bluuebunny/crossref_metadata_2025 huggingface dataset:
Six‐Month Consistency of NIH Toolbox Cognition Battery Scores in Healthy Older Black Women with Subjective Cognitive Decline
Authors: Halter Colt M. , Moll Allison C. , Adams Hannah , Hanna Sophie , DiCerbo Loraine M. , Daugherty Ana M. , Woodard John L. , Giordani Bruno , Kavcic Voyko
Published: December 2023

Background

Interest in the NIH Toolbox Cognition Battery (NIHTB‐CB) for the clinical assessment of older adults is burgeoning. Longitudinal neuropsychological assessments are the most sensitive way to establish cognitive decline and dementia risk of older adults. The psychometric property of measurement invariance is essential to valid interpretations of change. However, few studies have evaluated the stability of NIHTB‐CB scores in a sample of cognitively normal older adults with subjective cognitive decline (SCD). This study aims to analyze measurement consistency of NIHTB‐CB performance over 6 months.

Method

N = 29 cognitively normal, older Black adult women (65‐81 years of age) with SCD were administered the NIHTB‐CB at baseline and six‐month follow‐up. Diagnostic status was determined via consensus conference following NACC UDS guidelines. We evaluated the mean change by matched‐pairs t‐tests, and measurement consistency by two‐way mixed effects models of intraclass correlations coefficients and Bland‐Altman plots. Uncorrected standard scores and fully corrected T scores were analyzed from NIHTB‐CB Cognition Composites of Total Cognition, Fluid Cognition, and Crystallized Cognition.

Result

There were no significant mean differences from baseline to follow‐up for corrected and uncorrected Total Cognition Scores. The uncorrected Fluid Score significantly increased by 2.5 points at follow‐up (t(28) = 2.18, p = .04), and the corrected Crystallized Score increased by 1.8 points at follow‐up (t(28) = ‐2.25, p = .03). The uncorrected Crystallized Score and the corrected Fluid Score did not differ across assessments. Consistency for the uncorrected and corrected Total scores was good, (ICC(3,1) = 0.83 and 0.80, respectively). Similarly, consistency for uncorrected and corrected Fluid Scores was also good (ICC(3,1) = 0.77 and 0.78). Consistency was excellent for uncorrected Crystallized Scores (ICC(3,1) = .92), but good for corrected scores (ICC(3,1) = .87). Discrepancy scores (baseline vs follow‐up) derived from uncorrected scores for the three composites were unrelated to age and education. Bland‐Altman plots of uncorrected scores for the Composite Scores were consistent with the ICC analyses, showing good agreement between measures.

Conclusion

NIHTB‐CB corrected and uncorrected composite scores have good longitudinal psychometric properties in a sample of older Black adult women with SCD, a relatively under‐investigated examinee sample. These findings also suggest that change in fluid or crystallized cognition over six months is unlikely in persons with SCD.
Cross‐Sectional Associations Among Sleep Quality, Hippocampal Volume, and Memory Complaints in the Offspring Study
Authors: Hokett Emily , Lao Patrick J. , Turney Indira C , Chapman Silvia , Osorio Ricardo S , Brickman Adam M. , Palta Priya , Manly Jennifer J.
Published: December 2023

Background

Poor sleep quality, a modifiable risk factor for dementia, that is prevalent in non‐Hispanic Black and Hispanic adults, is associated with greater memory complaints and smaller hippocampal volumes in predominantly non‐Hispanic White samples. These associations among sleep quality, memory complaints, and hippocampal volumes are understudied in non‐Hispanic Black and Hispanic adults—populations disproportionately affected by poor sleep quality and cognitive performance. The objective of the current study was to examine associations among sleep quality, memory complaints, and hippocampal volumes in a racially and ethnically diverse, community‐based sample. Given sociocultural and environmental differences that affect sleep, brain measures, and cognitive performance, we hypothesize that poorer sleep quality is associated with more memory complaints and smaller hippocampal volumes, especially in Black and Hispanic adults.

Method

Participants included Black, Hispanic, and White adults from the Northern Manhattan community (n = 1175; 56±11 years; 67% women; 14±3 years of education; 17% Non‐Hispanic White; 20% Non‐Hispanic Black; 63% Hispanic). Participants self‐reported their sleep quality with the 9‐item Pittsburgh Sleep Quality Index, which measures average sleep disturbance over the past month. Participants self‐reported experiences with forgetting (e.g., names, faces, directions) with an abbreviated version of the Memory Functioning Questionnaire. In a subsample of participants, hippocampal volumes were measured on T1‐weighted MRI scans with FreeSurfer software. Sleep quality, hippocampal volume, and memory complaints were treated as continuous variables. We ran multivariable regression analyses adjusted for age, education, gender identity, depression severity, and intracranial volume for analyses with hippocampal volume.

