychological tests were constructed into three factor scores (general cognitive performance, memory, processing speed/executive function). Healthy metabolic status was defined as the absence of all NCEP ATP III (2005) criteria (excluding waist circumference). MHO participants who scored positively for one or more of NCEP ATPIII parameters in the follow-up period were defined as unresilient MHO. No significant difference on the change in cognitive function over time was observed between MHO and metabolically healthy normal weight (MHN) individuals (all p > 0.05). However, a lower processing speed/executive functioning scale score was observed in unresilient MHO participants compared to resilient MHO participants (β = -0.76; 95% CI = -1.44, -0.08; p = 0.030). Retaining a healthy metabolic status over time represents a more important discriminant in shaping cognitive function compared to body weight alone.

Evaluation of Cognitive Functioning Before and After Cochlear Implantation in Adults Aged 55 Years and Older at Risk for Mild Cognitive Impairment

Given the rapidly rising dementia incidence, management of modifiable risk factors, such as hearing loss, is vital. Multiple studies have demonstrated an improvement of cognitive functioning in older adults with severe hearing loss after cochlear implantation; however, few of these studies, to the authors' knowledge, specifically analyzed participants achieving poor cognitive results preoperatively. To evaluate the cognitive functioning of older adults with severe hearing loss at risk for mild cognitive impairment (MCI) before and after cochlear implantation. This prospective, longitudinal cohort study performed at a single center reports data obtained over a 6-year period (April 2015 to September 2021) of an ongoing prospective, longitudinal cohort study on cochlear implant outcomes in older adults. A consecutive sample of older adults with severe hearing loss eligible for cochlear implantation was included. All participants obtained a Repeatable Battery for the Assessment of Neuropsychological Status for hearing-impaired patients (RBANS-H) total score indicative of MCI preoperatively. Participants were assessed before cochlear implant activation and 12 months after cochlear implant activation. The intervention consisted of cochlear implantation. The primary outcome measure was cognition, measured by the RBANS-H. A total of 21 older adult cochlear implant candidates were included in the analysis (mean [SD] age, 72 [9] years; 13 [62%] men). Cochlear implantation was associated with an improvement of overall cognitive functioning 12 months after activation (median [IQR] percentile, 5 [2-8] vs 12 [7-19]; difference, 7 [95% CI, 2-12]). Eight participants (38%) surpassed the MCI cutoff (16th percentile) postoperatively, while the overall median cognitive score remained under this cutoff. In addition, participants' speech recognition in noise improved, with a lower score indicating improvement (mean [SD] score, +17.16 [5.45] vs +5.67 [6.3]; difference, -11.49 [95% CI, -14.26 to -8.72]), after cochlear implant activation. Improvement of speech recognition in noise was positively associated with improvement in cognitive functioning (rs, -0.48 [95% CI, -0.69 to -0.19]). Years of education, sex, RBANS-H version, and symptoms of depression and anxiety were not related to the evolution in RBANS-H scores. In this prospective, longitudinal cohort study, cognitive functioning and speech perception in noise showed a clinically meaningful improvement 12 months after cochlear implant activation in older adults with severe hearing loss at risk for MCI, suggesting that cochlear implantation is not contraindicated in cochlear implant candidates with cognitive decline and should be considered after multidisciplinary evaluation.

Cognitive trajectories during the menopausal transition.

Female sex is associated with an increased prevalence of dementia. Menopause may have a role to play in explaining sex differences in cognition, and possibly the risk of future dementia. We aimed to determine if the rate of cognitive decline differed between stages of the menopausal transition. Women with data on menopause and longitudinal cognitive function from the UK Biobank study were stratified into three groups: premenopausal, perimenopausal and postmenopausal. We studied associations of these menopause groups with rate of change in reaction time, verbal-numeric reasoning, prospective memory, visual memory and attention/working memory, adjusted for age, education, ethnicity and APOEε4 genotype. We also explored the effect of menopausal hormonal therapy (MHT) use and cross-sectional brain magnetic resonance imaging (MRI) volumes on these models. We included 15,486 women (baseline mean age 52 years) over a mean duration of 8 years. An interaction between menopausal group status and time was found for reaction time (p < 0.01). Compared with premenopausal women, the rate of increase (worsening) in reaction time was least in postmenopausal women (β = -1.07, p for interaction = 0.02). In general, compared with premenopausal women, perimenopausal and postmenopausal women had overall poorer performance in fluid intelligence and memory over the study duration, with no difference in rates of change. The models were unaffected by MHT use and brain volume measures. Perimenopause and post-menopause are associated with cognitive changes. Psychomotor speed appears to be most sensitive to the menopause transition, whereas other cognitive functions may be less susceptible. More sensitive structural or functional brain imaging may be required to understand the underlying neural basis for these findings.

