bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal functional activation during response inhibition in mild cognitive impairment: an fMRI study
Authors: Pommy Jessica , Umfleet Laura Glass , Cohen Alexander D , Ristow Kelly , Mason Lilly , Obarski Shawn , Franczak Malgorzata , Wang Yang
Published: December 2023

Background

Declines in response inhibition are observed both typical and atypical aging, i.e., mild cognitive impairment (MCI). Increased functional activation in frontoparietal regions during response inhibition has been interpreted to represent the emergence of a compensatory mechanism in older adulthood. While electrophysiology studies suggest the decline in response inhibition in MCI reflects a similar but amplified process as seen in normal aging this has not been examined thoroughly using functional MRI (fMRI).

Methods

31 cognitively normal older adults (M age = 73.6, 9 male) and 22 adult patients with MCI (M age = 67.2, 14 male) performed a Go/NoGo task during an fMRI scan. Group differences in accuracy and reaction time were examined for Go and NoGo trials. Individual BOLD signal change during task fMRI was examined, then voxel‐wise group comparison was conducted for MCI vs. HC groups, using age, gender, education, and gray matter density as covariates. Permutation‐estimated cluster size at alpha <.05 was defined to correct for errors of multiple comparisons.

Results

Behaviorally, the MCI group made significantly more errors during NoGo and Go trials (p<.001, p = .032, respectively), however, average reaction time did not differ significantly between groups. During NoGo trials, greater activation in the anterior default mode network (DMN), right dorsolateral prefrontal cortex (DLPFC), and motor areas was observed for MCI vs. HC, while during go trials, there was greater activation in DMN and right insula (corrected p<0.05). However, when Go vs. NoGo trials were examined, MCI showed more activation in right insula and DLPFC, but less activation in the motor area at trend level (p<0.05, uncorrected). While, there were no significant task performance differences between MCI subtypes (amnestic vs. non‐amnestic), amnestic MCI (aMCI) showed more activation in posterior DMN and dorsal attention area during NoGo trials (corrected p<0.05).

Conclusion

MCI demonstrated significantly greater activation during both Go and NoGo trials and made significantly more errors in performance during both trial types as well. While the MCI subtypes did not exhibit differences in performance on the task, the aMCI exhibited significantly greater activation in multiple regions. Our findings suggested inefficient DMN suppression during task performance in the MCI cohort, especially in the aMCI subgroup.
Financial hardship in families of older adults with physical disability, dementia or both: a population based study of the dementia research group 10/66
Authors: Márquez Inés Hernández , Acosta‐Castillo Gilberto Isaac , Ibarrola Mariana Longoria , Sosa‐Ortiz Ana Luisa
Published: December 2023

Background

The proportion of older people have consequences for labor and financial market. Older adults (OA) can consume economic resources that they cannot afford, total health care spending is three times greater in households with at least one OA with a disability, 70% of the costs of caring for someone with dementia are borne by families and reported emotional and financial hardships are twice as high for caregivers of this OA. This study focuses on the impact of physical and cognitive disabilities on the economic difficulties of the families.

Method

This was an observational, cross‐sectional study. It involved 2396 people aged 65 years and older, identified within the dementia research group protocols (DRG)10/66. Measures included the WHODAS 2.0 and the INDEP economic hardship study assessments. We performed descriptive statistics of the sociodemographic distribution and explored the association of physical disability, dementia, or both, with the presence of sociodemographic and economic variables with different types of supports for coping the “financial hardship” using bivariate tests and logistic regression models, odds ratios were estimated to assess the associations of interest.

Result

The distribution of disability with or without cognitive impairment was greater in women and cognitive impairment was greater in men (p = 0.010). When analyzing the distribution of the types of economic support, resorting to social assistance programs showed an association with the presence of cognitive impairment with disability odds ratio (OR) of 10.4 (95% confidence interval = 95%CI 1.3‐81.1) and without disability OR 8.0 (95%CI 1.1‐59.7) in the adjusted estimators (RR). Recourse to the work setting support was associated with the presence of disability in simple RR, OR 2.2(95%CI 1.2‐4.2) and adjusted OR 2.5(95%CI 1.3‐4.8). Support from friends or relatives was associated with the presence of disability and cognitive impairment also in simple RR OR 2.0 (95%CI 1.4‐3.0) and adjusted OR 2.1(95%CI 1.4‐3.3).

Conclusion

In older Mexican adults, cognitive impairment increases the use of social assistance programs, physical disability increases the use of savings or property, and the presence of cognitive impairment with physical disability increases the use of social assistance programs, support in the work setting and from friends or family.
APOE4 Genotype Relates with Body Mass and Percent Fat Mass in Cognitively Normal Older Adults
Authors: Smith Aaron N. , Keller Jessica E , Taylor Matthew K , Burns Jeffrey M. , Sullivan Debra K
Published: December 2023

Background

Lower body mass is related to the progression of Alzheimer’s disease (AD). Carriers of the APOE e4 (APOE4) allele have an increased risk of developing AD, and APOE4 status has been shown to be associated with decreased body mass and fat mass in AD. However, this relationship in cognitively normal older adults is unclear. We investigated whether body mass index (BMI) and body composition are related with APOE4 status in cognitively normal older adults.

