bluuebunny/crossref_metadata_2025_split huggingface dataset:
Education or Socioeconomic Status: which proxy of cognitive reserve associates better with cognitive function and amyloid imaging results?
Authors: Sohrabi Hamid R , Weinborn Michael , Shemehsavar Soudabeh , Verma Shipra , Dore Vincent , Xia Ying , Taddei Kevin , Rainey‐Smith Stephanie R , Martins Ralph N 
Published: December 2023

AbstractBackgroundCognitive reserve (CR) is partially responsible for inter‐individual differences in developing dementia due to Alzheimer’s disease (AD). However, education years, as the primary proxy of CR, does not capture various life experiences, vocational background, and resources available to those who did not have an opportunity to complete formal education. We compared education years against Hollingshead Four‐Factor Index of Socioeconomic Status (SES‐Adults) to examine the latter’s utility as a better proxy of cognitive reserve. The SES‐Adults is a survey collecting information on marital status, retired/employed status, educational attainment, and occupational prestige for participants and their partners. The survey results are then converted into one of the 5 social class categories including low, working, middle, upper‐middle, and upper socioeconomic status.MethodA cross‐sectional study was conducted on a cohort of adults and older adults (n = 264) with mean age of 67.96 years. Participants were recruited from a longitudinal study investigating neuropsychological and biological correlates of dementia, namely the Western Australian Memory Study (WAMS). We examined the relationships between education years and the SES‐Adults scores, with cognitive function and amyloid load while controlling for age, gender (male/female), and APOE ε4 carriage. Amyloid load was measured using 18F‐NAV‐469 tracer.ResultThe cohort included 190 females and 74 males with 80 APOE ε4 carriers (available genotyped individuals = 203). Linear regression results showed education years was significantly correlated with both general cognitive function (MoCA) and amyloid load (R2 = 0.2935, Adjusted‐R2 = 0.2513; p<0.026) while controlling for the effects of age, gender, and APOE ε4 carriage. The SES‐Adults was not significantly related to cognition or amyloid load (p = .914). When SES was included in regression model, the relationships between education years and outcome measures turned non‐significant.ConclusionWe found education years to be significantly related to both cognition and amyloid load. However, no significant results was noted for the SES‐Adults. This cross‐sectional study showed that education is a reliable CR proxy as compared to a comprehensive measure of socioeconomic status(SES‐ Adults) .
Rational design of a vaccine for Alzheimer’s disease using a computationally‐derived conformational epitope to selectively target toxic amyloid‐beta oligomers
Authors: Kaplan Johanne , Napper Scott , Scruten Erin , Gibbs Ebrima , Coutts Juliane , Peng Xubiao , Plotkin Steven S , Cashman Neil R 
Published: December 2023

AbstractBackgroundAmyloid‐beta (Aß) vaccines have the potential to protect against disease but also carry the risk of eliciting proinflammatory T cell responses causing meningoencephalitis, and plaque‐reactive antibodies that can increase the risk of brain edema (ARIA‐E). To circumvent these issues and induce an antibody response that selectively targets soluble toxic Aß oligomers (AßO), without inducing potentially detrimental B or T cell responses against plaque or normal Aß, we used our Collective Coordinates computational platform to design a vaccine consisting of a conformational epitope of AßO, coupled to keyhole limpet hemocyanin (KLH) as a carrier protein to provide T cell help.MethodMice received 3 immunizations, 4 weeks apart, with vaccine conjugate in alum or QS‐21 as adjuvants. Serum titers of total IgG, IgG1 and IgG2a antibodies to the peptide epitope were measured by ELISA. The selectivity of serum antibodies for toxic AßO versus monomers was evaluated by surface plasmon resonance, and plaque reactivity was assessed by immunohistochemistry on AD brain sections. T helper type 1 (Th1) and type 2 (Th2) responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes.ResultA robust antibody response against the conformational AßO epitope was observed with both adjuvants and remained undiminished out to 6 months after the last immunization. Alum gave rise to a predominantly IgG1 response while QS‐21 produced a more comparable IgG1/IgG2a response. The serum antibodies showed the desired binding profile and reacted with AßO only, not Aß monomers or plaque. ELISPOT analysis showed a lack of Th1 (interferon‐gamma) or Th2 (IL‐5) cytokine production in response to stimulation with the AßO epitope thereby indicating that the peptide only contains a B cell epitope. T cell help was provided by the carrier and, as expected, stimulation with KLH induced Th cytokine production.ConclusionA vaccine consisting of an AßO‐restricted conformational B cell epitope conjugated to KLH produced a strong Aß antibody response with no measurable pro‐inflammatory T cell response against Aß. In addition, the oligomer selectivity of the antibodies focused the response on pathogenic AßO, potentially reducing the risk of ARIA‐E associated with binding to plaque and vascular deposits of Aß.
The association between depressive symptoms and amyloid positivity
Authors: Wiels Wietse A , Oomens Julie Elisabeth , Engelborghs Sebastiaan , Baeken Chris , Verhey Frans R.J. , Visser Pieter Jelle , Jansen Willemijn J. ,   the Amyloid Biomarker Study group
Published: December 2023

AbstractBackgroundAmyloid deposition and hippocampal atrophy have been linked to late‐life affective disorders, raising concerns for Alzheimer’s Disease (AD). However, biomarker and autopsy studies have been inconclusive. It remains unclear if and in what way depressive symptoms imply an increased risk of amyloid positivity.MethodUsing data from 49 centers in the Amyloid Biomarker Study, we investigated the association between depressive symptoms and amyloid positivity. We included participants with normal cognition (NC) (n = 9776) and MCI (n = 2995). Amyloid positivity was defined using standardized CSF (n = 5926) and PET (n = 6845) measures. Depressive symptoms were obtained through medical history (12%) and various rating scales (88%). Symptoms on rating scales were classified as (1) present/absent using established cut‐off values, (2) severity using center‐based trichotomisation. We examined associations between depressive symptoms and amyloid positivity using generalized estimating equations and evaluated potential moderation by age and APOE‐e4 status.ResultMean age was 69 years and 33.8% were amyloid positive. In NC, no association between the presence or severity of depressive symptoms and amyloid positivity was observed, nor was there when including APOE‐e4, sex or education. In MCI, persons with depressive symptoms were ∼10% less often amyloid positive than those without depressive symptoms (p = 0.001), this was even more pronounced in persons with moderately severe symptoms (p = 0.01). We identified an interaction between depressive symptom severity and APOE‐e4 status (p = 0.034). In APOE‐e4 noncarriers with MCI, persons with moderate depressive symptoms were 20% less often amyloid positive than those with no or mild depressive symptoms. In APOE‐e4 carriers with MCI, depressive symptom severity was not associated with amyloid positivity.ConclusionIn persons with normal cognition, depressive symptoms are not associated with amyloid positivity. In MCI patients, however, those with depressive symptoms were ∼10% less often amyloid positive. This association increased in persons with moderately severe symptoms and appeared to pertain to APOE‐e4 noncarriers. These data suggest that the presence of depressive symptoms in MCI patients is no reliable indicator of amyloid positivity. This may have diagnostic implications for this group.
Promoting memory retention in older adults with and without Alzheimer’s Disease using the mobile app Blank Slate
Authors: Marin Anna , Smith Amy , DeCaro Renée , Hughes Gregory , Rivard Nathaniel , Feinn Richard , Turk Katherine W , Budson Andrew E 
Published: December 2023

AbstractBackgroundSpaced retrieval is an effective technique for supporting learning and memory. It involves repeatedly recalling information that one desires to learn after increasingly lengthy intervals of time. It is still unclear how older adults, including individuals with Alzheimer’s Disease (AD), can best implement spaced retrieval in their daily life mostly due to their difficulty in self‐adhering to schedules and their metacognitive deficits. We examined the usability and efficacy of a mobile application called Blank Slate Technologies (BST) for helping older adults with and without cognitive impairment due to AD retain new and old memories using the spaced retrieval technique.MethodTwenty healthy older adults and 20 older adults with mild cognitive impairment (MCI) or dementia due to AD engaged with the BST app each day for four weeks to practice retrieving recently learned information (facts about the country Georgia) and older, fading information (celebrity names that they knew but had difficulty recalling). Automatic notifications prompted participants to access the BST platform and review their assigned flashcards for a few minutes daily. Over time, each participant reviewed the information they were most likely to quickly forget. At the end of the four weeks, participants took two recognition tests, spaced one week apart. Recognition performance on the two tests was measured across all item types.ResultHealthy and AD participants correctly recognized respectively 86.2% and 85.4% of the items studied using the app, compared to 57.6% and 54.1% of the items not studied on the app. A week after the training, the effect of the BST training was sustained such that both healthy and AD participants correctly recognized 85.3% and 78.6% of the items studied on the app compared to 58.1% and 53.0% of the items not studied on the app.ConclusionThanks to its reminder notifications and customized learning schedule, the BST app is an effective and easy‐to‐use platform to help improve and sustain long‐term memory retention in the aging population and in individuals with AD at different stages of the disease. Future research should examine the efficacy of the BST app also for improving the free recall of information.
Memory impairment due to recurrent vascular insults in mice was rescued by pleiotrophin
Authors: Gupta Mayank , Talukdar Ankita , Hussain Rehab , Diwakar Latha 
Published: December 2023

AbstractBackgroundSmall vessel infarcts, ischemic attacks, microbleeds are considered a common cause of vascular dementia appears as white matter hyperintensities (WMH) in MRI of many patients. However, we don’t know how these WMH contribute to cognitive decline, and little is known about the underlying pathogenesis of Blood Brain Barrier (BBB) dysfunction. Thus, in the current study we have developed a mouse model with recurrent small vessel strokes leading to memory dysfunction and BBB loss. Further, we infused pleiotrophin (PTN) a trophic factor important for maintaining pericyte, the component of BBB for regulation of cerebral blood flow to rescue from multiple vascular insults.Method3‐4 months old C57/BL6J male mice was implanted with cannula into intracerebroventricular cavity. ET‐1 (Endothelin‐ 1), a 21 amino acid vasoconstricting peptide was injected through guide cannula into the ventricle for a period of 9 weeks at an interval of 21 days. Another set of mice were given 3 doses of ET‐1 along with PTN two days earlier and 3 days after along with ET‐1 injection. Mice were assessed for memory deficits with different behavioral task after 9 weeks. Animals were perfused and brain was processed for immunohistochemistry to assess vascular pathology.ResultMice injected over a period of three weeks with ET‐1 showed discrepancies in the blood vessel integrity and loss of pericytes potentiating multiple vascular insults cause BBB dysfunction leading to memory impairment. However, maintaining PTN level during ET‐1 injections in mice significantly improved memory function in novel object task and contextual fear conditioning test as well as protected BBB. These data suggest that rescue of BBB integrity by PTN infusion during chronic vascular insults prevents memory decline in mice.ConclusionRepeated vasoconstriction by ET‐1 in small vessels lead to BBB breach resulting in irreversible learning and memory deficits. This could be rescued by PTN treatment restoring BBB structure and memory function intriguing to further study novel therapeutic targets.
Specific memory binding indexes and their potential to discriminate between Alzheimer´s disease biomarker‐positive and biomarker‐negative older adults with amnestic mild cognitive impairment
Authors: Horakova Hana , Mazancova Adela Fendrych , Matuskova Veronika , Veverova Katerina , Laczó Jan , Hort Jakub , Vyhnalek Martin 
Published: December 2023

AbstractBackgroundThe Memory Binding Test (MBT) and Face‐Name Associative Memory Exam (FNAME‐12) are challenging tests based on relational memory binding paradigm. Recent studies support their sensitivity to subtle memory changes; however, their specificity to Alzheimer´s disease (AD) related memory deficit has not been studied. This study aimed to explore differences in MBT and FNAME‐12 scores between patients with amnestic mild cognitive impairment (aMCI) due to AD (aMCI‐AD), those with aMCI with non‐Alzheimer´s etiology (aMCI‐nonAD), and cognitively normal older adults (CN) as a control group, and to compare the potential of the challenging tests and the standard Rey Auditory Verbal Learning Test (RAVLT) to discriminate between the aMCI groups.MethodSixty‐seven Czech Brain Aging Study participants (aMCI, n = 37; CN, n = 30) underwent neuropsychological assessment (including the MBT and FNAME‐12), laboratory evaluation, and brain magnetic resonance imaging, and were further classified as aMCI‐AD (n = 18) or aMCI‐nonAD (n = 19) based on the results of amyloid positron emission tomography or AD cerebrospinal fluid biomarkers. The groups were compared using the multivariate analysis of covariance controlling for sex, age, education, and global cognition.ResultIn MBT, aMCI‐AD patients scored the lowest on the paired cued recall scores (CR) (aMCI‐AD<aMCI‐nonAD<CN, ps≤0.003). In FNAME‐12, aMCI‐AD patients scored the lowest on the CR of face‐occupation pairs (aMCI‐AD<aMCI‐nonAD<CN, ps<0.001). On the CR of face‐name pairs, both aMCI groups scored lower than CN (p<0.001); however, they did not differ from each other [p = 0.525; (aMCI‐AD = aMCI‐nonAD)<CN]. In RAVLT, aMCI‐AD patients did not differ from the aMCI‐nonAD patients, except for the delayed free recall (FR) (p<0.001). Adding the RAVLT delayed FR as covariate, the differences in the MBT and FNAME‐12 paired CR scores remained significant. To discriminate aMCI‐AD from aMCI‐nonAD, the MBT paired CR and FNAME‐12 CR of face‐occupation pairs yielded areas under the curve (AUCs) of 88% and 85%, respectively, which was comparable to RAVLT delayed FR (87%). Controlling for RAVLT, the AUCs were 91% for MBT and 88% for FNAME‐12.ConclusionOur findings support excellent discriminative ability of selected MBT and FNAME‐12 scores for AD‐related memory deficit and suggest their potential for differential diagnosis of memory deficit in older adults in addition to the standard RAVLT.
Automated lexical analysis of story recall in healthy controls
Authors: Ip Martin Ho Kwan , Cousins Katheryn A Q , Nevler Naomi , Liberman Mark Y , Grossman Murray , Cho Sunghye 
Published: December 2023

AbstractBackgroundImpaired episodic memory is one of the earliest and most prominent symptoms of Alzheimer’s disease (AD). Examining how patients produce words and phrases in story recall tasks is useful for tracking and understanding progression of their disease. Traditional approaches rely on manual assessments of recalled stories which can be limited, time‐consuming, and not applicable in large‐scale studies. Here, we implement an automated, computational approach to measure verbal episodic memory in a digitally recorded story recall task performed by young healthy speakers using natural language processing models.MethodWe analyzed digitized speech samples of pre‐recorded immediate and delayed Craft Story recall tasks performed by healthy speakers (n = 67, mean age = 20.31 years, SD = 2.17, 45 (67%) females). All transcripts were transcribed by trained annotators and automatically scored for number of verbatim and paraphrase recall, total recall score ( = verbatim+paraphrase), and semantic distance from the original story (degree of semantic similarity between the original craft story and the recalled story based on the Word2vec module in python). We also calculated total word count and number of unique words, and rated all recalled words for word familiarity, concreteness, and semantic ambiguity based on published norms. Number of pauses and total durations of speech and silent pauses were also measured.ResultWe found larger semantic distance between successive words in the delayed recall task compared with immediate recall within speaker (p<.001). Delayed recall also elicited lower total recall scores than immediate recall (p = .03). Comparing the effect sizes of semantic distance vs. total recall scores, our model comparison showed a smaller prediction error for semantic distance (AIC = 95.45) than total recall score (AIC = 736.18). In addition, speakers in the delayed recall task performed more paraphrase recall, had higher total word count, number of unique words, more ambiguous words, and produced more speech (all p‐values<.001).ConclusionOur findings suggest that automated speech analysis can provide informative and cost‐effective measures from a recorded story recall task. The study provides an automated and quantitative way to better measure memory abilities by including semantic distance. Future work will test procedures in patients with AD or other neurodegenerative diseases.
Genetic Architecture of Cortical Thickness and White Matter hyperintensities: Evidence of Gene‐Environment Interaction with Cardiovascular Health and Late‐Life Depression
Authors: Zhukovsky Peter , Tio Earvin S. , Coughlan Gillian T , Mulsant Benoit H. , Voineskos Aristotle N. , Felsky Daniel 
Published: December 2023

AbstractBackgroundModifiable risk factors account for over 40% of dementias, offering potential for intervention. However, the impact of these risk factors, including depression and vascular disease, on brain health in the context of variable genetic influences is not well understood. Here we map the genetic landscape of brain structure, testing for gene‐by‐environment (GxE) interactions and relevance to cognitive performance in mid‐ and late‐life.MethodWe conducted genome‐wide association studies (GWAS) to identify genetic variants associated with cortical thickness in over 34,500 UK Biobank participants. We used postmortem bulk RNA sequencing of frontal cortex paired with antemortem MRI in a late‐life sample (n = 66) to directly corroborate implicated GWAS loci. Focusing on GWAS‐significant loci, we tested for GxE interactions and associations with cognition in 25,254 Canadian Longitudinal Study of Ageing (CLSA) participants.ResultWe identified 367 loci in the UK Biobank participants (age 45‐81), associated with global or regional cortical thickness (p<5×10−8), with genetic correlations between pairs of anatomical regions identifying three distinct modules. Corroboration with postmortem bulk RNA sequencing and MRI in a late‐life sample confirmed effects of STMN4, ARL17A and ARL17B genes on cortical thickness. Ten GWAS‐implicated loci from the UK Biobank were also associated with executive function or memory in CLSA, including rs1562330, a locus linked to the STMN4 gene. Notably, 37 variants also showed significant interactions with cardiovascular health or depression (P<2×10−4).ConclusionThese findings advance our understanding of the genetic architecture of brain structure and show that modifiable factors alter the effects of heritable genetic background on brain and cognitive health.
Sex differences in marmoset neurocognitive aging, a nonhuman primate model for brain aging and age‐related neurodegenerative diseases
Authors: Rothwell Emily , Cobo Carmen Freire , Varghese Merina , Hof Patrick R , Lacreuse Agnès 
Published: December 2023

AbstractBackgroundNonhuman primate models of human aging are necessary to understand functional decline and identify vulnerabilities to aging pathologies. Longitudinal studies are critical and common marmosets (Callithrix jacchus) are ideal as they have a short lifespan (∼12 yr) and naturally develop neuropathology relevant to Alzheimer’s disease (AD).MethodWe studied 28 marmosets (14 females) from midlife (∼5 yr old) to old age across four years. Simple discrimination and reversal learning was used to evaluate cognitive performance. Additional yearly tests included motor, stress reactivity, and social behavior assessments. A subset of animals (n = 17, 9 females) were studied for AD‐relevant neuropathology in post‐mortem tissue of the dorsal lateral prefrontal cortex (dlPFC) and CA1 of the hippocampus.ResultMultilevel models revealed age‐related changes for cognitive performance with improved reversal learning during the first three years due to practice followed by decline in the final year with the onset of old age. Cognitive decline was steeper and began earlier for females compared to males. Based on cognitive trajectories which were highly variable across individuals, we categorized marmosets as cognitively impaired or non‐impaired. Mild amyloid β (Aβ) deposition was observed in the dlPFC and CA1 but did not differ between males and females. Aβ burden was higher in cognitively impaired compared to non‐impaired marmosets, but this difference did not reach statistical significance. However, cognitively impaired marmosets showed signs of accelerated brain aging including higher astrogliosis associated with Aβ deposits and dendritic spine loss, both in the dlPFC and hippocampus. In addition, increased activation and changes in microglial phenotypes were observed in the dlPFC.ConclusionLike humans, aging marmosets displayed intra‐individual variability in cognitive decline, neurodegeneration and neuronal aging. Female marmosets showed greater vulnerability to cognitive impairment, which is translationally relevant to the higher prevalence of AD in women. While trajectories of cognitive decline did not strongly map onto Aβ burden for females or males, evidence of accelerated brain aging was found in the impaired marmosets. This study highlights the value of marmosets as a nonhuman primate model of AD to identify vulnerabilities to aging pathologies, such as sex differences.