bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a clinical timeline of Alzheimer’s disease; a multivariate cognitive perspective
Authors: Cox Timothy , Cespedes Marcela Ines , Gillis Cai , Maserejian Nancy Nairi , Maruff Paul , Fowler Christopher J , Rainey‐Smith Stephanie R , Martins Ralph N , Masters Colin L , Doecke James D ,   The AIBL Research Group
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease characterised by a long period of neuronal loss which manifests clinically as cognitive decline and ultimately dementia. Understanding the nature and magnitude of cognitive decline prior to dementia is critical to understanding the disease course. Here we quantify change in six cognitive composite scores to compare their temporal sequence and rates of change early in the AD disease course.MethodAmyloid‐beta positive (Aβ+) cognitively unimpaired (CU), MCI and AD participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing with ≥three study visits (N = 857), were used to derive composite scores for executive function, language, attention and processing, recognition, visuospatial, and a general composite used in clinical trials (AIBL‐PACC). A multivariate method for combining cognitive change trajectory curves was used to place each composite score trajectory in a common numerical space. Using the mean AIBL‐PACC scores for the prodromal group (MCI‐Aβ+) as a reference, change over a three‐year period for each composite was estimated. Given the AIBL requirement for a minimum 1.5 SD change in two or more cognitive domains to justify progression to MCI/AD, disease time was set with the zero point at a ‐1.5 AIBL‐PACC score, representing a 1.5 SD decline in AIBL‐PACC from the mean CU Ab‐ population at baseline.ResultThe AIBL‐PACC, language and visuospatial functioning scores showed the steepest trajectories indicating AD related decline in these scores was fastest (Figure 1). AIBL‐PACC reached the ‐1.5 point on the y‐axis first followed closely by memory recognition, with steeper trajectory of decline for the AIBL‐PACC across the age range. Focusing on AIBL‐PACC, it took 2.15 years to transition from ‐1.5 to the mean of the prodromal group (‐1.87). At five years past the start of the prodromal stage, the data suggests a drop in the AIBL‐PACC to ‐2.54, an approximate decline of ∼0.22 points per year.ConclusionThis is the first presentation of a novel multivariate disease trajectory method examining expected change across the AD continuum among Aβ+ persons. A 3‐year change in the PACC composite demonstrated here will be relevant to measure disease progression during clinical trials.
The Influence of Prior Head Injury on Late‐Life Cognition and White Matter Microstructure in Older Adults At‐Risk of Alzheimer’s disease
Authors: Chiu Larissa Kristi , Ai Meishan , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Geddes Maiya R. ,   the PREVENT‐AD Research Group
Published: December 2023

AbstractBackgroundThe long‐term combined effects of mild traumatic brain injury (mTBI) and APOE ε4‐allele carrier status (APOE+/‐), a genetic risk factor of Alzheimer’s disease (AD), on cognition and white matter structural integrity in older adults at‐risk of AD is not fully understood.MethodTo investigate mTBI effects on late‐life neurobehavioural outcomes, a subsample of the PREVENT‐AD cohort was analyzed. Participants were cognitively normal adults over age 55 with a parental or multiple‐sibling history of AD. The mTBI group included individuals who self‐reported at least one prior mTBI with loss of consciousness and/or memory gap (n = 48, 33.3% APOE4+). Rey Auditory Verbal Learning Test measured immediate and delayed memory, Color‐Word Interference Test measured cognitive flexibility and inhibitory control, and Trail Making Test measured processing speed and attention.The control group included demographically‐matched (age, sex, years of education) participants from the same cohort without self‐reported mTBI (n = 62, 29.0% APOE4+). Data were analyzed using 2‐way ANOVAs with weighted means on years of education, corrected for multiple comparisons. To evaluate underlying structural differences in white matter tracts between mTBI and control groups, diffusion tensor imaging (DTI) metrics, including fractional anisotropy, axial and radial diffusivity, using the JHU‐atlas parcellation.ResultsmTBI/APOE4+ individuals performed significantly worse on cognitive outcomes of delayed recall, cognitive flexibility, and inhibitory control compared to controls; however, they performed significantly better on tests of processing speed and visual attention compared to mTBI/APOE4‐ individuals. DTI results showed that the mTBI group, compared to the control group, had significantly decreased axial diffusivity in the left internal capsule, right superior longitudinal fasciculus, and superior frontooccipital fasciculus (SFOF) (p<0.05 uncorrected). Within the mTBI group, significant positive correlation between lower processing speed and decreased axial diffusivity of SFOF, accounting for age and sex.ConclusionOur findings suggest that prior mTBI impacts cognitive aging in older adults at‐risk of AD differentially depend on APOE4 status, where APOE4+ individuals with prior mTBI had worse working memory, cognitive flexibility, and inhibitory control but better processing speed outcomes. Lower cognitive outcomes in mTBI individuals may be supported by decreased diffusivity in specific white matter tracts. These results can inform dementia prevention in these individuals.