Method

Baseline data from 211 cognitively normal older adults in an ongoing nutrition intervention RCT (Nutrition Intervention for Cognitive Enhancement; NICE study) were analyzed. Whole blood was attained, and genetic analyses were used to determine APOE genotype. Participants with ≥ 1 APOE4 allele were classified as APOE4 carriers. BMI was calculated from weight and height. Fat mass percentage was measured using dual energy x‐ray absorptiometry. We compared means between APOE4 carriers and non‐carriers for BMI and fat mass percentage using covariate‐adjusted ordinary least squares (OLS) regression models (i.e., ANCOVA), adjusting for age and sex. Statistical analyses were performed using R (v. 4.2.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.

Result

Participants were 75% female with a mean age of 71.4 ± 4.9 years. 34% of participants were APOE4 carriers. Mean BMI and percent fat mass were 28.4 ± 4.6 kg/m2 and 40% ± 4.6, respectively. ApoE4 carriers had significantly lower BMI (27.5 kg/m2 ± 3.9 vs. 28.9 kg/m2 ± 4.8, p = 0.02) and lower body fat percentage (38% ± 8.0 vs. 42% ± 6.7, p < 0.01) compared to non‐carriers, respectively.

Conclusion

In this study, cognitively normal older adult APOE4 carriers had lower BMI and lower body fat percentage compared to non‐carriers. These findings suggest that APOE4 status may influence body weight and body composition, which may represent a way APOE4 increases the risk of symptomatic AD. Future studies are needed to explore the mechanisms underpinning the relationship of APOE4 with decreased body mass and differential body compositions and to determine if these results are consistent in different life stages.
Exercise training mitigates the deleterious effects of experimental bed rest on intraindividual variability of executive functioning in older adults: A randomised controlled trial
Authors: Balbim Guilherme Moraes , Falck Ryan S , Barha Cindy K , Tai Daria , Best John R. , Hajj‐Boutros Guy , Madden Kenneth , Liu‐Ambrose Teresa
Published: December 2023

Background

In older adults, bed rest can occur because of chronic conditions, injury, surgery, or hospitalization. Extreme levels of physical inactivity due to bed rest initiate a downward spiral in several body systems. Exercise is a countermeasure to many of these changes; nonetheless, little is known about the effect of exercise on older adults’ cognition during bed rest. We thus examined the effects of exercise on the intraindividual variability (IIV) of cognitive performance in older adults exposed to 14 days of experimental 6° head‐down bed rest (HDBR) and whether sex moderates its effects. We chose IIV as our outcome measure because it is more sensitive than traditional summary scores of cognitive performance, albeit no studies have explored exercise effects on older adults’ IIV submitted to bed rest.

Method

A non‐blinded, parallel‐group, randomised controlled trial. Twenty‐three healthy older adults aged 55‐65 were randomised to: 1) 14 days of HDBR (CON); or 2) 14 days of HDBR with daily aerobic and strength exercise (EX). Data were collected at baseline, HDBR completion, and end of seven‐day‐recovery. The National Institutes of Health Toolbox Cognitive Battery assessed executive function (Flanker Incongruent and Congruent and Dimensional Change Card Sort) and processing speed (Pattern Comparison). IIV was indexed by intraindividual coefficient of variation (ICV) and residual intraindividual standard deviation (R‐ISD), with R‐ISD as our primary measure of interest. Linear mixed models assessed group differences and the moderator role of sex.

Result

At HDBR completion, EX had significantly lower (better) Flanker incongruent ICV (Estimated mean difference = ‐0.10, 95%CI ‐0.19;‐0.003, p = 0.022) and R‐ISD (Estimated mean difference = ‐3.63, 95%CI ‐6.10;‐1.17, p = 0.005) vs. CON. Sex moderated the effect of exercise; females in EX had significantly lower Flanker incongruent ICV vs. CON (Estimated mean difference = ‐0.23; 95%CI ‐0.34;‐0.12, p<0.001). At the end of the seven‐day recovery, EX had significantly lower Flanker incongruent R‐ISD vs. CON (Estimated mean difference = ‐3.11, 95%CI ‐5.70;‐0.052, p = 0.019). Summary scores and processing speed IIV changes were not statistically significant (ps>0.05).

Conclusion

Exercise during HDBR preserved executive functioning, especially in females. Our findings support the delivery of exercises to older adults during bed rest to preserve their cognitive function.
Emotional Enhancement of Memory in Alzheimer’s Disease: A Systematic Review
Authors: Kapoor Arunima , Levine Linda , Mather Mara , Nation Daniel A.
Published: December 2023

Background

Progressive decline in episodic memory is a hallmark of Alzheimer’s disease (AD). Emotional arousal is known to enhance memory. The amygdala, locus coeruleus, hippocampus, and other regions, are key brain structures involved in the facilitation of memory through emotions. Amygdala‐mediated enhanced encoding of emotionally arousing stimuli or events may improve memory in AD patients, however whether this effect is present in patients with AD remains unclear.

Method

A systematic search of the literature was conducted in accordance with PRISMA guidelines to identify relevant literature on emotional enhancement of memory (EEM) in AD. We utilized MEDLINE and PsycInfo. Search terms related to emotional memory and Alzheimer’s were searched as keywords and mapped to medical subject headings.