Longitudinal changes of cognitive function and its relationship with subdomains of negative symptoms in patients with adult-onset first-episode schizophrenia: A 4-year follow up study

BackgroundsThis study explores the longitudinal changes and trajectories of cognitive functions in patients with adult-onset first-episode schizophrenia (FES) over four years and their relationships with the baseline subdomains of negative symptoms. MethodsA total of 177 patients of age 25–55 with FES were recruited. Baseline demographics, clinical, social and cognitive functions were assessed. Diminished expression and diminished motivation of negative symptoms were assessed with Scale for the Assessment of Negative Symptoms (SANS). Patients had yearly follow-up of cognitive function assessments over four years. Latent class growth analysis (LCGA) and mixed linear regression model were used to explore the longitudinal changes of cognitive functions and the effect of baseline negative symptoms on the longitudinal cognitive function changes. Relationships of baseline negative symptoms subdomains and cognitive functions were also explored. ResultsTwo trajectories of cognitive functions were identified. Longitudinal improvements were found in most cognitive functions apart from the logical memory. One trajectory of patients had significant deterioration of logical memory while the other group had significant improvement. Baseline diminished expression was associated with baseline and longitudinal changes of processing speed and verbal fluency while diminished motivation was associated with baseline and longitudinal changes of processing speed. ConclusionsAdult-onset FES patients had a homogeneous longitudinal improvement in most cognitive functions but not for logical memory suggesting the unique nature of verbal memory. The distinct relationship between baseline subdomains of negative symptoms with baseline and longitudinal cognitive functions suggesting the presence of differential overlapping etiology between negative symptom subdomains and cognitive functions.

Meaningful cognitive decline is uncommon in virally suppressed HIV, but sustained impairment, subtle decline and abnormal cognitive aging are not

High antiretroviral therapy (ART) coverage and viral suppression among people with HIV (PWH) in Australia provide a unique context to study individual cognitive trajectories, cognitive aging and factors associated with longitudinal cognitive function during chronic and stable HIV disease. Participants from the Predictors of Adherence to Antiretroviral Therapy study (n=457, recruited between September 2013 and November 2015, median age=52 years, and all with HIV RNA <50 copies mL) completed a cognitive assessment with CogState Computerized Battery (CCB) at baseline, Month-12, and Month-24. Demographics, psycho-social and socioeconomic factors, healthcare seeking behaviors, HIV disease characteristics and comorbidities were assessed. The CCB data were corrected for age, sex and practice effect and averaged into a global z-score (GZS). Cognitive impairment was defined with the global deficit score method (GDS>0.5). Meaningful cognitive change was statistically defined (decline or improvement versus stability, i.e., 90% CI, that is p<0.05, 2-tailed) using a novel evidence-based change score: the linear mixed-effect regression (LMER)-based GZS change score. A separate LMER model with a top-down variable selection approach identified the independent effects of age and other demographic, HIV disease characteristics, socioeconomic and health-related factors on the demographically corrected GZS. The combined definitions of change and cross-sectional impairment enabled the identification of cognitive trajectories. At Month-12 and Month-24, 6% and 7% showed meaningful cognitive decline and 4% and 3% improved respectively. Only 1% showed sustained decline. Incident impairment due to subtle cognitive decline (i.e., below the threshold of meaningful cognitive decline) was 31% and 25% at Month-12 and Month-24, while 14% showed sustained impairment (i.e., cognitively impaired at all study visits). Older age (≥50 years) and time interaction was associated with lower demographically corrected GZS (β=-0.31, p<0.001). Having a regular relationship, excellent English proficiency, and perceived stigma (avoidance) were associated with higher GZS (all p<0.05). Relying on government subsidy, severe depression, and lower belief in ART necessity and higher concerns were associated with lower GZS (all p<0.05). No HIV disease characteristics had a significant effect. Meaningful cognitive decline was not different from normal expectation in chronic stable HIV disease. Despite this, subtle cognitive decline, sustained cognitive impairment, and greater than normative-age cognitive aging were evident. Funding for the PAART study was provided in part by unrestricted educational grants from Gilead Sciences (www.gilead.com) (Grant Number: IN-AU-264- 0131), the Balnaves Foundation (www.balnavesfoundation.com), the Victorian Department of Health and Human Services (Australia) (www.dhs.vic.gov.au/home), Western Australia Health (www.health.wa.gov.au), the ACT Ministry of Health (Australia) (www.health.act.gov.au), and in-kind support from the Queensland Department of Health (Australia) (www.health.qld.gov.au), and NHMRC Partnership grant APP1058474 (PI: Carr, Andrew).