Result

Across racial and ethnic groups, poorer sleep quality was associated with more memory complaints (n = 1175, B = ‐0.31, CI: [‐41,‐.22]). These associations were similar when analyses were stratified by racial and ethnic group. Among Hispanic adults, there was a trending association between poorer sleep quality and smaller left hippocampal volumes (n = 246, B = ‐8.94, CI: [‐18.75,0.88]).

Conclusion

Poorer sleep quality was associated with more memory complaints across racial and ethnic groups and showed a trending association with smaller hippocampal volumes in Hispanic adults. Future studies with larger samples should replicate these findings with longitudinal data to quantify the temporal relationship of sleep quality with memory complaints and structural brain changes.
A systematic evaluation of hippocampal GABA levels in transgenic mouse models of amyloid and tau
Authors: Mensch André Nunes , Carello‐Collar Giovanna , Bellaver Bruna , Ferreira Pamela C.L. , Ramos Vanessa G. , Pascoal Tharick A. , Rosa‐Neto Pedro , Zimmer Eduardo R
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of amyloid‐β (Aβ) plaques and neuronal deposition of tau tangles, mainly in cortical regions and the hippocampus. Beyond these neuropathological hallmarks, it is suggested that neurotransmission dysfunctions, such as in the γ‐aminobutyric acid (GABA)ergic system, contribute to AD pathophysiology. However, the impact of Aβ and tau in the GABAergic system is still unknown. Thus, we aimed to examine GABA levels in the hippocampus of transgenic mouse models of Aβ and tau.

Method

We systematically reviewed the literature following the PRISMA 2020 guidelines. We searched PubMed and Web of Science databases for studies reporting GABA levels in the 3xTg‐AD and 5xFAD mouse models. These models present APP and PSEN1 mutations, but the 3xTg‐AD also harbors the MAPT P310L tau mutation, which is found in frontotemporal dementia.

Result

The search identified 3,576 articles. Six met the inclusion criteria (n = 26 3xTg‐AD and 26 wild‐type (WT); n = 16 5xFAD and 17 WT). The studies reported no significant differences in the levels of GABA in the hippocampus of 3xTg‐AD mice compared to their WT, but GABA levels decreased as a function of age. By contrast, the 5xFAD mouse model presented higher levels of GABA than their WT littermates.

Conclusion

Here, we show no significant changes in GABA levels in the hippocampus of 3xTg‐AD mice, whereas the levels of GABA were increased in the 5xFAD. Interestingly, the model harboring APP, PSEN1, and MAPT P310L mutations does not present changes in hippocampal levels of GABA. Our results suggest that Aβ alters GABA levels in the hippocampus, which may be an early change in AD. In addition, hippocampal GABAergic changes seem sensitive to different pathological features of AD.
Within and between‐network functional connectivity disruptions in posterior cortical atrophy and dementia with Lewy bodies
Authors: Singh Neha Atulkumar , Goodrich Austin W , Weigand Stephen D. , Graff‐Radford Jonathan , Machulda Mary M. , Carlos Arenn Faye , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Boeve Brad F. , Josephs Keith A , Kantarci Kejal , Whitwell Jennifer L
Published: December 2023

Background

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show overlapping patterns of hypometabolism affecting posterior regions of the brain. Both syndromes show disruptions in functional connectivity, but it is unknown how patterns of disruption within and between networks compare between PCA and DLB.

Method

Thirty amyloid‐positive PCA, 27 amyloid‐positive DLB (DLB+), 24 amyloid‐negative DLB (DLB‐) patients and 30 cognitively normal amyloid‐negative (CN) individuals were recruited at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore nine networks: visual, sensorimotor, dorsal‐attention, cerebellar, frontoparietal, memory, language, salience, and default mode networks (DMN). Multivariate linear regression models corrected for multiple comparisons and adjusted for age and sex were fit to analyze within‐network connectivity (Fisher’s R‐to‐Z transformations). Between‐network connectivity was assessed with group level difference maps (two‐sample t‐test) corrected for false discovery rate at p<0.05.

Result

Multivariate linear regression models showed reduced within‐network connectivity across all DMN components, sensorimotor, and dorsal‐attention networks, with trends for the visual network in PCA compared to CN. Both DLB‐ and DLB+ showed reduced within‐network connectivity for the cerebellar network, with DLB+ showing reduced connectivity in the posterior‐DMN, memory, and salience networks compared to CN. DLB‐ showed increased connectivity in dorsal‐attention and DMN, while DLB+ showing reduced connectivity in the memory network compared to PCA. Between‐network analysis showed an increase in cerebellar‐to‐sensorimotor connectivity in all three groups, with increase in cerebellar‐to‐dorsal‐attention connectivity in DLB‐ and PCA compared to CN. DLB‐ showed a decrease in posterior‐DMN‐to‐sensorimotor connectivity, while PCA showed reduced connectivity between all DMN components and dorsal‐attention‐to‐sensorimotor connectivity compared to CN. There was an increase in connectivity between all DMN components and a reduction in dorsal‐DMN‐to‐sensorimotor connectivity in both DLB‐ and DLB+ compared to PCA.