Result

1545 studies were screened; 40 were included. Participant age ranged from 64 to 84 years. Sample sizes ranged from 20 to 126. Only 11 of the 40 (27.5%) included brain MRI and evaluation of amygdala volume. 34 studies examined long‐term memory. Results showed that 12 out of 34 studies (35.3%) showed clear EEM for long‐term memory among participant with AD. A further 10 studies (29.4%) found that EEM was influenced by stimuli type, valence of emotion, level of encoding, or intensity of emotion. Yet 12 studies (35.3%) found no effect of EEM in AD. Of the 6 studies that specifically explored flashbulb memories in AD, 3 found no EEM and 3 observed that the effect was content‐dependent, such that personal details were remembered more often than factual details of events.

Conclusion

Studies which included brain imaging showed that amygdala volume is the strongest predictor of EEM in AD, regardless of level of cognitive impairment. The conflicting literature on EEM in AD reveals the importance of evaluating volumes or networks of brain regions known to be involved in emotional memory processing. AD patients included in these studies likely had varying degrees of atrophy in the amygdala, locus coeruleus, hippocampus and frontal regions involved in modulating emotional memories. However, without confirmation from brain imaging, the integrity of these brain structures cannot be established. Future studies are needed to confirm whether atrophy of important brain regions diminishes EEM in AD.
Stereotype threat in telephone‐administered neuropsychological assessment in older Veterans with and without cognitive impairment
Authors: DeCaro Renée , Kasha Sabrina , Marin Anna , Turk Katherine W , Budson Andrew E
Published: December 2023

Background

Neuropsychological evaluation is ubiquitous in Alzheimer’s disease clinical care and research—from diagnosing cognitive deficits to evaluating treatment and outcomes. However, performance during evaluation can depend on factors other than one’s cognition, including stereotype threat. Stereotype threat occurs when people feel at risk of conforming to stereotypes about their social group, in this case, memory declines associated with aging. While stereotype threat in neuropsychological evaluation in healthy older adults has been established, we tested, for the first time, this construct in older adults with cognitive impairment.

Method

Twenty older adults (range 63 – 89; mean age = 77.2, SD = 6.8) recruited from the Veteran’s Affairs Boston Healthcare system were administered a telephone Repeatable Battery of Neuropsychological Assessment (RBANS). Following baseline assessment, one‐week later participants received a stereotype threat condition prior to neuropsychological evaluation. Participants also received a reduced threat condition which de‐emphasized memory diagnosis (during a separate week, counterbalanced with the threat condition). In the fourth week and final session, supplemental measures were administered, including a telephone‐MoCA, demographics, and surveys measuring mood, dementia worry, beliefs about aging, and subjective memory complaints. Planned analyses include a mixed‐effects analysis of variance, with group (healthy; cognitively impaired) and condition (stereotype‐threat; threat‐reduced).

Results

Older adults with cognitive impairment demonstrated lower performance across all domains of the RBANS, including list learning, story recall, fluency, digit span, delayed recall, and recognition, ηp
2 = .87‐.99. Older adults with impairment scored numerically lower but not statistically lower in list learning under stereotype threat (M = 17.4; SD = 6.6) compared to the reduced threat condition (M = 19.9; SD = 7.2). Confirmation of the analyses, including examination of covariates, will follow final subject recruitment (N = 28).

Conclusion

We found that stereotype threat did not significantly impact performance of healthy older adults and older adults with cognitive impairment. We note that small, numerical differences emerged for list learning. Differences of just one point in neuropsychological evaluation can be impactful, especially with respect to norms and cutoff scores. As such, the results carry implications for neuropsychological evaluation in clinic practice and research broadly.
Generation of microglia‐containing APOE4 cerebral organoids as a model of Down syndrome associated Alzheimer’s disease
Authors: Summers Rose , Johnson Noah R , Dooling Breanna , Potter Huntington
Published: December 2023

Background

Down syndrome (DS) is among the most common forms of familial Alzheimer’s disease (AD), resulting from triplication of the amyloid precursor protein (APP) gene on chromosome 21 which leads to increased amyloid beta (Aβ) peptide accumulation in the brain. As a result, all people with DS will develop Aβ plaques and tau tangles by the age of 40, and the majority will eventually develop AD‐related cognitive decline. Carrying the e4 allele of the apolipoprotein E gene (APOE), APOE4, because it catalyzes the formation of neurotoxic Aβ oligimers. The combination of APOE4 and trisomy 21 results in a very high risk for DS associated AD. APOE4 has also been shown to drive altered microglial activity in the AD brain, leading to increased neuroinflammation, neurodegeneration and cognitive decline. Studying mechanisms underlying APOE4‐microglial interactions could lead to identification of new therapeutic targets for DS‐AD treatments. Microglia‐containing cerebral organoids (MCOs) derived from human induced pluripotent stem cells (hiPSCs) with both trisomy 21 and APOE4 would offer a distinct advantage over prior models.

Method

Isogenic hiPSC disomic or trisomic for chromosome 21 from an individual mosaic for trisomy 21 and carrying the APOE3/3 genotype and CRISPR‐Cas9 gene editing was then used to generate hiPSCs with the APOE4/4 genotype. hiPSCs were then differentiated into hematopoetic progenitor cells (HPCs) and neural progenitor cells (NPCs) and co‐cultured at a 7:3 ratio (NPCs:HPCs) to form MCOs.