Spatial‐temporal subtypes of amyloid deposition show distinct baseline and longitudinal cognitive profiles

AbstractBackgroundWe recently identified three distinct spatial‐temporal trajectories of amyloid deposition through the application of a machine‐learning model (i.e., Subtype and Stage Inference [SuStaIn]) to amyloid positron emission tomography (PET) data. These included Frontal, Parietal, and Occipital subtypes, defined by the earliest regions to show abnormality. The current study aimed to determine whether these subtypes of amyloid accumulation hold value in predicting baseline and longitudinal cognitive functioning in addition to a validated measure of global amyloid burden, i.e. Centiloid (CL) units.MethodThe Frontal, Parietal, and Occipital subtypes were applied to the amyloid‐PET standard uptake value ratios (SUVr) of 2,510 subjects from 3 cohorts (ADNI, EMIF‐AD, OASIS‐3). Of these, 570 subjects with a high subtype probability assignment (&gt;50%), assigned stage ≥ 1, and available cognition were included in the analyses. Subtypes were compared on global cognition and several cognitive domains including memory, attention, executive functioning, language, and visuospatial functioning. To assess whether subtype assignment added to baseline CL in predicting baseline and longitudinal cognition (range follow‐up=0.4‐11 years), linear models (predictors: subtype and CL) and linear mixed models (predictors: subtype*time and CL*time) were performed, respectively. All models were adjusted for baseline age, sex, education, and baseline cognitive stage.ResultParticipant characteristics are shown in Table‐1. The majority was assigned to the Frontal subtype (57%), followed by Occipital (22%) and Parietal (20%). After adjusting for baseline CL, the Occipital subtype showed lower baseline language scores than the Parietal subtype (β=‐0.34, p=.046) (Fig‐1A) and lower baseline attention scores than both Frontal (β=‐0.39, p=.047) and Parietal (β=‐0.73, p=.002) subtypes (Fig‐1B, Table‐2). In addition, the Occipital subtype declined faster over time on global cognition (Fig‐2A) and language (Fig‐2B) as compared to the Frontal (βglobal cognition=‐0.35, pglobal cognition=.007; βlanguage=‐0.10, planguage=.015) and Parietal (βglobal cognition=‐0.50, pglobal cognition=.002; βlanguage=‐0.13, planguage=.015) subtypes.ConclusionOur results show the added value of amyloid subtype assignment on top of CL measures on baseline and longitudinal cognition. Specifically, the Occipital subtype was associated with lower baseline performance and showed faster rates of cognitive decline. These findings suggest that subtype assignment based on amyloid PET might improve prognosis and patient stratification in clinical trials.

Older Adults with Acute Myeloid Leukemia (AML) Treated in a Pragmatic Trial: How Do Patients’ Function and Health-Related Quality of Life Change with Treatment?