Conclusion

PCA was associated with connectivity disruptions across all DMN components, sensorimotor, dorsal‐attention and visual networks, while both DLB groups showed disruptions in cerebellar networks, with DLB+ showing further disruptions in posterior‐DMN, memory and salience networks. These findings suggest that both PCA and DLB have unique brain network disruptions, with amyloid status influencing connectivity in DLB.
Effect of white matter hyperintensities and amyloid on neurodegenerative change and cognitive trajectory in cognitively unimpaired older adults
Authors: Maillard Pauline , Han Ji Won , Sapkota Shraddha , Harvey Danielle J. , Fletcher Evan , Martinez Oliver , Johnson David K , Olichney John M. , Farias Sarah Tomaszewski , Decarli Charles
Published: December 2023

Background

Overwhelming evidence of association between amyloidosis and neurodegeneration, particularly in the hippocampus, has been reported. However, the recognition of cerebrovascular disease (CVD), the most common comorbidity in elderly patients with dementia2, as a contributor to neurodegeneration process has remained modest. The objective of this study is to investigate the contributions of amyloidosis, as measured by amyloid PET, and CVD, as reflected by white matter hyperintensity (WMH), on neurodegenerative change and how their combination impacts cognitive trajectory in cognitively unimpaired (CU) individuals.

Method

139 CU participants from the University of California, Davis Alzheimer’s Disease Research Center diversity cohort received at least two cognitive assessments and underwent a PET exam at baseline, and baseline and follow‐up MRI imaging (Table 1). Z‐score measures of DVR19 and SUVR20 values were used as measure of baseline amyloid beta (Aβ) burden. Baseline WMH volume was log‐transformed and regressed against intracranial volume (TCV). Four markers of neurodegeneration were used, including hippocampal volume (regressed against TCV), mean cortical GM thickness and two cognitive‐related signature region of interest (sROI), including episodic memory and executive function. We used structural equation modeling (SEM) analyses (Figure 1) to investigate associations between cognitive performance trajectories (∼6 years), including episodic memory and executive function, and baseline Aβ, baseline WMH and change in the four neurodegeneration markers.

Result

SEM analysis revealed significant effects of increased baseline Aβ and greater baseline WMH on accelerated decrease in neurodegeneration marker measures in all models (Figure 2). Increased baseline amyloid and WMH, but not neurodegenerative change measures, were also associated with accelerated decline in episodic memory performance (pvalues<0.05, Figure 2, panels A‐C‐E). Finally, increased baseline Aβ and accelerated decreased in cortical GM and sROI thickness were found to be associated with accelerated decline in executive function (pvalues<0.05, Figure 2, panels B‐D‐F).

Conclusion

Our findings suggest that both CVD and amyloidosis simultaneously impact neurodegenerative change and that these pathologies are associated with cognitive trajectories, but the dynamics of these trajectory are different for executive and memory, suggesting different early path of vulnerability for these domains and emphasizing the need to thoroughly understand the interaction between amyloidosis, CVD, and neurodegeneration.
Epigenetic age from peripheral blood predicts progression to Alzheimer’s disease, white matter disease burden, and cortical atrophy
Authors: Bonham Luke W. , Sirkis Daniel W. , Pang Alina PS , Sugrue Leo P , Santamaría‐García Hernando A , Ibanez Agustin , Miller Bruce L , Yokoyama Jennifer S. , Corley Michael J ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Cross‐sectional studies suggest a limited but promising relationship between epigenetic clocks, estimated using DNA methylation patterns, and Alzheimer’s disease (AD) pathophysiology and risk. However, prior analyses did not utilize longitudinal analyses or neuroimaging biomarkers of AD. Herein, we employed survival and structural neuroimaging analyses to test the hypothesis that DNA methylation age predicts AD progression.

Method

Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we calculated two established epigenetic ages, ‘DNAmPhenoAge’ and ‘DNAmGrimAge’ which proxy biologic age and mortality risk, respectively. Using Cox proportional hazard regression analysis in normal controls (NC), we tested whether DNAmPhenoAge/DNAmGrimAge associated with progression to mild cognitive impairment (MCI) or AD. Structural magnetic resonance (MR) images were segmented using Freesurfer 5.1 and a previously described white matter hyperintensity (WMH) quantification pipeline. Multiple regression analysis was used to test whether DNAmPhenoAge/DNAmGrimAge predicted WMH volumes and cortical atrophy.