Result

Control cerebral organoids (COs) lacking HPCs were reduced in size compared to age‐matched MCOs, suggesting the successful integration of HPCs with NPCs during co‐culture. Immunohistochemical analysis showed neural rosettes characteristic of COs and shows that neurons, astrocytes and microglia were all present in MCOs throughout development.

Conclusion

We have developed a novel model for DS‐AD that will be critical for identifying APOE4‐microglial interactions as a therapeutic target in DS‐AD. These MCOs may be used in pre‐clinical testing of potential therapies, which may lead to treatment for the highly vulnerable population of APOE4 carriers with DS‐AD.
RESILIEN‐T: Field testing a lifestyle coaching app for subjective cognitive decline
Authors: Astell Arlene J. , Bernick Alana , Acenas Maria , Saney Danielle , Swaminathan Swathi , Casaccia Sara , Scalise Lorenzo , Pollini Alessandro , Oberholzer Pierre , van Megen Xandra , Hermanns Joost , Krijger Regina , Felici Elisa , Sabatini Tania , Rossi Lorena
Published: December 2023

Background

Links between subjective cognitive decline (SCD) and dementia are encouraging older adults to optimize their physical and mental health. Self‐managing lifestyle factors such as physical activity, healthy eating, social and cognitive stimulation can contribute to this optimization. RESILIEN‐T is an international project co‐producing and field testing an integrated goal‐setting and coaching app with and for older adults.

Method

Phase 1 iterative co‐production of the user interface, goal‐setting and coaching elements. Phase 2 mixed methods pilot trial with 15 participants with SCD (mean age 80 years) in four countries evaluated the prototype for two months. Phase 3 mixed‐methods field trial with 221 participants with SCD across four countries randomly assigned to the RESILIEN‐T intervention or control arm for three months. Minimum Data set of SCD (MAC‐Q) and health (EQ5D‐5L) were completed at baseline and end of trial, when usability (System Usability Scale) was also assessed.

Result

All pilot participants reported positive experiences with RESILIEN‐T, enjoying the easy‐to‐use interface and the daily suggestions to keep active. In the field study the MAC‐Q score improved in both groups, but this was only significant in the RESILIEN‐T group who improved significantly more than the control group. Health score improvement was higher in the RESILIEN‐T group but not significantly and SUS score was acceptable (71.9).

Conclusion

The RESILIEN‐T project confirms the interest among older adults with SCD of self‐managing lifestyle factors to promote cognitive health. The results of this short‐term intervention show promise for people with SCD to positively impact their cognition
Evaluating cognitive phenotypes and associations with neuroimaging biomarkers of dementia in a sample of aging individuals using unsupervised machine learning
Authors: Rudolph Marc D. , Ma Da , Bateman James R. , Hughes Timothy M. , Sachs Bonnie C. , Whitlow Christopher T , Sai Kiran K. Solingapuram , Craft Suzanne , Lockhart Samuel N.
Published: December 2023

Background

Otherwise cognitively normal individuals can experience age‐related cognitive dysfunction and may present with heterogenous patterns of cognitive impairment. There is limited knowledge regarding the presence and stability of cognitive subtypes observed in individuals with mild cognitive impairment and dementia (e.g., dysexecutive, non‐amnestic). Further, the extent to which cognitive subtypes related to age‐ and dementia‐related neuroimaging biomarkers is uncertain.

Method

This study sought to evaluate the presence and composition of cognitive subtypes in a large diverse community sample of aging individuals without dementia (NC; Baseline N = 337; Table 1). Participants enrolled in the Wake Forest ADRC and completed an annual battery of cognitive assessments (Uniform Data Set; NACC), the Mini‐Mental State Exam (MMSE), and Clinical Diagnostic Rating Scale (CDR). Unsupervised machine learning (e.g., clustering: hierarchical, k‐means, and k‐medoids algorithms; 1000 bootstrap iterations; majority voting rule) was applied to the battery of cognitive assessments. Demographic characteristics and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), diffusion‐weighted fractional anisotropy (FA), and NODDI freewater (FW) were compared across prospective clusters using general linear models. Highly correlated cognitive metrics (r>.85) were removed prior to analysis.

Result

Cluster analyses using baseline cognitive scores suggested NC participants could be partitioned into two to eight clusters; two primary clusters representing one large homogenous group of relatively unimpaired individuals and another heterogenous cluster composed of 4‐7 possible cognitive subgroups (Figure 1). The two‐cluster solution partitioned NC participants into higher and lower cognitive performers. Across cluster solutions, lower performing individuals were older, had higher Aβ‐PET, and lower total brain volume on average (p<.05; Figure 2).

Conclusion

We did not observe well‐defined clusters representing distinct cognitive subtypes reported in previous studies (e.g., dysexecutive, amnestic, visuospatial). However, a heterogenous subset of NC participants exhibited substantial variability across assessments. Three‐ and four‐cluster solutions identified individuals with greater impairment in executive functioning, and verbal learning and memory respectively. Findings highlight the need to model complex patterns of cognitive abilities in otherwise healthy older adults. Future longitudinal work will assess how health information and neuroimaging biomarkers of dementia contribute to the composition and stability of cognitively defined subgroups.
Impact of sex and ApoE4 on the longitudinal association of plasma ptau‐181 and NFL with cognitive decline in non‐demented older adults
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Ezzati Ali
Published: December 2023

Background

APOE4 is a strong genetic risk factor for Alzheimer’s disease (AD). Sex‐dependent differences has been shown in AD pathophysiology and clinical course. Here, we aim to assess the association between longitudinal changes in ptau‐181 and neurofilament light protein (NfL) and concurrent changes in cognitive measures in non‐demented individuals and to evaluate if this association is impacted by sex and ApoE4 status.