Background: Over one-third of older adults with AML do not receive chemotherapy because of fear of toxicities and functional decline. This highlights the critical and urgent need to generate knowledge of functional changes following newer treatments. Methods: As a part of a pragmatic single-center phase II investigator-initiated trial (ClinicalTrials.gov ID: NCT03226418), we enrolled older adults (≥60 years) with a new diagnosis of AML. We repeated geriatric assessment (GA) and health-related quality of life (HRQOL) before and 3 months after chemotherapy initiation. GA included measures of physical function (e.g. short physical performance battery or SPPB), Montreal Cognitive Assessment (MoCA), Hematopoietic Cell Transplantation Comorbidity Index, Patient Health Questionnaire-9 (PHQ-9), Mini Nutritional Assessment-Short Form. Frailty was defined as impairment in 2 or more domains on geriatric assessment (excluding MoCA). HRQOL was measured using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (v 3.0). Established cutoffs were used to determine a clinically meaningful change in various measures from baseline to 3 months. Results: 59 eligible patients were enrolled and had median age of 69 years and median KPS of 80. Patients received treatment with predominantly low-intensity chemotherapy (hypomethylating agent +/-venetoclax or midostaurin); six patients received intensive chemotherapy. 56% of patients had ≥2 comorbid conditions, and 69% each had impaired MoCA scores and impaired objective physical function at baseline. Whereas 29% had an established diagnosis of depression or anxiety, 66% had abnormal PHQ-9 with a score of 5 or more. 61% had impaired nutritional screen. A total of 43 patients completed some or all of the optional follow-up assessments at 3 months. Cognitive function or MoCA scores improved (64.5%) or stabilized (9.6%) from baseline to 3 months after treatment (Figure 1). We also noted improvement (51.6%) or stabilization (22.6%) in objective physical function (Figure 2). PHQ-9 scores showed improvement or stabilization in about 90% of patients. Nutritional scores showed variable changes with 40% demonstrating improvement. On HRQOL assessment, global health status score, and role functioning moderately improved from baseline to three-month after enrollment. Longitudinal cognitive function over 3 months differed based on the presence of frailty and multimorbidity (≥2 comorbid conditions) at baseline. Improvement in MoCA scores was noted in 31.8% (95% CI 16.4-52.7%) and 50.0% (95% CI 23.7-76.3%) of patients with versus without baseline frailty. The risk of worsening of cognitive function was 31.5% (95% CI 15.4-54.0%) for patients with multimorbidity at baseline versus 16.7% (95% CI 4.7-44.8%) for those without. Conclusion: We demonstrated an overall improvement or stabilization of functional status and HRQOL in a high proportion of older adults with AML, despite high prevalence of functional impairments and significant comorbidity burden at baseline. These results should encourage oncologists to offer chemotherapy even to older adults with multiple comorbid conditions or poor functional status at the time of diagnosis of AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of COVID-19 policies on perceptions of loneliness in people aged 75 years and over in the cognitive function and aging study (CFAS II).

The COVID-19 pandemic and associated social distancing measures have profoundly impacted society and social contact patterns, with older people disproportionately affected. Concerns have been raised about a resulting pandemic of loneliness in older people, although the current evidence is mixed. This study provides a unique perspective on the prevalence of loneliness in a population cohort of older people before the pandemic, followed up after the introduction of social restrictions. Data analysis was conducted using Wave 3 of the longitudinal Cognitive Function and Aging Study II (2018-2019) and a sub-study focusing on experiences during the COVID-19 pandemic (2020). The sample comprised 379 adults aged over 75 living in Cambridge, Newcastle, and Nottingham. Multivariable binary logistic regression was conducted to identify correlates of prevalent loneliness, adjusted for confounding covariates, during the pandemic. The prevalence of loneliness during the pandemic was compared to loneliness in 2018-2019. Prevalence of loneliness in this sample during the pandemic was 25.1% (95% CI 20.9%-29.7%) compared to 17.2% (95% CI 13.7%-21.3%) in 2018-2019 (χ2 =14.1, p < 0.01). Variables associated with increased odds of prevalent loneliness included: prior loneliness, living alone, female gender, living in an area of higher deprivation, frequent pre-pandemic social contact at community groups, and separation from family during the pandemic, adjusted for age and sex. Weekly technology-mediated contact using telephone or video calls was associated with lower odds of loneliness. COVID-19 recovery plans should address loneliness in older people. Target groups should include those who have previously been lonely, people who live alone, those living in deprived areas, and those who had previously been socially active through community groups.

Fragmentation of rest periods, astrocyte activation, and cognitive decline in older adults with and without Alzheimer's disease.

Sleep disruption is associated with astrocyte activation and impaired cognition in model organisms. However, the relationship among sleep, astrocyte activation, and cognition in humans is uncertain. We used RNA-seq to quantify the prefrontal cortex expression of a panel of human activated astrocyte marker genes in 1076 older adults in the Religious Orders Study and Rush Memory and Aging Project, 411 of whom had multi-day actigraphy prior to death. We related this to rest fragmentation, a proxy for sleep fragmentation, and to longitudinal cognitive function. Fragmentation of rest periods was associated with higher expression of activated astrocyte marker genes, which was associated with a lower level and faster decline of cognitive function. Astrocyte activation and fragmented rest are associated with each other and with accelerated cognitive decline. If experimental studies confirm a causal relationship, targeting sleep fragmentation and astrocyte activation may benefit cognition in older adults. Greater fragmentation of rest periods, a proxy for sleep fragmentation, is associated with higher composite expression of a panel of genes characteristic of activated astrocytes. Increased expression of genes characteristic of activated astrocytes was associated with a lower level and more rapid decline of cognitive function, beyond that accounted for by the burden of amyloid and neurofibrillary tangle pathology. Longitudinal and experimental studies are needed to delineate the causal relationships among sleep, astrocyte activation, and cognition.

Educational and Clinical Associations With Longitudinal Cognitive Function and Brain Imaging in American Indians: The Strong Heart Study.

Little is known about incidence of vascular and Alzheimer dementias in American Indians. We conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64-95 years from 11 tribes across 3 states, with neurologic examinations, 1.5T MRI, and extensive cognitive testing. Visit 1 in 2010-2013 (n = 817) and visit 2 in 2017-2019 (n = 403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini-Mental Status Examination (MMSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association (COWA), and California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer Coordinating Center Uniform Data Set cognitive battery (v3 form C2), including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement. The mean time between examinations was 6.7 years (SD 1.1, range 3.8-9.1 years). Years of formal education had modest correlation with WRAT reading score (r = 0.45). Prevalence and incidence (respectively) of infarcts were 32% and 12.8/1,000 person-years (PYs) hemorrhages 6% and 4.4/1000 PY worsening sulci 74% and 19.0/1000 PY worsening ventricle 79% and 30.1/1000 PY worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% MMSE, 1.2% WAIS, 0.6% COWA, and 2.2% CVLT. The mean MoCA scores were 18.9 (SD 4.3). These are the first data on longitudinal cognitive and imaging changes in American Indians and first reports of Alzheimer disease-related features. The mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education were a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death, and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

171P Association of breast cancer therapy with cognitive decline in older women with early breast cancer: Findings from the CLIMB study

Studies investigating the long-term effects of breast cancer treatment on cognition in older breast cancer survivors are lacking, even though intact cognition is a highly valued outcome by the older population. Specifically, concern has been raised about detrimental effects of endocrine therapy (ET) on cognition. Therefore, we aimed to investigate longitudinal cognitive functioning and predictors of cognitive decline in older women treated for breast cancer. We prospectively enrolled Dutch women aged 70 years or older with stage I-III breast cancer in the CLIMB study. The Mini-Mental State Examination (MMSE) was performed at baseline, and 9, 15 and 27 months. Longitudinal trajectories of MMSE scores were analyzed for the minimal clinically important difference (2.3 points) in the whole cohort and in women treated with ET. To compare MMSE scores between patients with impaired and normal cognition and to identify the association between possible predictors and cognitive decline, linear mixed models were estimated. Among the 273 participants, mean age was 75.8 years (standard deviation (SD) 5.2) and 48% received adjuvant ET. Mean MMSE at baseline was 28.24 (SD 1.95). Cognition did not decline over time to clinically important differences in the whole cohort or in women receiving ET. MMSE scores of women with pretreatment cognitive impairments improved over time (significant interaction terms) in the whole cohort and in women receiving ET. Older age, lower education level and impaired mobility were independently associated with cognitive decline, but this decline was not clinically significant. Cognition of older women with early breast cancer did not decline up until two years after treatment initiation, irrespective of endocrine therapy. Our findings might indicate that fear of declining cognition does not justify de-escalation of breast cancer treatment in older patients.

Cerebrospinal fluid growth-associated protein 43 levels in patients with progressive and stable mild cognitive impairment.

Cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) is prominently elevated in Alzheimer's disease (AD) dementia patients in comparison to normal controls. CSF GAP-43 levels in mild cognitive impairment (MCI) individuals who have different clinical trajectories need to be studied. We examined 137 cognitively normal (CN) controls, 218 stable MCI patients (sMCI), 99 progressive MCI (pMCI) patients, and 120 AD dementia patients. Associations between the CSF GAP-43 levels and the four diagnosis groups were evaluated with multiple-variable linear regression. The relationships between CSF GAP-43 and core CSF biomarkers were assessed by Spearman correlations. Cox regression analysis was performed to assess the values of GAP-43 in predicting MCI conversion. We examined associations between baseline CSF GAP-43 levels and longitudinal cognitive function, hippocampal volumes, and brain glucose metabolism using linear mixed-effects models. CSF GAP-43 was elevated in the pMCI and AD groups in comparison to the CN group and in the pMCI and AD groups in comparison to the sMCI group. CSF GAP-43 significantly predicted conversion from MCI to AD. CSF GAP-43 was a significant predictor of cognitive decline, hippocampal atrophy, and brain hypometabolism over time. Furthermore, elevated CSF GAP-43 levels were associated with accelerated deterioration in cognition and neurodegeneration. CSF GAP-43 is increased in the predementia stage of AD, and it may enhance the neurodegenerative process. Future efforts on pharmacological interventions targeting synaptic dysfunction could be promising in AD treatment.