Result

Replicating prior work, we found no significant differences in DNAmPhenoAge and DNAmGrimAge between NC (n = 128), MCI (n = 251), and AD (n = 50) diagnoses. Strikingly, however, in NC participants, both DNAmPhenoAge (p = 0.004) and DNAmGrimAge (p = 0.05) associated with progression to MCI or AD (Figure 1). Even after correction for chronologic age, DNAmPhenoAge remained significantly associated with progression to MCI or AD (p = 0.01). Utilizing samples from across the spectrum of normal aging to AD, DNAmPhenoAge and DNAmGrimAge strongly associated with WMH in all diagnoses (Table 1). Moreover, DNAmPhenoAge remained significantly associated with WMH in select groups after correction for chronologic age (Table 1). Finally, both DNAmPhenoAge and DNAmGrimAge predicted cortical thickness in multiple AD‐relevant regions (Figure 2).

Conclusion

In contrast to earlier work suggesting limited applicability of blood‐based DNA methylation scores in the context of AD, our novel survival and neuroimaging analyses have revealed the broad utility of second‐generation epigenetic clocks not only in predicting progression to MCI and AD but also via their association with neuroimaging biomarkers of AD, including white matter disease burden and cortical atrophy in AD‐relevant regions. Easily accessible, blood‐based measures of biologic age therefore represent promising predictors of AD risk and pathophysiology.
Novel mouse models of late‐onset Alzheimer’s disease
Authors: Sasner Michael , Oblak Adrian L , Pandey Ravi S , Uyar Asli , Garceau Dylan , Kotredes Kevin P , Soni Disha , Lin Peter Bor‐Chian , Ingraham Cynthia , Lamb Bruce T , Howell Gareth R , Carter Gregory W ,   MODEL‐AD
Published: December 2023

Background

The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Consortium was established to generate and characterize more translatable animal models for late‐onset Alzheimer’s disease (LOAD) based on human genetic risk variants. While numerous genetic risk loci for LOAD have been identified, few have been experimentally verified in vivo and in many cases the risk variants have not been validated. The development of new models incorporating LOAD genetic risk should improve our understanding of disease mechanisms and improve preclinical testing of potential therapeutics.

Method

Coding and non‐coding LOAD risk variants were prioritized based on human data sets, with the goal of targeting diverse pathways (e.g., neuroinflammation, vascular risk, metabolic function, lipid homeostasis). Risk variants in Abca7, Adamts4, Bin1, Erc2, Mthfr, Mtmr4, Plcg2, Ptk2b, Slc6a17, Snx1, Sorl1 and other loci were engineered into mouse models expressing humanized APOE4 and the Trem2*R47H risk variant; in more recent models, a humanized Abeta allele was also included. A novel transcriptomic panel, based on clinical LOAD samples (Preuss et al, 2020) was used to evaluate how well each model replicated clinical transcriptomic changes with disease. Models were aligned to ROSMAP clinical subtypes.

Result

We have identified specific human AD‐related pathways disrupted in an age‐dependent manner in these novel mouse models. Specifically, mouse models carrying human AD risk variants Abca7*A1527G, Mthfr*C677T, and Plcg2*M28L exhibited transcriptomics changes similar to those seen in LOAD patients. Most models could be readily matched to either the inflammatory or non‐inflammatory subtype.

Conclusion

We have prioritized mouse models expressing LOAD risk variants in Abca7, Mthfr, and Plcg2 for comprehensive phenotyping using clinically relevant measures including transcriptomics and proteomics, biomarkers, neuropathology and in vivo imaging at advanced ages (24 months). Ongoing projects will use human data to guide how to combine alleles to create models that match multi‐omic signatures of AD subtypes and test the effects of environmental risk factors such as high‐fat diet. Through this effort we aim to develop improved models for testing targeted therapeutics.
Usefulness of R2 maps to detect GM changes in AD continuum: a pilot study
Authors: Martin‐Echave Marta , Montesinos Paula , Grau‐Rivera Oriol , Suarez‐Calvet Marc , Puig‐Pijoan Albert , Minguillon Carolina , Cascales‐Lahoz Diego , Contador José , Fernández‐Lebrero Aida , Navalpotro Irene , Sanchez‐Gonzalez Javier , Gispert Juan Domingo , Falcon Carles
Published: December 2023

Background

MRI multi‐echo sequences can be used to compute quantitative R2 maps (1/T2). This pilot study aimed to determine whether R2 maps might offer relevant information on GM changes in AD continuum.