I‐CONECT Intervention Effects on Weekly Time Spent Outside of Home and Social Contacts among Socially Isolated Older Adults with Normal Cognition and Mild Cognitive Impairment
Authors: Yu Kexin , Wu Chao‐Yi , Silbert Lisa C , Kaye Jeffrey A , Dodge Hiroko H 
Published: December 2023

AbstractBackgroundSocial isolation has been linked to an increased risk of cognitive decline and incident dementia. Socially isolated individuals tend to lack access to cognitively stimulating activities. This may adversely impact their cognitive health. The Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT) was designed to deliver online conversation sessions to socially isolated older adults to slow cognitive decline and ultimately delay the onset of dementia. The current study examined the intervention effects on participants’ weekly time spent out‐of‐home and their social interaction with family and friends as clinically meaningful functional outcomes.MethodsIntervention group engaged in 30‐minutes video chat 4 times/week and 10‐minute weekly phone calls, while control group received only 10‐minute weekly phone calls over 48 weeks. In each call, we asked participants to report time spent out‐of‐home and whether they contacted family or friends during the week (yes/no). Linear mixed‐effect models were run for time spent out‐of‐home, and mixed‐effect models with a logistic link were performed for contact with family and friends. The intervention effect was modeled by including an interaction term of time (in weeks) and group assignments. We ran analyses separately for participants with normal cognition (NC) and mild cognitive impairments (MCI). All models controlled for age, sex, race, education, and a pre vs. post COVID‐19 pandemic indicator.ResultsAs weeks passed, participants (N = 155, mean age 81, 72.3% female, 17.53% African American, 51.95% MCI) in both groups reported spending more time out of home, indicated by a significant time main effect (B = , p<.001). Among NC participants, the intervention group had a steeper increase in their reported time spent out‐of‐home compared to the control group (B = , p = .016). Among MCI participants, the intervention group had an increased likelihood of contacting friends over time (OR = 1.013, p = .001), while the intervention effect on contact with family was not significant for either the NC or MCI group.ConclusionPreviously we reported the I‐CONECT intervention positively affected cognitive functions. The current results suggest the translational effects of I‐CONECT to functional outcomes beyond cognitive test scores, activating weekly activities among socially isolated older adults. The intervention provides a remote social interaction platform that brings cognitive stimulation to at‐risk populations.
Subjective Cognition as A Predictor of Objective Cognitive Decline Among Older Black/African Americans: A STAR Study
Authors: Chen Nancy X , George Kristen M , Lor Yi , Glymour M. Maria , Gilsanz Paola , Farias Sarah Tomaszewski , Barnes Lisa L. , Mayeda Elizabeth Rose , Gradwohl Natalie M , Peterson Rachel , Whitmer Rachel A. 
Published: December 2023

AbstractBackgroundSubjective evaluations of cognition are convenient to administer and can be useful if they accurately identify or predict cognitive impairment. We investigated the relationship between subjective and objective measures of cognition in a cohort of Black older adults.MethodThe Study of Healthy Aging in African Americans (STAR) comprises community‐dwelling Black adults ages 50+ who are long‐term Kaiser Permanente Northern California members. Verbal episodic memory (VEM) and executive function (EF) were assessed at three interview waves by the Spanish and English Neuropsychological Assessment Scales (SENAS). We operationalized subjective cognition two ways. 1) Participants self‐rated changes in their everyday cognition using the Everyday Cognition Scale (ECog). Responses, rated 1 = “Better or no change” to 4 = “Consistently much worse, were averaged across the 16 items. 2) Participants responded (yes/no) to the question: “Are you concerned that you have a memory or other thinking problem?” (Subjective memory concerns). Linear mixed models with random intercept and slope estimated associations of ECog or subjective memory concerns with VEM and EF at baseline and over time. All models adjusted for baseline age, gender, education, parental education, and interview mode (in‐person or phone). Sensitivity models stratified by gender and age (+/‐ 65 years).ResultParticipants’ (n = 671) baseline mean age was 68.4 (SD = 8.7) years, 70.2% were women, mean ECog was 1.26 (SD = 0.3), and 40.1% reported subjective memory concerns (Table 1). Subjective memory concerns were associated with worse baseline VEM and EF, but not associated with rate of change for either domain (Table 2A; Table 3A). In contrast, ECog was associated with rate of change for VEM (b = ‐0.09, 95% CI ‐0.17,0.002; Table 2B) and EF (b = ‐0.07, 95% CI ‐0.13,‐0.003; Table 3B). Among women, higher ECog was associated with faster decline in VEM (b = ‐0.12, 95% CI ‐0.22,‐0.02; Table 2B) and EF (b = ‐0.09, 95% CI ‐0.17,‐0.02; Table 3B). Among participants ages 65 and older, higher ECog was associated with a faster decline in VEM (b = ‐0.11, 95% CI ‐0.22,‐0.001; Table 2B).ConclusionA well‐validated measure of subjective memory concerns, the ECog, was associated with worse objective executive function and verbal episodic memory and faster declines in both domains in this sample of middle‐aged and older Black adults.
Genetic Contributions of APOE ε4 and TOMM40 rs2075650 to Mitochondrial Dysmorphia
Authors: Wang Qian , Dove Makayla , Sanden Mckenzie , Thackery Mackenzie , Willette Auriel A 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is the most well‐known disease from ageing. On the Alzheimer’s disease (AD) side, APOE ε4 and TOMM40 rs2075650 are known risk factors from GWAS studies. On the ageing side, mitochondria are theorized to play a central role in the decrease of bioenergy production, rise of oxidative stress and inflammation activation. APOE is an apolipoprotein that facilitates the transportation of cholesterol, which affects the downstream processing of cholesterol in mitochondria. TOMM40 is the channel‐forming subunit of the translocase of the outer mitochondrial membrane complex. It is essential for the import of protein precursors into mitochondria. Interestingly, both genes are also in proximity on chromosome 19 and share linkage disequilibrium. We hypothesize that the two minor alleles work together to influence mitochondrial function.MethodAPOE ε4 and TOMM40 genes are cloned into cDNA plasmids and expressed in cells through transient transfection. Depending on the expression level, this mimics the heterozygous conditions of APOE ε4 and TOMM40 rs2075650 carriers. Mitochondria are fluorescently labeled and imaged for their morphology. The centerline length and average width of mitochondria units are measured to quantify morphology.ResultPreliminary results showed that mitochondria in cells expressing high risk alleles were stressed. The mitochondria appeared swollen with shorter length and wider average width.ConclusionSince dysmorphia is a sure sign of mitochondrial dysfunction and also widely observed in specimen from Alzheimer’s patients, results from heterozygous APOE ε4 and TOMM40 rs2075650 transfected cells may provide insight into the mechanism of AD development. Future study will explore the interaction between the two alleles. The goal is to improve our understanding of the key components of mitochondrial functions and their effects on ageing.
Midpoint baseline results of the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)
Authors: Hammers Dustin B. , Eloyan Ani , Taurone Alexander , Thangarajah Maryanne , Beckett Laurel , Gao Sujuan , Kirby Kala , Nudelman Kelly N. H. , Dage Jeff L. , Polsinelli Angelina J , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundFewer than 5% of patients with Alzheimer’s disease are diagnosed between 40‐64 years old, making “early‐onset Alzheimer’s disease” (EOAD) an uncommon phenomenon (Zu et al., 2015). To date, only basic knowledge on EOAD is known, no uniform criteria for EOAD have been implemented, and sample sizes in research have been small. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) aims to provide a comprehensive understanding of EOAD symptomology, with the current project profiling baseline clinical, cognitive, and basic genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodData from 371 participants undergoing the LEADS protocol were compared based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]). Because LEADS focuses on sporadic early‐onset dementia, impaired individuals with genetic mutations in Amyloid Precursor Protein (APP), Presenilin‐1 (PSEN1) or Presenilin‐2 (PSEN2), Microtubule Associated Protein Tau (MAPT), Chromosome 9 Open Reading Frame 72 (C9ORF72), or Granulin Precursor aka Progranulin (GRN) were excluded.ResultDemographic characteristics for each group are shown in Table 1. After adjusting for age, education, and sex, EOAD performed worse than CN for all domains (ps<.001, η2s = 0.05‐0.66), and worse than EOnonAD for all domains except language (ps<.001, η2s = 0.06‐0.29). As shown in Table 2, EOAD showed worse performance on Episodic Memory (z = ‐2.38), followed by Speed Attention (z = ‐1.93) and Executive domains (z = ‐1.43) relative to CN. An amnestic presentation was common among impaired participants, with several clinical phenotypes present. The EOAD group possessed a significantly greater proportion of apolipoprotein ε4 homozygous participants than the EOnonAD group (p = .01, Cohen’s w = 0.15), and a trend of greater proportions of ε4 heterozygous participants than both CN and EOnonAD (ps = .05‐.07, Cohen’s ws = 0.11; Table 3). Finally, LEADS participants generally consented at high rates to optional trial procedures like lumbar puncture (60%) and genetic disclosure (89%).ConclusionThis work represents the best baseline characterization of sporadic EOAD in the U.S. to date. Early‐onset dementia presents with widespread cognitive impairment, characterized by several known clinical phenotypes. Apolipoprotein ε4 allele carrier status appears to remain important in EOAD. Future investigation will explore many potential associations between EOAD and cognition, neuropsychiatric symptoms, genetics, and imaging.
The role of FNDC5/Irisin in brain energy metabolism in models of Alzheimer’s Disease
Authors: Fonseca Ariene Soares , Chauvet Mariana Gomes , Lourenco Mychael V. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) brains present defective metabolic profiles that are associated with amyloid‐β (Aβ) accumulation. We have previously shown that physical exercise promotes the expression of FNDC5/irisin, which in turn acts in the brain to trigger neuroprotection in AD models. Here, we investigated whether irisin rescues defective mitochondrial function induced by Aβ oligomers (AβOs).MethodHippocampal slices from 4‐month‐old wild‐type C57BL/6J mice were prepared and exposed to AβOs (1 µM) in the presence or absence of recombinant irisin (25 nM) for 3 h. We assessed levels of proteins related to mitochondrial fusion (MFN1, OPA1) and fission (DRP1) by Western blotting and mitochondrial function, by high‐resolution respirometry. Biochemical assays were used to determine glucose uptake, lactate content and NAD levels.ResultsAcute exposure to AβOs or irisin did not trigger any significant changes in proteins associated with mitochondrial dynamics or the amount of lactate released after AβOs exposure. Initial results indicate that irisin prevents the variations caused by AβOs in NAD+ levels and glucose uptake in hippocampal slices. Slices exposed to AβOs show a trend of reduction in ATP synthesis‐, complexes II/III‐coupled O2 and in residual O2 consumption. Treatment with irisin seems to prevent these events.ConclusionIrisin seems to preserve against the impact of AβOs on selective mitochondrial properties in the hippocampus. Future studies will further elucidate the mechanisms by which irisin is neuroprotective in AD mice.
Comparing the efficacy of domain‐specific and general cognitive composites in Alzheimer disease research
Authors: McKay Nicole S. , Millar Peter R , Aschenbrenner Andrew J. , Nicosia Jessica , Cruchaga Carlos , Schindler Suzanne E. , Benzinger Tammie L.S. , Morris John C , Hassenstab Jason J. 
Published: December 2023

AbstractBackgroundBalancing the need to standardize cognitive measures with the need to evolve alongside advances in scientific knowledge is an inherent challenge for longitudinal studies of Alzheimer disease (AD). The Uniform Data Set (UDS) offers a solution for this in cognitive batteries and is implemented across Alzheimer Disease Research Centers (ADRCs). Using equipercentile equating, we combined data spanning two versions of the UDS and derived domain‐specific and general cognitive composites. We compared the relationships of these measures with common biomarkers of AD, as well as their statistical power to detect cognitive change in clinical trials.MethodUsing longitudinal data from the Knight ADRC, domain‐specific cognitive composites were created using an exploratory factor analysis. The resulting four factors clustered episodic memory, semantic memory, working memory, and attention/processing speed tasks (Figure 1). We also computed a commonly‐used preclinical Alzheimer cognitive composite (PACC), an alternative Knight‐ADRC‐PACC, which did not include MMSE, and a global composite. Relationships between each cognitive composite and neuroimaging metrics of amyloid, tau, atrophy, and clinical symptoms, were compared cross‐sectionally and longitudinally (Figure 2). We also performed power analyses of all composites to calculate necessary sample sizes to observe a medium‐sized effect in a four‐year clinical trial.ResultOverall, general metrics of cognition slightly outperformed domain‐specific composites, although the working memory composite consistently reflected a poor relationship with AD biomarkers (Figure 2). Power analyses revealed that the global, Knight‐ADRC‐PACC, and attention/processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the ADCS‐PACC, required two to three times as many individuals (Figure 3).ConclusionWe found that data‐driven, domain‐specific, composites of cognitive performance can complement already‐established general cognitive composites, with the possible exception of the present working memory composite. In line with prior work, we highlight that attention and processing speed may be sensitive metrics of cognitive change in AD. The inclusion of the MMSE, such as in the ADCS‐PACC, may greatly reduce the sensitivity and statistical power of summary cognitive composites. Our results have important implications for the development of cognitive outcome metrics for future clinical trials.
Characterization of a R493X progranulin haploinsufficient knockin mouse model of frontotemporal dementia
Authors: Cai Wenji , Nygaard Haakon B. , Wendt Stefan , Sorrentino Stefano 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common form of dementia in young individuals, characterized by impairments in social cognition, language processing and executive function. Heterozygous loss‐of‐function mutations in the progranulin gene (GRN) are well known as a major genetic cause of a TDP‐43‐positive subtype of FTD (FTD‐GRN). The role of progranulin in the pathogenesis of FTD is not fully understood but has been shown to be associated with lysosomal dysfunction, impaired neuronal survival, and neuroinflammation. Rodent models of FTD‐GRN have been extensively used to model disease pathophysiology, but most studies utilize mice null for GRN. Our lab recently published a comprehensive neuropathological and behavioural assessment of a GRN R493X homozygous mouse model, confirming several phenotypes relevant to human FTD.To our knowledge, haploinsufficient R493X mice have not previously been studied. Here we assessed whether haploinsufficient GRN 493X mice would demonstrate relevant phenotypes for FTD pathophysiologic studies and drug screening.MethodWe characterized behavioural and neuropathological phenotypes of aged GRN R493X+/‐, GRN R493X‐/‐ and age‐matched C57BL/6J wildtype mice. The open‐field test was used to assess anxiety phenotype. Brain lysosomal dysfunction was assessed by western blot, and neuroinflammation, including astrogliosis and microgliosis, as well as hippocampal and thalamic synaptic dysfunction were analyzed by immunohistochemistry.ResultAs expected, our preliminary data show a higher progranulin level in GRN R493X+/‐ mice in comparison with the homozygous GRN R493X mice. Behavioural data, as well as analysis of neuroinflammation, lysosomal dysfunction and brain excitatory and inhibitory synaptic function, are being analyzed and will be presented.ConclusionHeterozygous GRN R493X mice more closely resemble the human genetic condition. Our characterization and comparison of neuropathologic phenotypes in aged GRN R493X+/‐ and GRN R493X‐/‐ mice provide insights into the molecular mechanisms underlying the effects of GRN haploinsufficiency and the suitability of this model for drug screening studies in FTD‐GRN.