Method

Participants (N = 738) were non‐demented (cognitively unimpaired or mild cognitive impairment) older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 738) with up to 4ys of longitudinal data. Linear Mixed Effects (LME) models were used to study the effect of ptau‐181 and NFL on cognition as measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog11; Range 0‐70) and Clinical Dementia Rating, sum of boxes (CDR‐SB). Sex by time and APOE4 by time interactions were assessed in the models for the entire sample. Analyses was repeated after separately stratifying sample by sex and APOE4.

Result

At baseline, both ADAS‐11 and CDRSB values correlated with plasma p‐Tau181 and NfL measures (Table 1). The longitudinal change in plasma p‐Tau181 correlated only with baseline CDR‐SB while that of NfL correlated with baseline ADAS‐11. The APOE4*time interaction, but not sex‐time interaction, were significant in LME models of both p‐Tau181 and NFL (Table 2). When stratified by sex, in females longitudinal increase in p‐Tau181 was associated with cognitive decline measured by both ADAS‐11 and CDR‐SB. In males, longitudinal increase in p‐Tau181 was associated with increase in ADAS‐11 scores and NfL was associated with cognitive decline on both outcomes. When stratified by APOE4 status, longitudinal changes in plasma biomarkers were only associated with cognitive decline in the APOE4+ subsample.

Conclusion

Plasma NfL and pTau increase during early AD and can be used to monitor disease progression. The relationship between increase in plasma ptau‐181 and NFL levels and worsening of cognition is affected by APOE4 status.
Basal Forebrain Volume Mediates the Relationship Between Cortical Cholinergic Level and Cognition in Parkinson’s Disease
Authors: Crowley Sam Joseph , Kanel Prabesh , Roytman Stiven , Bohnen Nicolaas I , Hampstead Benjamin M.
Published: December 2023

Background

Cholinergic denervation is associated with cognitive decline in Parkinson’s disease (PD). This is likely due to atrophy of the basal forebrain, which is affected by α‐synuclein early in PD. Studies show associations between basal forebrain volume and cognition and between cortical cholinergic levels and cognition, but no study has determined if basal forebrain volume mediates the relationship between cholinergic levels and cognition.

Method

Participants included 103 non‐demented individuals with idiopathic PD (M:F = 76:27; Age = 67.3±7.6 yrs) who underwent structural MRI and [18F] fluoroethoxybenzovesamicol (FEOBV) cholinergic PET imaging. We averaged cholinergic PET values in 7 ROIs derived from FreeSurfer in a prior publication (van der Zee, 2022): 1) bilateral temporoparietal regions (PC1); 2) subcortical and limbic regions (PC2); 3) bilateral cingulate regions (PC3); 4) left frontal regions (PC4); 5) right frontal and temporal regions (PC5); 6) cerebellum (PC6); and 7) bilateral entorhinal and left temporal regions (PC7). We used an executive function composite (Stroop Color‐Word Inhibition/Switching, Trail Making Switching, Letter Fluency, WASI‐IV Matrix Reasoning) and a verbal recall measure (CVLT‐II Long Delay Free Recall) as outcome variables.

Result

After controlling for age, basal forebrain volume fully mediated the associations between PC3 (indirect effect:β = 0.075, 95% CI = 0.002‐0.166; total effect:β = 0.235, p = .02; direct effect:β = 0.161, p = .13) and PC7 (indirect effect:β = 0.069, 95% CI = 0.007‐0.141; total effect:β = 0.212, p = .02; direct effect: β = 0.142, p = .15) and executive function. Basal forebrain volume fully mediated the association between PC1 and verbal recall (indirect effect:β = 0.079, 95% CI = 0.014‐0.163; total effect:β = 0.222, p = .02; direct effect:β = 0.141, p = .14) and partially mediated the association between PC3 (indirect effect:β = 0.076, 95% CI = 0.003‐0.156; total effect:β = 0.345, p<.001; direct effect:β = 0.269, p = .01), PC5 (indirect effect:β = 0.070, 95% CI = 0.003‐0.150; total effect:β = 0.341, p<.001; direct effect:β = 0.271, p<.01), and PC7 (indirect effect:β = 0.072, 95% CI = 0.005‐0.150; total effect:β = 0.298, p<.01; direct effect:β = 0.226, p = .02) and verbal recall.

Conclusion

This is the first study to demonstrate that basal forebrain volume mediates the relationship between cholinergic level and cognitive function. Future studies will investigate additional cognitive domains and measure structural integrity of individual nuclei in the basal forebrain.
Relationship between metabolic syndrome, sleep quality and cognitive impairment
Authors: Olivar Natividad , Dunovits Cynthia , Rojo Matias , Muchnik Carolina , Germani Sandra , Brusco Luis Ignacio
Published: December 2023

Background

Metabolic syndrome is a risk factor for cardiovascular diseases, which have been related to cognitive impairment and Alzheimer disease. Sleep disorders in older adults have a negative impact on cognitive performance. However, a link between metabolic syndrome, sleep, and cognitive decline has not been established.