Method

The sample consisted of 60 subjects: 20 healthy controls (HC), 20 cognitively unimpaired individuals with CSF Aβ42/40<0.071 (preAD) and 20 subjects with clinical diagnosis of Alzheimer disease (AD) validated by biomarkers (Ab42/p‐Tau181 ratio <10.25; Lumipulse‐Fujirebio). The MRI protocol included 3D T1W (voxel size: 1.2×1.2×1.2mm3, TR = 9.8ms, TE = 3ms, TI = 900ms) and multi‐echo (GRASE, voxel size: 2×2.2×2 mm3, TR = 2000ms, 32 echoes, TE: successive multiples of 9.3ms). R2 maps were obtained through linear regression of the logarithm of multi‐echo images. GM and R2 maps were spatially normalized to the MNI and smoothed (8mm FWHM). Voxel‐wise one‐way 3‐group ANOVA and post‐hoc paired t‐tests were performed on modulated GM (GMv) and R2 maps using age and sex as confounders and applying a common GM mask (SPM12, statistical threshold: p<0.001 uncorrected; k>100 voxels (∼0.33cm3) in all analyses).

Result

Table 1 displays the descriptive statistics of the sample. Figure 1 shows the results from post‐hoc two‐sample t‐tests between HC and AD for GMv and R2 maps. GMv decrements were mostly located in temporal and parietal regions, as expected. Differences in R2 maps covered those regions but also others such anterior cingulate. No differences were found between HC and preAD neither in R2 maps nor in GMv.

Conclusion

Results might indicate that changes in R2 are not only reflecting atrophy but other undetermined tissular changes. Further research is warranted to further determine the mechanisms underlying R2 maps changes and the potential usefulness of R2 maps in AD characterization and diagnosis.
Association between coronary artery atherosclerosis and Alzheimer’s disease pathology: preliminary results
Authors: Yahagi‐Estevam Maristella , Farias‐Itao Daniela Souza , Grinberg Lea T. , Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Pasquallucci Carlos Augusto , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: December 2023

Background

Coronary heart disease (CHD) is the leading cause of mortality worldwide. Dementia is also among the ten most common causes of mortality, and it is one of the main causes of disability in older people. However, the association of direct morphometric percentage of obstruction in coronary arteries with Alzheimer’s disease (AD) type‐pathology remains unclear. We investigated the association of the percentage of obstruction of coronary arteries with AD type‐pathology.

Method

The heart and brain of participants 50 years or older, who underwent full‐body autopsy were collected. The main coronary arteries were dissected and the region with the largest luminal narrowing or with unstable plaques were sampled. The percentage of obstruction was calculated using the lumen and internal elastic lamina areas. The dependent variable was defined by the presence of at least moderate AD‐type pathology (Braak≥3 and CERAD≥B), according to the Braak staging for neurofibrillary tangles, and CERAD for neuritic plaques. Regression models were adjusted for sociodemographic and clinical factors, with robust standard error to account for repeated measures in the same individual.

Result

The sample included 193 participants (mean age = 75±12 years old, 56% men, and 70% white). The percentage of obstruction of coronary arteries was not associated with the neuropathological diagnosis of AD (OR = 1.00, 95% CI = 0.99; 1.01, p = 0.52), Braak staging (β = ‐0.002, 95% CI = ‐0.009;0.003, p = 0.36) or CERAD (β = ‐0.0002; 95% CI = ‐0.005;0.004, p = 0.93).

Conclusion

There is no association between coronary artery obstruction and AD type‐pathology in this autopsy study with morphometric measurements of atherosclerosis.
The association of neighborhood socioeconomic status, cognition, cardiovascular risk factors, and vascular risk biomarkers in the HABS‐HD study
Authors: Vintimilla Raul
Published: December 2023

Background

Neighborhood socioeconomic status (NSES) is linked to poorer cognition and physical health, influencing the risk of cardiovascular disease and mortality. Adverse neighborhood conditions have been also associated with higher cardiovascular biomarker levels. This study goal is to examine whether NSES is associated with cognitive function and whether this relationship is explained by associations between NSES and cardiovascular risk and biomarker factors in a sample of non‐Hispanic Whites (NHW) and Mexican American (MA) elders.

Method

We studied 1391 subjects from the Health and Aging Brain Study (HABS‐HD) with signed consent, fasting blood samples, 3T MRI, clinical evaluation, and cognitive testing. Area deprivation index (ADI) was used as a measure NSES. Cardiovascular risk factors (CVRF) were ascertained by self‐ report and medical history, and biomarkers were assayed via a multiple‐plex biomarker assay platform using electrochemiluminescence. Three linear regression models examined the association of ADI with cognitive performance, adjusting for age, sex, and education, CVRF, and vascular risk biomarkers.

Result

Sixty percent of the sample were female. MA were significantly younger, less educated, and had higher ADI scores than NHW. They also had lower scores in global cognition and executive function measures. MA had a higher prevalence of hypertension, diabetes and obesity (p = <0.0001). After controlling for demographic variables, ADI was associated with SEVLT [NHW (B = ‐0.003, t = ‐2.18, p = 0.02); MA (B = ‐0.005, t = ‐2.96, p = 0.003)] and Trails B [NHW (B = ‐0.006, t = ‐2.55, p = 0.01); MA (B = ‐0.01, t = ‐3.76, p = <0.001)] scores in both ethnic groups. Dyslipidemia influenced the association of ADI with SEVLT in MA, while obesity influenced the association of ADI and trails B in NHW. The association of ADI and trails B was partially influenced by IL6 in MA, and this association was partially influenced by TNF, CRP, and VCAM values in NHW.

Conclusion

NSES may influence cognitive functioning. This relationship is only partially explained by CVRF and vascular blood biomarkers. Future research is needed on the longitudinal relationships of NSES, cognitive impairment, and vascular factors.
Entorhinal Cortex Circuit Dysfunction in Mouse Models of APOE4 and Chemotherapy‐Induced Cognitive Impairment
Authors: Luo Nancy , Vicini Stefano , Rebeck Bill
Published: December 2023

Background

APOE4 has broad effects, one of which is worsened cognitive outcomes in cancer survivors following chemotherapy treatment compared to APOE3.

Method

1‐2 month old female APOE3 and APOE4‐Targeted Replacement (TR) mice were used for whole cell patch‐clamp experiments in the entorhinal cortex. Chemotherapy was introduced via a single injection of doxorubicin (10 mg/kg) or saline (control) and treated APOE‐TR mice were euthanized 1 week post‐injection. 0.5% biocytin internal solution was used to visualize cell morphology post hoc under a confocal microscope.

Results

Pyramidal cells in the entorhinal cortex of APOE4‐TR mice (4 mice, n = 26 cells) exhibit significantly decreased spontaneous excitatory and inhibitory postsynaptic current frequencies, thereby contributing to an elevated excitatory‐inhibitory balance compared to APOE3‐TR mice (4 mice, n = 23 cells). Doxorubicin‐treated APOE3‐TR mice (4 mice, n = 33 cells) show a significant increase in spontaneous excitatory and inhibitory postsynaptic current amplitudes compared to controls (2 mice, n = 16 cells), while doxorubicin‐treated APOE4‐TR mice (5 mice, n = 20 cells) display no such synaptic changes compared to controls (4 mice, n = 19 cells).

Conclusion

APOE4 has baseline effects on entorhinal cortex circuit inhibition and the lack of response to chemotherapy may reflect reduced resilience to stressors.
Biofluid markers of Alzheimer’s disease‐associated CNS inflammation in adults with Down syndrome
Authors: Belbin Olivia , Iulita Maria Florencia , Serrano‐Requena Sara , Videla Laura , Barroeta Isabel , Benejam Bessy , Altuna Miren , Tamayo Natalia Valle , Cervantes‐Gonz Alba , Gil Laia Lidón , Dols‐Icardo Oriol , Bejanin Alexandre , Alcolea Daniel , Lleó Alberto , Fortea Juan , Carmona‐Iragui Maria
Published: December 2023

Background

Down syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), and a priority population to study early AD changes. This study explores inflammatory markers in biofluids over the course of the AD continuum in adults with DS.

Method

This is a cross‐sectional study of the Olink Target 96 Inflammation (v.3022) panel in paired plasma and CSF from adults with DS from the DABNI cohort across the AD continuum (83 asymptomatic and 109 symptomatic), 60 cognitively unimpaired controls and 130 sporadic AD (sAD) patients. See Table for demographics. We used linear regression to compare group differences, including age and sex as covariates. Age was excluded and intellectual disability was added as a covariate when comparing across AD stages in DS. We controlled the false discovery rate using the Bonferonni‐Hochberg method and considered only statistically and biologically relevant changes (fold‐change+/‐10%, adj.p<0.05).

Result

We detected 59/96 inflammatory markers on the panel in CSF and 81/96 in plasma. In asymptomatic DS vs CN, 12 inflammatory markers were decreased (<0.84‐fold, adj.p<0.02) and 3 were increased (>1.27‐fold, adj.p<0.03) in CSF. In the same comparison in plasma, 2 were decreased (<0.84‐fold, adj.p<0.03) and 26 were increased (>1.13‐fold, adj.p<0.04). Over the AD continuum in DS, 29 inflammatory markers were increased (>1.1‐fold, adj.p<0.04) and 1 was decreased (0.78‐fold, adj.p = 0.003) in CSF. We did not see the same profile in sAD vs CN CSF (1 marker; 1.59‐fold, adj.p<0.0001). To focus on CNS inflammation, we restricted plasma analyses to the 11 inflammatory markers that showed AD‐associated changes in CSF and correlated between both biofluids (r2 = 0.03‐0.43; p<0.04). CCL23, CCL3, CXCL9 and CXCL10 were increased over AD stages in plasma (>1.15‐fold, adj.p<0.03) with similar effect sizes to those in CSF (>1.17‐fold, adj.p<0.02). We observed no change in those inflammatory markers in sAD vs CN plasma (all adj.p>0.14).

Conclusion

Trisomy 21 is associated with a distinct inflammatory profile in CSF and plasma. However, certain markers showed similar changes in both biofluids across the AD continuum in DS. CCL23, CCL3, CXCL9 and CXCL10 represent promising novel plasma biomarkers of AD‐related inflammation in DS.

Table. Demographics (%/mean+sd) for the participants used in this study.
Developing video content for New Zealand’s online iSupport
Authors: Sani Tara P , Cheung Gary , Peri Kathy , Yates Susan , Stuckey Adrian , Kaa Beryl , Nepia Bobby , Whaanga Hēmi , Cullum Sarah J
Published: December 2023

Background

The Empowering Dementia Carers in an iSupport Virtual Assistant (e‐DIVA) project aims to develop a website based on the World Health Organisation’s iSupport to support carers in Aotearoa New Zealand (NZ), Australia, Indonesia, and Vietnam. The website will be supplemented with culturally‐appropriate videos showing different scenarios in caring. As NZ had limited funding for the adaptation process, we decided to utilise the videos already developed by the Australian team and modify them to be locally‐relevant to NZ culture. There are some similarities in the culture and ethnic populations of the two countries, but also considerable differences. Here we aim to understand the need of cultural adaptation and describe the process of developing locally‐relevant videos for self‐paced dementia training to support carers in NZ.

Method

We worked with carers and social and health care practitioners to adapt the iSupport manual for use in NZ. We conducted separate focus groups with carers and care practitioners to agree on adapted videos for use in different modules in iSupport website. We reviewed the scripts and visuals and discussed how to ensure the content (scenario, dialogue) and delivery (music, visuals) were acceptable and relatable for NZ carers from different backgrounds.

To adapt for Māori carers, we took the manual and videos that had been adapted for non‐Māori, and conducted focus groups with Māori carers and care practitioners to produce content that was culturally‐appropriate and Māori‐friendly.

Result

Using co‐design and consultation with carers and care professionals from specific cultures, we made changes to the backgrounds and visual representation of the characters to better reflect NZ culture, and ensuring inclusion and representation of Māori and Pasifika in the videos. We will present the adapted videos in AAIC 2023 next to the poster.

Conclusion

Adapting existing videos can be a low‐cost approach to provide supporting media for an online training tool such as iSupport.
A cloud‐based application for cognitive stimulus therapy for the Togolese elderly population
Authors: Mawuli Lawson Laté Jean Paul
Published: December 2023

The diagnosis, management, and prevention of Alzheimer’s disease and vascular dementia are still in their early stage in Togo, a small West African country with a population of 8,966,632 and a percentage of the population over 65 years old of 3.57%. With a steadily growing elderly population, Togo has an old‐age dependency ratio of 94.5%. As clinical psychologists, practicing neuropsychological assessments, we receive more and more patients referred by medical doctors for symptoms affecting memory and reasoning. In our desire to contribute to the prevention of Alzheimer’s disease and to fight against the early onset of symptoms in our population, we propose a cloud‐based therapeutic and preventive tool called “Susu” (which is the name of memory in our local language). Susu is a cloud‐based application that allows people at risk of developing dementia to save content from their daily lives, in pictures or videos, with precise descriptions and annotations. This includes, for example, photos or videos of family members, places visited, and content specific to the person’s culture of origin. These pieces of information are stored in the cloud and will later be used in cognitive stimulation therapy based on the data stored in the cloud when the first symptoms of memory loss appear. The whole eSusu platform is a digital mental health marketplace dedicated to the prevention and care of dementia, where professionals and patients with their families can meet, exchange, and go through the process together, from assessment to therapy. As we say in our culture, the person who has lost his memory has simply forgotten the path leading to the memory hut: this memory hut is always preserved. Our commitment is simply to re‐draw the path to that memory house.
Increased regional brain inflammation predicts longitudinal brain atrophy in individuals in the Alzheimer’s disease continuum
Authors: Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Lussier Firoza Z , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Tissot Cécile , Therriault Joseph , Bezgin Gleb , Servaes Stijn , Benedet Andrea Lessa , Stevenson Jenna , Rahmouni Nesrine , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Karikari Thomas K , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick Ali
Published: December 2023

Background

Neuroinflammation typically involves the activation of microglial cells in the brain and has been linked to Alzheimer’s disease (AD) pathology. However, how microglial activation influences brain neurodegeneration in individuals across the AD continuum is still poorly understood. Here, we aimed to investigate the influence of microglial activation in longitudinal brain atrophy in individuals across the AD continuum. We hypothesize that high levels of regional brain inflammation predict widespread brain atrophy.

Method

We assessed 95 individuals from the TRIAD cohort (60 cognitively unimpaired and 35 cognitively impaired) with available [11C]PBR28‐PET, a measure of microglial activation, and a 2‐year longitudinal MRI (mean = 2.07 years). We generated grey matter voxel‐based morphometry (VBM) images using SPM12 and DARTEL, smoothed with a Gaussian kernel of full‐width half maximum of 8mm. We built the uncorrected (p < 0.05) association matrix between the [11C]PBR28‐PET SUVR and longitudinal VBM ROIs (z‐score) with the β‐estimates from linear regressions accounting for age, sex, and diagnosis. We divided the [11C]PBR28‐PET levels into terciles (low, intermediate, and high) to generate the averages of longitudinal VBM changes.

Result

Baseline ROI‐based [11C]PBR28‐PET levels associate with longitudinal brain atrophy not only locally but also in distinct brain regions (Fig 1a). After FDR‐correction, the inferior temporal cortex was the region where [11C]PBR28‐PET levels were better associated with widespread longitudinal brain atrophy (Fig. 1b). Brain atrophy was observed in AD‐related regions, including the amygdala, insula, and the superior temporal cortex, independently of global amyloid load and tau (Fig. 1b). Accordingly, individuals with higher [11C]PBR28‐PET levels in the inferior temporal cortex presented increased longitudinal brain atrophy compared to individuals with lower [11C]PBR28‐PET (Fig. 1c).

Conclusion

We identified increased baseline [11C]PBR28‐PET levels in the inferior temporal cortex that were highly associated with longitudinal brain atrophy in individuals across the AD continuum. Our results demonstrated that higher levels of inflammation in key brain regions could predict widespread longitudinal brain atrophy, suggesting that microglial activation has a detrimental impact on AD‐related neurodegeneration progression.
Comparing intra‐individual variability on executive functioning tasks in individuals with Mild Cognitive Impairment and Dementia of the Alzheimer Type: Results from the ARMADA Study
Authors: Ho Emily , Karpouzian‐Rogers Tatiana , Dworak Elizabeth , Weintraub Sandra , Gershon Richard C.
Published: December 2023

Background

Cognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi‐site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups.

Method

As part of the Advancing Reliable Measurement in Alzheimer’s Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item‐level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT.

Results

We observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5‐fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test.

Conclusion

This study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.
Development and assessment of a composite score for overall brain pathology in the Adult Changes in Thought (ACT) autopsy cohort
Authors: Sinha Sagnik , Gibbons Laura E , Latimer Caitlin S , Crane Paul K , Keene C Dirk , Mukherjee Shubhabrata
Published: December 2023

Background

Many people with clinically diagnosed Alzheimer’s disease (AD) dementia during life show multiple comorbid neuropathologies at autopsy. We sought to develop and evaluate a composite brain pathology score (BPS) score in the Adult Changes in Thought (ACT) study.

Method

We chose nine standard neuropathological variables to derive the BPS: Thal phase, Braak stage, CERAD score, cerebral amyloid angiopathy (CAA) score, presence of Lewy Body disease, presence of hippocampal sclerosis, total microinfarcts, LATE stage, and presence of arteriolosclerosis. We used confirmatory factor analyses (CFA) to derive a composite score for BPS. We compared BPS to the AD Neuropathologic Change (ADNC) score.

We performed non‐nested modeling to compare the association of each score (BPS vs ADNC) using the last cognitive score (memory, executive function, language, and visuospatial ability) prior to death, adjusting for age at death and sex. Non‐nested models were compared with the Adjusted‐R2, the Davidson‐MacKinnon J‐test, and the Cox–Pesaran test. We focused on people whose last cognitive data were≤2 years prior to death. We compared associations of ADNC and BPS with last known clinical diagnosis (no dementia vs. any dementia), adjusting for age at death and sex by considering area under receiver operator characteristic (ROC) curves.

Result

Sample size was 886 with mean age of death was 89 and 57% were female. A bifactor model fit the best (Figure 1) with residual correlations for Thal phase and CERAD score, and for LATE stage and presence of hippocampal sclerosis. The BPS explained more of the variance for each of the cognitive scores (Table 1) and was superior and statistically significant compared to the ADNC score in comparisons of non‐nested models (Table 2). The BPS was also more strongly associated (Odds Ratio = 3.2) with dementia diagnosis than the ADNC score (Odds Ratio = 2.0). The area under the ROC curve for ADNC score was 0.74, while it was 0.78 for BPS score. The difference between the areas under ROC curves was statistically significant (p‐value < 0.0001).

Conclusion

We demonstrate an approach to developing a composite brain pathology score which incorporates multiple forms of pathology. Future efforts will be focused on co‐calibrating and harmonizing BPS in other autopsy cohorts.
Amyloid‐, tau‐, and FDG‐PET in amyloid‐negative patients clinically diagnosed with early‐onset Alzheimer’s disease in the LEADS study
Authors: Mundada Nidhi S. , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Iaccarino Leonardo , Shankar Ranjani , Amuiri Alinda , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud
Published: December 2023

Background

Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.

Methods

We identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.

Results

Compared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).

Conclusions

Amyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes.