bluuebunny/crossref_metadata_2025 huggingface dataset:
The importance of study partners in Alzheimer’s clinical trials: An examination of the association between relationship type and protocol adherence
Authors: Parnitivithikul Tara , Abdulmumin Razyya L
Published: December 2023

Background

Clinical trials for Alzheimer’s Dementia (AD) often require the involvement of a study partner, or knowledgeable informant, who serves as a data source for outcomes related to participants’ cognition and function. Study partners are essential to the success of AD trials (Largent et al., 2018). Although participants are not required to be related to their study partners, research has found that those with spouses as study partners were more likely to qualify for trials compared to those with adult children as their study partners (Grill et al., 2012). Furthermore, those whose spouses served as their study partners were less likely to drop out than those whose study partners were neither spouses nor adult children (Grill et al., 2013; Nuno et al., 2022). The current study further contributes to these prior works by examining how study partner type relates to participants’ compliance while enrolled in a clinical trial.

Method

Secondary data analyses of a Phase 3 Early AD clinical trial will be conducted to examine how relationship type relates to adherence to protocol visits. Specifically, one way analysis of variance will be conducted to test the effect of relationship type (i.e., spouse, other family, other/non‐family) on adherence to protocol visit windows (i.e., number of out of window and missed visits). Correlation analyses also will be conducted to assess whether the average number of hours participants spend with their study partners per week is related to their compliance with study visits.

Result

Results from the study will provide insight on study partner types that can facilitate greater adherence to protocol‐related procedures. Findings also may indicate whether the number of hours participants spend with their study partners are an important component of protocol adherence. Findings would have implications for study partner requirements of future AD trials.

Conclusion

The current study will provide greater understanding of the role of study partners, and how different relationship types and number of hours spent with participants may relate to overall study compliance.
Challenges of recruitment and biomarkers collection in Caribbean Hispanics
Authors: Reyes‐Dumeyer Dolly , Piriz Angel , Soriano Belisa , Franco Yahaira , Coronado Zoraida Dominguez , Recio Patricia , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Vardarajan Badri N , Honig Lawrence S. , Mayeux Richard
Published: December 2023

Background

Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (CH) has been ongoing for over 20 years. Our primary goal was to identify genes in large well‐phenotyped, multiplex families, and sporadic cases and controls. This longitudinal collection of data represents a unique resource for the scientific community. The project is led by collaborators in the United States (US) and the Dominican Republic (DR). For the past three years, our efforts have been centered on the collection of cerebrospinal fluid (CSF), plasma, serum and Paxgene tubes for RNA to study core biomarkers. Collection of blood samples for DNA to conduct genetic analyses is also ongoing.

Method

The cohort consisted of participants aged 50 and older from the DR, including those living in the New York City area, willing and able to provide a blood and CSF samples. Interviewers in the DR were trained to collect data, blood samples and CSF. DNA samples were sent overnight to Columbia university (CU) for processing. CSF, Paxgene tubes, serum and plasma samples were processed in the DR and stored at ‐80F for batch shipping to CU. APOE genotyping was conducted in the US. Biomarkers, metabolomics, and proteomics data was generated at Columbia University. Methylation assays from Paxgene was conducted at Uniformed Services University (USUHS).

Result

We have databased a total of 1899 individuals with plasma samples, 1707 with Paxgene, 1731 with serum and 203 with CSF. Blood samples from 1079 participants have genome wide arra, whole genome sequencing and APOE genotyping. 192 CSF samples have proteomics completed, 153 CSF samples have metabolomics data and 742 have plasma biomarkers (Ab40, Ab42, T‐tau, P‐tau181, NFL and GFAP)).

Conclusion

Sample collection for genetic studies in developing countries present important logistical challenges. Despite these challenges, sample quality is comparable to those collected in New York. Biomarkers from CSF, serum and plasma can give us a closer look into underrepresented populations such as Caribbean Hispanics. Results suggest that similar protocols can be successful in Latin America. Future work will augment the biosample collection of the cohort by collecting samples from additional subjects.
Promoting Dementia Prevention in African Americans: Qualitative Findings from Developing a Smoking Cessation Messaging Campaign
Authors: Johnson Adrienne L. , Gleason Carey E. , Lathen Lorraine
Published: December 2023

Background

African Americans (AA) are twice as likely to develop dementia compared to White counterparts. Cigarette smoking is a known modifiable risk factor for dementia and harder to quit with worse health outcomes for AA versus White adults. Because age is the strongest predictor of dementia onset, and older adults are half as likely to quit smoking compared to younger counterparts, older AA adults who smoke may be at higher risk for dementia compared to older non‐Hispanic whites. Culturally‐specific interventions for AA smokers are beneficial in terms of intentions to quit, utilization of quit‐smoking resources, and quitting success. However, there has yet to be a culturally‐specific message for older adult AA smokers to motivate cessation attempts and increase the use of evidence‐based quitting treatments.

Method

8 focus groups and key informant interviews were conducted with current and former AA smokers between 50‐80 years old with no history of dementia or MCI. Interviews lasted 60 minutes, used a semi‐structured interview guide, and were completed in person or virtually and led by a trained moderator knowledgeable of smoking in AA communities.

Result

Directed content analyses using a combination of deductive/inductive coding identified themes in 5 domains: concerns about aging, previous tobacco prevention advertisements, recommendations for future tobacco prevention advertisements, smoking and health risks, and smoking cessation treatments. Participants reported multiple concerns about aging; most were related to their smoking. Contrary to previous research with primarily White older adults who smoke, AA participants indicated dementia was no more important than any other health condition in motivating quitting. Most participants reported a strong existing motivation to quit, but multiple barriers impeded their success. One key barrier to quitting was access to cessation resources, and participants reported a strong desire for support groups with similarly aged and race‐concordant peers trying to quit smoking. Participants felt existing cessation advertisements were not made for them and did not include enough information to be helpful.

Conclusion

Findings highlight a need for increased resources to support cessation efforts in older adult AA communities, utility of developing culturally‐specific messages, and importance of discussing priorities with communities prior to developing dementia prevention messaging.
TREM2‐related Polygenic Risk Score predicts defect Innate Immune Activation in Alzheimer’s Disease
Authors: Dijkstra Janna I.R. , Tijms Betty M. , Vermunt Lisa , Teunissen Charlotte E. , Flier Wiesje M. , Holstege Henne , Visser Pieter Jelle , Lee Sven J
Published: December 2023

Background

TREM2 plays a central role in immune response which, in turn, is strongly related to Alzheimer’s disease (AD) pathology. We previously found an AD‐subtype with and without innate immune activation based on CSF proteomics. Possibly, genes associated with TREM2 pathways could explain differences between these two subtypes since R47H and R62H mutations are associated with decreased microglial activation. We tested this hypothesis in a large single site cohort, and compared them on PRS including previously reported GWAS genes associated with TREM2 pathways.

Method

We included participants from the Amsterdam Dementia Cohort who had AD subtyping based on CSF proteomics available (n = 466). Based on literature, we labelled 19 of 83 known AD risk genes as belonging to TREM2 pathways and used these to construct a TREM2‐PRS. We studied associations between a standard AD‐PRS with 83 SNPs, TREM2‐PRS with 19 SNPs and non‐TREM2‐PRS with 64 SNPs between two AD‐subtypes being (1) without innate immune activation and (2) with innate immune activation, using logistic regression models (correcting for sex, age and 5 principal components).

Result

The cohort involved 146 controls (mean age 61 years, 34% female) and 195 AD cases: 97 without immune activation subtype (mean age 64 years, 52% female) and 98 with immune activation subtype (mean age 68 years, 54% female). Both subtypes showed comparable increased risk on the standard AD‐PRS compared to controls (OR 1.65, 95%CI 1.2‐2.3, p = 0.002 and OR 1.7, 95%CI 1.1‐2.5, p = 0.006) (Table 1). A higher TREM2‐PRS was associated with no immune activation subtype (OR 1.5, 95%CI 1.1‐2.1, p = 0.008). The PRS of the other 64 risk variants, which were not labelled as belonging to TREM2 pathways, was associated with immune activation subtype (OR 1.5, 95%CI 1.1‐2.1, p = 0.02).

Conclusion

AD individuals with a CSF proteomic‐based subtype without immune activation show more genetic variants in TREM2 pathways, whereas these SNPs are not related to the subtype with innate immune activation. These findings provide evidence for genetic differences underlying AD‐subtypes, and suggest that therapies targeting immune functioning may need to tailor therapies to AD‐subtype (i.e., additional activation vs. decreasing activation).
Common neurobiological mechanisms underlying anosognosia and neuropsychiatric symptoms across the Alzheimer’s disease spectrum
Authors: Gagliardi Geoffroy Pierre , Mimmack Kayden J. , Wang Sharon , Fawzy Michael Elnemais , Cacciamani Federica , Munro Catherine E , Gatchel Jennifer , Marshall Gad A , Vannini Patrizia
Published: December 2023

Background

Both loss of awareness for cognitive decline (a.k.a. anosognosia) and neuropsychiatric symptoms (NPS) are common symptoms in Alzheimer’s disease (AD) and have been associated with AD pathology. Recent studies have shown a co‐occurrence between these symptoms across the AD spectrum, suggesting shared underlying neurophysiological processes, especially within the default mode network (DMN). Here, we investigated the relationship between NPS and altered awareness and the structural integrity (as assessed with diffusion tensor imaging, DTI) of brain regions supporting the DMN in participants with and without amyloid pathology.

Methods

Three‐hundred participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent an amyloid positron emission tomography (PET), using 18F‐AV45 (florbetapir), and were classified into two groups: amyloid‐positive (A+) and negative (A‐). Individual mean fractional anisotropy (FA) was calculated from tracts overlapping the DMN regions. An awareness index was computed using the discrepancy between Everyday Cognition questionnaire scores from participants and informants. The Neuropsychiatric Inventory Total Score was used to assess the informant‐reported NPS. We compared amyloid groups on demographics and our different measures of interest. Pearson correlations were used to determine associations between measures of interest in each amyloid group. A multivariate multiple regression (MMR) model was performed to determine whether structural brain integrity predicts altered awareness and NPS jointly.

Results

A+ participants were significantly older (74 ± 7 vs. 72 ± 7 for A‐), more impaired (CDR global), and showed lower awareness and diffusion, and greater NPS (all p<0.001, see Table 1). Significant correlations were found between the FA, NPS, and awareness measures in A+ participants, with decreased FA associated with decreased awareness and more NPS. The MMR confirmed these associations between FA, awareness and NPS (p<0.02, see Table 2). The Pillai test revealed that the DTI effect jointly contributed to both models. No significant relationships were observed in the A‐ group.

Conclusion

Our results show that, in amyloid‐positive individuals across the AD spectrum, decreased awareness and increased NPS were related to decreased structural integrity of the DMN. This supports the hypothesis of common neurobiological mechanisms underlying anosognosia and NPS in AD.
Instant diagnosis of dementia in older patients who were admitted with forgetfulness to a single geriatric memory clinic
Authors: DOST Fatma Sena , ONTAN Mehmet Selman , Mutlay Feyza , KAYA Derya , ISIK Ahmet Turan
Published: December 2023

Background

Aging is a process associated with progressive and predictable changes that can cause many diseases. As in other systems, structural changes occur in the brain, behavior, and cognitive functions with age. Older people often complain about the decrease in cognitive skills, especially in the memory area and forgetfulness is one of the most common cognitive complaints. In this study, we evaluated the diagnosis of major and minor cognitive impairment in older people who were admitted with forgetfulness to our clinic

Method

This cross‐sectional study, retrospectively desgned, was conducted between January 2018 and January 2022 on a total of 1440 participants who applied to the Geriatrics department with the complaint of forgetfulness, without any acute health problems and with a complete geriatric assessment, including activities of daily living, evaluation of cognitive functions and mood, and blood tests. Dementia diagnosis was made according to the DSM‐V and related specific diagnostic criteria. All demented patients had brain imaging, and cerebrospinal fluid biomarkers, if possible.

Result

The mean age and female frequency were higher in patients with major and minor cognitive impairment while estimated glomerular filtration, folate, and TSH levels were lower. The prevalence of major and minor cognitive impairment was 7.70% and 21.30% respectively. Most of the 3 major neurocognitive impairment diagnoses were Alzheimer’s Disease (7.40%), dementia with Lewy body (3.50%), and Parkinson’s Disease Dementia (1.70%).

Conclusion

Considering the risk of dementia in older adults, evaluating the memory complaints has of great importance. This study shows that the majority of the older adults who applied with the complaint of forgetfulness do not have dementia. It is remarkable that the rate of major and minor cognitive impairment was too high to be ruled out in our study population.
Determinants of dementia phenotype in North African & Mid‐eastern Israelis
Authors: Keret Ophir , Rabinovici Gil D. , Rosen Howard J. , Goldberg Ilan , Beninger Felix , Glik Amir
Published: December 2023

Background

Diverse ethnic ancestry and adverse social health determinants are increasingly recognized to impact dementia on multiple dimensions: genetically and environmentally determined risk, clinical presentation, detection, and the utility of cognitive testing and management. Most evidence originates from ethnically diverse cohorts in North America, with little representation of other world regions. We aimed to assess dementia clinical and neuroimaging phenotype in individuals of Middle Eastern and Northern African (MENA) descent, a population severely underrepresented in brain health research.

Methods

The Alzheimer’s and atypical dementias in Israelis of diverse ancestry and disparate social health determinants (ADIDAS) project started on January 1st, 2022, and will prospectively recruit 200 individuals aged 40‐80 years reporting a new cognitive decline. The ADIDAS protocol includes APOE genotyping, structured assessment of early‐to‐late life social determinants, Israeli neighbourhood disadvantage index, medical history, vascular risk factors, cognitive testing, plasma Alzheimer’s biomarkers (Aβ40, Aβ42, total‐tau, p‐tau181, and NfL), and brain MRI. Ancestry was defined using participants and paternal country of birth. Countries were grouped into MENA, European, or neither, as defined by the World Bank. The project aims to assess the relationship between ethnic ancestry and associated social health determinants as predictors of brain neurodegeneration evident on neuroimaging and plasma biomarkers.

Preliminary Results

As of January 1st, 2023, the ADIDAS cohort recruited 51 participants (55% female, mean age 65.8±8.4 years) of MENA (n = 24), European (n = 23), and neither (n = 3) ancestry. A preliminary comparison of MENA and European groups reveals MENA in our cohort are on average younger (63.87±8.9 vs. 68.3±8.2 years), have fewer years of schooling(11.7±2.5 vs. 16.2±3.4 years), and more likely to obtain only elementary or vocational education (75% vs. 13%). MENA were more likely to score poor results on cognitive testing‐ MMSE (21.6±4.9 vs. 24.8±5.5), receive a higher clinical dementia rating sum of boxes (3.4±2.5 vs. 1.45±1.4), and a lower carriage rate of apoE4 allele (11% vs. 30%).

Conclusion

Preliminary non‐matched comparison suggests MENA with early‐stage cognitive impairment have a different social, cognitive, and genetic risk profile than individuals of European ancestry. Results of plasma biomarkers profile and MRI‐related structural changes will be shared at AAIC2023.
Influence of visible white matter lesions on volumes from automated parcellations.
Authors: Sudre Carole H , Carrasco Ferran Prados , James Sarah‐Naomi , Wong Andrew , Malone Ian B , Cash David M , Fox Nick C , Cardoso M Jorge , Schott Jonathan M , Barnes Jo
Published: December 2023

Background

White matter hyperintensities (WMH) are a common occurrence in ageing populations. Their hypointense appearance on T1‐weighted scans is known to affect automated processing and subsequent extraction of volumetric measurements. While lesion infilling with healthy appearing tissue is a common practice in the context of multiple sclerosis, this is not yet the case in studies of neurodegenerative diseases. We investigated the impact of WMH infilling on the volumetric outputs of two automated parcellation pipelines.

Method

T1‐weighted and T2‐FLAIR scans were acquired for 462 individuals in the Insight46 neuroimaging substudy of the MRC National Survey for health and Development (NSHD). WMH were automatically segmented and T1‐weighted scans were subsequently infilled over the lesion masks. Two automated parcellation methods Geodesic Information Flows (GIF) and FastSurfer (FS) were run on the two T1‐weighted scans (original and infilled). Cortex, lateral ventricles, basal ganglia (BG), whole brain and total intracranial volumes (TIV) were derived from the four resulting parcellations. Spearman correlation was used to assess the relationship within and across methods according to infilling status. Correlations were also calculated between the observed volumes or percentage difference (original vs infilled volumes) and the WMH burden expressed as percentage of TIV.

Result

The relationship between parcellated volumes and WMH burden varied across methods and tissues/brain areas. While there was little observable relationship for GIF between brain volume or TIV difference and WMH, this relationship was positive for FS. The relationship with cortical volume difference was in opposite directions for GIF (negative relationship) and FS (positive relationship), indicating a tendency to decrease the estimated volume when WMH were visible for GIF and increase it for FS. For lateral ventricles and basal ganglia, volumetric measurements were higher in the presence of visible WMH for GIF and FS (Figure1). Correlations between FS and GIF were slightly stronger after infilling but correlation with WMH burden were attenuated (Table2).

Conclusion

The impact of presence of visible WMH on T1‐weighted scan varies according to the chosen technique of analysis and strong correlations were observed between the difference in measured volumes and the WMH burden. Infilling should be considered when T1‐weighted derived volumes are studied.
Inflammation and working memory performance in everyday life: Gender differences among older adults with and without cognitive impairment
Authors: Harrington Erin E , Graham‐Engeland Jennifer E , Lipton Richard B. , Roque Nelson A , Sliwinski Martin J. , Engeland Christopher G.
Published: December 2023

Background

Inflammation is a risk factor for cognitive decline, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Past research suggests that inflammation relates to cognitive performance and MCI status in laboratory settings, but it remains unclear how inflammation relates to everyday cognitive performance. The present work addressed this gap by examining inflammatory biomarkers in association with working memory measured via ecological momentary assessments (EMA) among those with and without MCI. Gender differences in these links were also examined.

Method

Older adults (n = 270, Mage = 76.97, 68% female) enrolled in the Einstein Aging Study were classified as MCI (n = 78) or no MCI using Jak Bondi criteria. Participants completed a two‐week EMA protocol which included daily periodic assessments of spatial working memory and provided two blood samples (one before and one following EMA), from which circulating (basal) and lipopolysaccharide (LPS)‐stimulated cytokines were quantified. Analyses examined correlations between inflammatory markers and working memory performance (i.e., accuracy – mean error distance) stratified by MCI status and by gender.

Results

Among those with MCI, higher levels of circulating cytokines (interleukin [IL]‐1b, IL‐6, IL‐10) correlated with worse working memory performance. In the MCI group, higher levels of stimulated cytokines (IL‐4, IL‐6, IL‐8, IL‐10, tumor necrosis factor‐alpha [TNF‐ α]) were associated with better performance. When examined by gender, it was men with MCI who appeared to drive these effects, as higher levels of circulating IL‐1b correlated with worse performance and higher levels of stimulated cytokines (IL‐1b, IL‐6, IL‐8, IL‐10, TNF‐α) correlated with better performance. No significant associations were observed among men without MCI, or among women regardless of MCI status. Findings held when controlling for BMI, age, and education.

Conclusion

Keeping with past work, the present study suggests that higher levels of circulating inflammation relate to worse working memory in everyday settings. Further, exhibiting a more robust response to immunological challenge (i.e., higher stimulated cytokines) may relate to better everyday working memory. However, these associations were observed only in men with MCI. Future longitudinal research is needed to better understand the links between circulating inflammation, inflammatory responses, and MCI; ultimately, this might inform early risk detection for MCI and AD.
Variability in Sleep is Associated with Inflammatory Biomarkers: Results from the Einstein Aging Study
Authors: Ji Linying , Shen Yuqi , Harrington Erin E , Van Bogart Karina , Graham‐Engeland Jennifer E , Derby Carol A. , Engeland Christopher G. , Buxton Orfeu M.
Published: December 2023

Background

Prior research links poor subjective sleep and higher systemic inflammation, both of which are risk factors for cognitive decline in older adults. To expand upon previous findings, we investigated associations between multiple objective aspects of sleep health (including sleep variability) and inflammation (including stimulated inflammatory markers) among a diverse sample of older adults.

Method

Participants free of dementia (N = 218, mean age = 77.5 years, 66% females; 46% White, 38% Black, 14% Hispanic/other, MCI positive = 61) enrolled in The Einstein Aging Study were included. Wrist actigraphy (Spectrum Plus) over 16 days yielded measures of sleep disturbance by wake after sleep onset (WASO), sleep duration as total night sleep time (TST), sleep timing (midpoint of night sleep), and variability of each sleep measure. Inflammatory markers included circulating CRP and interleukin (IL)‐1β, IL‐4, IL‐6, IL‐8, IL‐10, and tumor necrosis factor (TNF)‐𝛼 plus lipopolysaccharide (LPS)‐stimulated levels of these same cytokines. Separate linear regression models evaluated the association of each inflammatory marker and the average level and variability of each sleep measure. Models controlled for BMI, gender, age, education, and race/ethnicity.

Result

Circulating inflammatory markers were generally not associated with objective sleep measures. However, after controlling for covariates, associations were observed between shorter average WASO and higher IL‐4, later average night sleep midpoint and higher IL‐6, and more variability in TST with higher IL‐1β. For stimulated cytokines, more WASO variability was associated with higher levels of all stimulated cytokines except IL‐6 and IL‐1β. More variability in sleep duration (TST) was associated with higher IL‐8 (but not other cytokines). Mean and variability of sleep timing, and mean WASO and TST were not significantly associated with any of the stimulated cytokines.

Conclusion

The present findings add substantially to research suggesting that sleep patterns are related to inflammation in older adults. Stimulated cytokines [IL‐4, IL‐10, IL‐8, TNF𝛼] were more strongly related to variability measures than mean sleep measures. Since stimulated cytokine levels reflect inflammatory reactivity to immune challenge, the present findings suggest future work should explore underlying relationships between poor sleep and central disruption, and possibly neurodegeneration, in older adults. Specifically, poor sleep (greater sleep variability) might contribute to higher reactivity of neuroinflammation pathways.
Loneliness and daily subjective cognitive concerns among cognitively normal older adults and individuals with MCI
Authors: Harrington Karra D , Zhaoyang Ruixue , Mogle Jacqueline , Diaz Jose , Van Bogart Karina , Rabin Laura , Engeland Christopher G. , Graham‐Engeland Jennifer E , Sliwinski Martin J.
Published: December 2023

Background

Loneliness is associated with increased dementia risk and is bidirectionally associated with cognitive decline across several years. Less is known about how loneliness and cognitive function are bidirectionally related on shorter timescales. This study examined daily associations between loneliness and self‐reported cognitive concerns in cognitively normal older adults and those with mild cognitive impairment (MCI).

Method

Community‐dwelling older adults from the Einstein Aging Study (n = 311, age 70‐90 years, 65.9% female, 41.8% Black/African American, 12.5% Hispanic, 30.9% met Jak/Bondi criteria for MCI) completed a two week ecological momentary assessment (EMA) protocol via smartphone. Participants rated their current feelings of loneliness up to 5 times per day (4 via notifications, and 1 at end of day). These ratings were averaged to obtain a loneliness severity score for each day. Subjective cognitive concerns (prospective and retrospective memory lapses, attention/executive function difficulties) were assessed at the end of each day. Participants also reported how much each concern bothered them and/or disrupted their daily activities. Multilevel models were used to assess same‐day and next‐day associations between loneliness and each of the subjective cognitive concern outcomes bidirectionally.

Results

There were bidirectional same‐day associations observed between loneliness severity and greater number and more bother of attention/executive concerns, as well as greater disruption of all cognitive concerns. When considering associations of present day loneliness with next day cognitive concerns, greater severity of loneliness predicted more bother of attention/executive concerns on the following day. Additionally, present day number of attention/executive concerns and disruption of all cognitive concerns predicted next day loneliness severity. All effects remained significant after adjusting for age, sex, years of education, and MCI status.

Conclusion

These findings demonstrate that loneliness is dynamically associated with attention and executive function, but not memory lapses, on a day‐to‐day basis. Associations between loneliness and experience of bother and disruption due to cognitive concerns, suggest that loneliness may signal greater severity of, or less ability to cope with, cognitive difficulties.
Within‐Day Variability in Mobile Cognitive Assessments: Associations with Mild Cognitive Impairment and Sociodemographic Factors
Authors: Cerino Eric S. , Gamaldo Alyssa A. , Hyun Jinshil , Buxton Orfeu M. , Engeland Christopher G. , Katz Mindy J. , Wang Cuiling , Derby Carol A. , Lipton Richard B. , Sliwinski Martin J.
Published: December 2023

Background

Greater within‐person variability in cognitive performance on mobile devices is emerging as a sensitive marker of mild cognitive impairment (MCI). It is unclear if sociodemographic differences are associated with this variability, and if so, whether these differences moderate associations between MCI status and within‐person variability. We use a digital health approach with ecological momentary assessments (EMA) to examine sociodemographic differences in within‐day variability among individuals with MCI and those who were cognitively unimpaired (CU).

Method

A sample of 308 community‐dwelling older adults from the Einstein Aging Study (mean age = 77.49 years, SD = 4.86, range = 70‐90; 67% female; 45% non‐Hispanic White, 41% non‐Hispanic Black) completed neuropsychological testing and self‐reported questionnaires. Ninety‐eight individuals met Jak/Bondi criteria for MCI. All participants performed mobile tests of processing speed and memory binding on a smartphone up to six times daily over a two‐week period. We employed heterogeneous variance multilevel models to assess sociodemographic and MCI status associations with within‐day variability across assessments. We further tested whether differences in age, gender, race, and education moderated associations between MCI status and within‐day variability.

Result

For processing speed, greater variability was apparent in individuals with MCI, non‐Hispanic Black participants, and individuals with less education (ps<.001). A MCI status*gender interaction occurred; the association between MCI status and variability remained significant for both genders but was smaller among women (p<.01). For memory binding, greater variability was apparent in individuals with MCI, older participants, non‐Hispanic Black participants, and individuals with less education (ps<.001). Numerous interactions occurred; in separate analyses, associations between MCI status and variability remained significant, but were smaller among women, non‐Hispanic Black participants, and individuals with less education (ps<.05).

Conclusion

Individuals with MCI exhibited greater within‐day variability in mobile cognitive performance than those who were CU, but the strength of these associations varied by sociodemographic factors. These indices of variability in everyday life may serve as sensitive markers of early cognitive impairment. Future research should examine daily mechanisms and environmental perturbations (e.g., stress, sleep, air pollution) that may explain why associations between MCI status and cognitive variability appeared smaller among women, non‐Hispanic Black participants, and individuals with less education.
Multi‐level Factor Analysis of Daily Data to Identify Subsyndromes of Behavioral and Psychological Symptoms
Authors: Pickering Carolyn E , Winstead Vicki , Yildiz Mustafa , Wang Danny , Yefimova Maria , Pickering Andrew
Published: December 2023

Background

Behavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. Many studies have used single‐level factor analysis approaches to identify subsyndromes of BPSD based upon meaningful groupings of co‐occurring symptoms yet, proposed subsyndromes have not been successfully replicated and lack stability over time. This may be due to measurement issues which do not account for dependencies in the data and create temporal misalignment. We applied an innovative multi‐level framework to overcome limitations of prior research to identify subsyndromes of BPSD.

Methods

This study used an intensive longitudinal design in which co‐residing family caregivers to persons living with dementia in the community were recruited to proxy‐report on their care recipient’s daily symptom experiences of 23 different BPSD for 8 consecutive days. A multi‐level exploratory/confirmatory factory analysis was utilized to account for nested data and separate within‐person variances from between‐level factor estimates.

Results

Family caregivers (N = 70) were on average African American (54%) females (69%) most often caring for a parent with dementia (62%) average 74 years old requiring assistance with 4.5/7 activities of daily living. Data were provided on 79% of sampled days (n = 443 diaries). Exploratory factor analysis identified a 4‐between 3‐within factor structure based on fit statistics and clinical interpretability. The between‐level subsyndromes include wandering/aggression/care resistance (F1), affective/apathy/psychosis/vocalizations (F2), cognitive/ lability/ euphoria/ impulsivity/ compulsions (F3), and hallucinations/uncooperative (F4). Reliability estimates were high: 0.88 (F1), 0.91 (F2), 0.83 (F3), and 0.79 (F4).

Conclusion

The between‐level factor structure identified through the multilevel factor analysis framework provide a more valid and reliable estimation of clinical subsyndromes within a population by separating out the variance due to within‐person daily fluctuations. At the between‐level, hallucinations was the only BPSD to cross‐load, which may indicate they are a byproduct of unmanaged depression in the affective/psychosis factor and their own unique subsyndrome. Support for the between‐level subsyndromes can be found in studies on shared neurobiological mechanisms of BPSD. The within‐level factors are similar to structures found in a recent systematic review. We argue these within‐level factors are more representative of symptom clusters, as they are driven by fluctuating contextual factors.
Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population
Authors: Seto Mabel , Hohman Timothy J. , Mormino Elizabeth C. , Papp Kathryn V. , Amariglio Rebecca E. , Rentz Dorene M. , Johnson Keith A. , Schultz Aaron P. , Sperling Reisa A. , Buckley Rachel F. , Yang Hyun‐Sik
Published: December 2023

Background

Alzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.

Method

Measures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐ε4 genotype, β‐amyloid (Aβ) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aβ was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aβ+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aβ levels and cognition covarying for the participant’s age, sex, and years of education where relevant.

Result

As previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aβ (p<0.001). The association between Aβ and history in both parents remained significant when covarying for APOE‐ε4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐ε4 and Aβ. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p<0.001) and in those with only maternal family history (n = 1776, p<0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: β = 0.03, p<0.001 in individuals with maternal history, β = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (βmaternal = 0.02, pmaternal = 0.01; βpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.

Conclusion

We confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐ε4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aβ burden among asymptomatic older individuals.
Feasibility and Efficacy of the LEAD Dementia Advance Care Planning Intervention
Authors: Iacob Eli , Dassel Kara B , Aruscavage Nancy R , Clayton Jordana L , Utz Rebecca , Supiano Katherine P
Published: December 2023

Background

Using our dementia‐focused advance care planning tool (ACP), known as the LEAD Guide (Life‐Planning in Early Alzheimer’s and Other Dementias),1‐3 we implemented a 9‐month NIH Stage‐14 behavioral intervention to promote ACP concordance in community‐based ADRD dyads. Dyads consisted of care recipients (persons concerned about dementia or those with a diagnosis of preclinical or early‐stage dementia) and their care partner. The goal of this study was to assess the feasibility and initial efficacy of the intervention.

Method

Feasibility was assessed by examining the percent of enrollment of eligible participants, retention rate, and completion of data collection across study timepoints through the post intervention assessment. To explore the initial efficacy of the LEAD Intervention on study outcomes (ACP completion and dissemination, relationship quality, decision‐making self‐efficacy), we utilized longitudinal survey‐based measures to assess dyadic constructs that illustrate how the dyad functioned over time. Baseline to post changes were examined utilizing mixed effects models.

Results

We screened 73 dyads, 58 dyads were eligible and 51 dyads participated in the study (see Figure 1 and Table 1). There were 34 dyads (67.7% retention) that completed baseline through the post‐intervention assessments. Table 2 shows results of changes in self‐report measures between baseline and post. Scores on the Decision‐Making Self‐Efficacy Scale5 revealed improved efficacy in both the care recipient and care partner at post intervention compared to baseline. Analysis showed no significant improvement in the positive domain of the Dyadic Relationship Scale6 in either care recipient or care partner, however, relationship strain domain significantly declined following the intervention in both the care recipient and care partner. Of the 51 starting dyads, 27 care recipients had already completed an advanced directive. By post, an addition 7 had completed an advanced directive, 9 were planning on completing, and 33 had shared ACP documents with others.

Conclusion

The web‐based, self‐administered LEAD Intervention is a feasible and effective platform to promote ACP planning in community‐based ADRD dyads. Participation in ACP conversations and documentation can help reduce relationship strain and improve decision‐making self‐efficacy, thus promoting future care decisions that align with the care recipient’s values and preferences.
Association of reactive astrogliosis and microglial activation with tau pathology in Alzheimer’s disease
Authors: Ferrari‐Souza João Pedro , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Lussier Firoza Z , Leffa Douglas Teixeira , Therriault Joseph , Tissot Cécile , Benedet Andrea Lessa , Soares Carolina , Aguzzoli Cristiano Schaffer , Zalzale Hussein , Rohden Francieli , Wang Yi‐Ting , Chamoun Mira , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , Souza Diogo O. , Soucy Jean‐Paul , Gauthier Serge , Triana‐Baltzer Gallen , Saad Ziad S. , Kolb Hartmuth C. , Schilling Lucas Porcello , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R
Published: December 2023

Background

Glial contributions to Alzheimer’s disease (AD) etiology and progression have been increasingly recognized. Experimental and clinical evidence suggests that both microglial activation and astrocyte reactivity have pivotal roles in the progression of tau pathology. However, it remains to be elucidated how microglia and astrocytes complement each other in AD pathogenesis. Here, we tested the associations between reactive astrogliosis and microglial activation with tau phosphorylation and aggregation in individuals across the aging and AD spectrum.

Method

We studied 95 participants (14 cognitively unimpaired [CU] young, 46 CU elderly, and 35 cognitively impaired [CI]) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aβ ([18F]AZD4694), tau tangles ([18F]MK6240), and microglial activation ([11C]PBR28). We further assessed reactive astrogliosis (plasma glial fibrillary acidic protein [GFAP]) and pathological tau phosphorylation (plasma phosphorylated tau [p‐tau] at threonine 231, 181, and 217).

Result

Demographic characteristics of the study population are reported in Table 1. Regression analyses revealed that reactive astrogliosis and microglial activation were synergistically associated with higher plasma phosphorylated tau levels independently of Aβ pathology in CU but not CI individuals (Figure 1A). On the other hand, no interactive effects of reactive astrogliosis and microglial activation on tau‐PET burden were observed in either CU or CI individuals (Figure 1B). Similar findings were observed in sensitivity analyses excluding CU young participants.

Conclusion

Our results suggest that reactive astrocytes and activated microglia have Aβ‐independent synergistic effects on the early progression of AD pathophysiology by contributing to tau phosphorylation but not tau aggregation. These findings can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development novel therapeutic strategies for AD targeting the interplay between astrocyte and microglial reactivity.
Diagnostic reactive astrogliosis biomarkers in Alzheimer´s disease continuum
Authors: Nordberg Agneta K , Chiotis Konstantinos , Fontana Igor C. , Malarte Mona‐Lisa , Gillberg Per‐Göran , Bucci Marco , Bluma Marina , Kumar Amit
Published: December 2023

Background

The Alzheimer’s disease (AD) biomarker field is moving rapidly. Creating a platform where multi‐PET tracer approaches and various fluid biomarkers with discriminative power in the early pathological stages could provide deeper insight into the role of reactive astrogliosis in the AD continuum. Accumulating data indicates that reactive astrogliosis may play a critical role in the early stages and, perhaps, precedes other pathological hallmarks of AD. Different PET tracers for imaging reactive astrogliosis are now available along with plasma GFAP showing a direct correlation with increased brain amyloid‐PET. We also propose that alpha‐7‐nicotinic acetylcholine receptors (α7nAChRs) might be early modulators of reactive astrogliosis and Aβ‐pathology in AD. New α7nAChRs‐PET‐tracers might be promising future new biomarkers of reactive astrogliosis with potential early diagnostic properties.

Method

Translational molecular imaging studies including in vivo multimodal PET investigations ([11C]‐deprenyl, [11C]‐PIB, [18F]‐Flutemematol, [18F]‐FDG, [18F]‐RO‐948), MRI, plasma GFAP analyses in control, presymptomatic ADAD, MCI to AD dementia and in vitro PET tracer binding studies (deprenyl, SMBT‐1, and BU99008) in postmortem brains using small/large section‐autoradiography and tissue‐homogenates.

Result

We hypothesize from our in vivo PET/in vitro brain imaging translational/clinical studies a ‘first and second wave of reactive astrogliosis’ with distinct close‐loop relationships with other pathological biomarkers across AD continuum. Validation of newly developed PET‐tracers BU99008 and SMBT‐1 for mapping and visualizing reactive astrogliosis in the brain demonstrated multiple binding properties in AD brain and highlighted the crucial need of multi‐PET tracer approach for understanding the complexity of reactive astrogliosis in AD. We have observed a significant positive correlation between plasma GFAP levels and [18F]‐flutemetamol binding in patients undergoing memory assessment. In presymtomatic ADAD patients, high [11C] deprenyl binding is observed earlier in the disease evolution than increase in plasma GFAP levels following a divergent direction. This clearly suggests plasma GFAP as a later biomarker than [11C]‐deprenyl in AD trajectory, possibly reflecting different types of reactive astrocytes at different stages of AD.

Conclusion

It’s an exciting time for the AD field with several new biomarkers/PET‐tracers for reactive astrogliosis, which will improve our understanding of underlying astrocytic complexity and add power to the existing diagnostic criteria in AD.