Method

A retrospective cross‐sectional study was carried out. Information was collected from clinical histories about demographic, metabolic parameters, sleep diaries, neurocognitive evaluation and neuroimaging studies. For statistical analyses, chi‐square tests of association were included for categorical variables (age, sex, educational level, social economy status (SES), hypertension, diabetes, BMI, depression, anxiety, smoking, sedentary lifestyle) for each memory problem. A binary logistic regression model was used to predict the probabilities of memory problems. Which was built including each variable independently.

Results

The logistic regression revealed that women and low educational level were associated with increased memory difficulties over time (odds ratio [OR] = 5.3, p < 0.001). Depression was associated with increased odds of memory problems (OR = 3.8, p <0.001). When the sleep quality variable was added, it was observed that the poor sleep quality partially reduced the impact of age, gender, and depression on memory. However, all continued to present an OR greater than 1. Of the medical conditions, type 2 diabetes and hypertension showed a significant interaction (OR = 1.7, p < 0.001).

Conclusion

We believe that there is an association between metabolic state, sleep quality and cognitive impairment. in such a way that those with metabolic disorders and poor sleep quality have decreased cognitive performance.
Disclosure of Amyloid PET results to Cognitively Impaired and Unimpaired Participants Enrolled in Alzheimer’s Disease Research Studies
Authors: O'Connell Abigail H , Fischer Eric , Latham Lauren , Bateman James R. , Craft Suzanne , Lockhart Samuel N. , Rundle Melissa M. , Okonmah‐Obazee Stephanie E. , Sai Kiran K. Solingapuram , Williams Benjamin J.
Published: December 2023

Background

Prior studies have demonstrated the safety of amyloid PET scan disclosure to research participants. However, existing research has been conducted in predominantly white, cognitively intact, and highly educated samples. The Wake Forest Alzheimer’s Disease Research Center (ADRC) implemented a protocol to provide amyloid PET disclosure to a diverse cohort of participants with and without cognitive impairment.

Method

Eligible participants who complete an amyloid PET scan at the Wake Forest ADRC may consent to receive amyloid PET scan results. Prior to consent, participants are informed of possible results (elevated/not elevated) and how these results are related to Alzheimer’s disease (AD) risk. The disclosure process involves three phases: 1) pre‐disclosure assessment of anxiety and depression, 2) feedback session with a trained clinician, and 3) post‐disclosure completion of the Impact of Events Scale (IES). Additionally, a qualitative survey was developed to collect participant feedback following the disclosure session.

Results

170 participants (CN = 103, MCI = 48, dementia = 17, other = 2) have received amyloid disclosure; age: 70.5 (7.9); education: 15.7 (2.7); 62% female; 87% white). There was a statistically significant difference in IES scores between CN/MCI participants (CN = 4.3(7.2), MCI = 8.6(10.7), t(165) = 2.8, p = 0.005). There was no significant difference between IES scores in other cognitive pairs (CN‐Dementia = t(165) = 1.5, p = 0.134, MCI‐Dementia = t(165) = 0.36, p = 0.729).

Post‐disclosure feedback surveys were completed by 41 participants (age = 71.7 (6.7) years, education = 15.9 (2.4) years, 63% female, 83% white) who reported (1 = strongly disagree, 5 = strongly agree) that receiving their results was a positive (M = 4.6 (0.6)) and informative (M = 4.78 (0.47)) experience, and given what they now know, they would chose to receive their results again (M = 4.58 (0.87)). There were no significant differences in responses between cognitive groups. Participants also reported that knowledge of their PET results will impact their future thoughts, feelings, and behaviors (M = 4.00 (1.02)).

Conclusion

Amyloid disclosure is safe and well tolerated by a diverse cohort, though participants with MCI reported higher IES scores post‐disclosure. Participants reported positive experiences on a feedback questionnaire and would choose to receive results again.
Detection of brain Tau deposition across Braak stages using plasma pTau181, MRI, and cognitive function assessments
Authors: Devanarayan Viswanath , Charil Arnaud , Sachdev Pallavi , Hu Helen , Nelson Todd , Koyama Akihiko , Reyderman Larisa , Hampel Harald , Irizarry Michael C. , Dhadda Shobha , Kramer Lynn D
Published: December 2023

Background

Non‐invasive methods for detecting neurofibrillary tangles that spread throughout the brain are needed for efficiently screening patients in Alzheimer’s disease (AD) clinical trials. This can be accomplished via machine‐learning models using baseline clinical characteristics. Adding plasma pTau181 and brain region volumes may improve detection accuracy.

Method

Regional MK6240 Tau‐PET SUVR data were available for 312 Amyloid‐positive patients from a clinical trial (182 MCI, 130 mild AD, 131 Tau‐negative, 181 Tau‐positive). Over 90% of the Tau‐positive subjects were in Braak 3‐6. Plasma pTau181 was measured using Simoa assay. Data were split randomly into 70%‐30% for training and testing purposes. Tau positivity for each Braak stage was defined via the one‐sided upper 99% confidence limit of a subset of 70 subjects with background SUVR.

Signatures for detecting Tau positivity in Braak 3‐6 and for further discriminating Braak 3‐4 and 5‐6 were derived via the stochastic gradient boosting algorithm and Bayesian ordinal logistic regression respectively. Demographics (age, gender, BMI), ApoE4 status, and cognitive assessments were included, and the added value of plasma pTau181 and volumetric MRI measures were assessed. Prediction performance was assessed via 10‐fold cross‐validation in the training set followed by evaluation in the test set.

Result

Signatures comprising psychometric data, ApoE4 status, and demographics achieved 76% accuracy (ROC AUC = 80.4%) for detecting Tau positivity in Braak 3‐6, and 60.8% accuracy for discriminating Braak 3‐4 versus 5‐6. Adding plasma pTau181 significantly improved the accuracy to 82.2% (ROC AUC = 86.6%, p<0.05) in Braak 3‐6, and to 67.6% accuracy (p<0.05) for Braak 3‐4 versus 5‐6. Besides plasma pTau181, key predictors were delayed word recall, ADAS‐cog‐14, BMI, CDR‐SB, and ApoE4 genotype.

Detection accuracy of Tau positivity in Braak 3‐4 versus the spread to Braak 5‐6 improved significantly from 67.6% to 74.6% (p<0.05) when combining MRI data with plasma pTau181, ApoE4, and demographics. Key MRI predictors were the thickness and volume of the inferior parietal cortex. Adding cognitive assessments did not improve the detection accuracy.

Conclusion

These results demonstrate the potential of non‐invasive investigations such as plasma pTau181, cognitive performance, and MRI data for detecting Tau deposition throughout the brain along the Braak stages.
Views and perceptions of amyloid imaging in a preclinical Alzheimer’s disease trial
Authors: Ritchie Marina , Raman Rema , Ernstrom Karin , Wang Shunran , Donohue Michael C. , Aisen Paul S. S , Henley David , Romano Gary , Novak Gerald P , Brashear H. Robert , Sperling Reisa A. , Grill Joshua D.
Published: December 2023

Background

Studies have shown that many cognitively unimpaired older individuals are interested in learning their Alzheimer’s disease (AD) biomarker results. Yet, little is known about what motivates participation in preclinical AD trials that require amyloid biomarker testing and disclosure, and whether these motivations differ by biomarker results (elevated or not‐elevated amyloid).

Method

Using data from the EARLY trial, a preclinical AD trial testing the safety and efficacy of a BACE1 inhibitor, we analyzed participant responses on the Views and Perceptions of Amyloid Imaging (VPAI) scale (Table 1) that was collected during the screening process; that is, before undergoing biomarker testing and disclosure. Participants were asked to rate how important 9 potential reasons for seeking amyloid imaging were to them. Response options included “not at all” (1), “a little” (2), “somewhat” (3), “very” (4), and “extremely” (5). We categorized raw scores into binary responses; those with high endorsement (scores ≥4) and those with low‐to‐moderate endorsement (scores <4). We stratified participant responses by amyloid group to examine whether their biomarker status impacted participant item‐level VPAI scores.

Result

Prior to biomarker testing and disclosure, participants most often endorsed the desire to contribute to research as a motivation to participate (Table 1). In general, the not‐elevated amyloid group had higher endorsement for the VPAI items than the elevated amyloid group. The proportions of participants endorsing “confirm feeling that I might be developing dementia” and “preparing family members” were observed to be higher among participants with elevated compared to not‐elevated amyloid; whereas “curiosity” was endorsed by a higher proportion of the not‐elevated amyloid group.

Conclusion

While there are individual differences in reasons for seeking an amyloid scan, preclinical AD trial participants may be largely motivated by altruistic factors. Differences in factors that motivate participants to learn biomarker results may be apparent between amyloid groups even before biomarker disclosure.
The M4 muscarinic acetylcholine receptor positive allosteric modulator VU0467154 normalizes non‐rapid eye movement sleep deficits in non‐pathologically aged mice.
Authors: Russell Jason K , Wan Laura , Ingram Shalonda , Bubser Michael , Lindsley Craig W , Jones Carrie K
Published: December 2023

Background

The central cholinergic system plays an important role in normal arousal and sleep/wake architecture, and is known to decline in non‐pathological aging and Alzheimer’s disease (AD). The M4 muscarinic acetylcholine receptor (mAChR) is expressed in cortical, limbic, and thalamic brain regions, crucial for the control of arousal and sleep/wake architecture. While previous clinical studies have identified M4 as an exciting target for the potential treatment of behavioral disturbances and other symptoms associated with AD, there remains limited data on its role in the control of sleep/wake architecture and arousal in non‐pathological aging and AD. In the current studies, we evaluated the effects of the selective M4 positive allosteric modulator (PAM) VU0467154 on sleep disruptions observed in non‐pathologically aged mice across the circadian rhythm.

Method

HD‐X02 telemetry devices (DSI) were implanted in young (4‐5‐year‐old) and aged (20‐21‐month‐old) C57/BL6 mice, followed by administration of vehicle or a dose of the M4 PAM VU0467154 during either the inactive and active phase. Time in wake, non‐rapid eye movement (NREM), and rapid eye movement sleep (REM) sleep were assessed across 24‐hours post‐ dosing. NREM sleep fragmentation was also assessed for the 8‐hours post‐dosing. Arousal, as measured by gamma power during wake, and sleep quality, as measured by delta power during NREM sleep, were expressed relative to a 1‐hour predose baseline. In addition, young mice were concurrently dosed with a maximally efficacious dose of VU0467154 (30 mg/kg) in combination with the M4 antagonist VU6028418 to confirm that the observed effects were mediated through an M4‐dependent mechanism.

Result

VU0467154 increased NREM sleep and decreased arousal following dosing during either phase; and reduced NREM sleep fragmentation and REM sleep following dosing during the inactive phase in young mice. These effects are attenuated by the M4 antagonist VU6028418. In aged mice, similar effects of VU0467154 are observed, with NREM sleep quality also enhanced during the inactive phase.

Conclusion

When evaluated across the circadian rhythm, the M4 PAM VU0467154 normalized deficits in NREM sleep fragmentation and increased NREM sleep duration and quality in non‐pathological aged mice in the inactive phase.
Distinct neuroinflammatory mechanisms in Alzheimer’s disease and Frontotemporal Lobar Degeneration
Authors: Thapa Simrika , Anastassiadis Chloe , Vasilevskaya Anna , Multani Namita , Taghdiri Foad , Salvo Cristina , Mora‐Fisher Daniela , Anor Cassandra Jessica , Varriano Brenda Maricela , Misquitta Karen , Tang‐Wai David F. , Kovacs Gabor G. , Fox Susan , Lang Anthony E , Tartaglia Carmela
Published: December 2023

Background

Neuroinflammation is an important pathophysiological process in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Frontotemporal Lobar Degeneration (FTLD). Limited studies have revealed distinct inflammatory markers between proteinopathies. Whether AD and FTLD have distinct neuroinflammatory profiles that relate to different clinical manifestations remains unclear. We assayed a large number of inflammatory proteins to delineate neuroinflammatory signatures across different proteinopathies.

Method

Using Olink Inflammation panels, we measured 737 inflammatory proteins in CSF from 22 AD [11 early‐onset (EOAD); 11 late‐onset (LOAD)], 45 FTLD patients and 5 healthy controls (HC). Multiple linear regression analyses were performed and comparison of expression between the groups was done by ANOVA F‐tests, adjusted for age, sex and age of onset, with FDR correction for multiple comparisons. The relationship between inflammatory markers and neurofilament light chain (NfL) was examined by Pearson correlation as well as linear regression analysis incorporating the interaction effect of NfL and disease groups.

Result

Out of 442 proteins that passed quality control, five neuroinflammatory proteins (PKLR, CAT, CXCL9, MMP1, MEPE) involved in extracellular matrix regulation, neuroprotection and chemoattractant activity were significantly downregulated in AD compared to HC (q<0.05, FDR‐corrected). Comparing AD and FTLD, 40 were significantly upregulated in AD (q<0.05, FDR‐corrected). C3, a pro‐inflammatory complement protein was significantly downregulated in AD compared to FTLD. Interestingly, seven inflammatory proteins were significantly correlated with NfL in AD following FDR correction: C7 (r = 0.79, q<0.05), LGALS9 (r = 0.72, q<0.05), LYVE1 ((r = 0.72, q<0.05), ADAMTS1 (r = 0.71, q<0.05), MRC1 (r = 0.69, q<0.05), SEMA3G (r = 0.69, q<0.05), and CCN2 (r = 0.68, q<0.05). No inflammatory proteins were correlated with NfL in FTLD. Comparing EOAD and LOAD, anti‐inflammatory cytokine TGF‐β, was upregulated in EOAD compared to LOAD (q<0.05, FDR‐corrected). A significant interaction effect of NfL and AD sub‐groups (EOAD and LOAD) was found with TNFRSF13B, CCL21, IL5RA, IL7, and MZB1 (q<0.05, FDR‐corrected), where except for IL7, all proteins were positively correlated with NfL in LOAD but not in EOAD.

Conclusion

AD and FTLD patients display distinct inflammatory profiles with varying relationships between inflammatory and neurodegenerative markers. EOAD and LOAD also showed distinct inflammatory patterns. Our results underscore that proteinopathy‐specific neuroinflammatory mechanisms are involved in disease pathogenesis.
Analyses of Quality of Life in Frontotemporal Lobar Degeneration: Findings from the ALLFTD Consortium
Authors: Nelson Kevin M , Forsberg Leah K. , Brushaber Danielle , Syrjanen Jeremy A. , Lapid Maria I. , Heuer Hilary W. , Boxer Adam L. , Rosen Howard J. , Boeve Brad F. , Consortium ALLFTD
Published: December 2023

Background

The DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit.

Method

We analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good).

Result

DEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant’s overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC‐FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC‐FTLD = 0: 19.4%, CDR®+NACC‐FTLD = 0.5: 42%, and CDR®+NACC‐FTLD = 1+: 33.2%), worse than (CDR®+NACC‐FTLD = 0: 15.1%, CDR®+NACC‐FTLD = 0.5: 13.3%, and CDR®+NACC‐FTLD = 1+: 15.2%), or the same (CDR®+NACC‐FTLD = 0: 65.6%, CDR®+NACC‐FTLD = 0.5: 44.8%, and CDR®+NACC‐FTLD = 1+: 51.6%).

Conclusion

Among participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC‐FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming.