bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal changes in the expression of Alzheimer’s disease‐related pattern and default mode network
Authors: Perovnik Matej , Tang Chris C , Šalamon Sandi , Eidelberg David ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundThe Alzheimer’s disease‐related pattern (ADRP) is an imaging biomarker of AD, for which expression levels correlate with cognitive impairment in individual patients. The default mode network (DMN) is a dominant metabolic network expressed in healthy individuals. Longitudinal changes in ADRP and DMN expression levels have not been comprehensively studied in patients with AD or mild cognitive impairment (MCI), or in cognitively normal (CN) subjects.MethodWe obtained longitudinal data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database of participants who were CN (n=59), or who had MCI (n=128) at baseline and underwent 3 or more FDG PET scans (nscans
=704) and had CSF amyloid and APOE information available. Groups were divided based on the conversion status, i.e., if they developed MCI/dementia at follow‐up. There were 36 stable and 23 converting CN participants and 73 stable (sMCI) and 55 converting (cMCI) participants. Amyloid positivity was defined as CSF Aβ42 < 880 pg/mL and APOE positivity as presence of one or more APOE4 allele. We used an automated algorithm to calculate standardized ADRP and DMN expression levels for each scan. Repeated measurements ANOVA (RMANOVA) was used to evaluate longitudinal changes in network expression in each group, as well as network interactions with conversion status, amyloid and APOE positivity.ResultsADRP expression increased over time, but at with different rates in the CN, sMCI and cMCI groups (p<0.001). The interaction effect was significant between CN and cMCI (p<0.001) and sMCI and cMCI (p=0.009), but not between CN and sMCI (p=0.51). There was no significant interaction between group and time on DMN expression (p=0.60). Analysis of each group separately revealed no significant interaction between APOE4 status and time on ADRP or DMN expression levels (all p>0.10). There was a significant interaction between conversion status and time on ADRP and DMN in CN group (p<0.04). There was also a significant main effect of time on ADRP and DMN in cMCI group (p<0.04) and a significant interaction between amyloid and time on DMN expression (p=0.03).ConclusionADRP progression was faster in cMCI compared to CN and sMCI. The longitudinal changes in DMN were not significantly different across groups.
Assessing the Unmet Needs of Spanish Speaking Family Caregivers of Persons Living with Dementia in the Greater Boston Area
Authors: Ramirez‐Gomez Liliana A. , Madarasmi Saira , Paulina Gutierrez Ramirez A , Ceciliana Aldarondo A , Mischoulon David , Pederson Aderonke B , Quiroz Yakeel T. , Ritchie Christine S , Jain Felipe A 
Published: December 2022

AbstractBackgroundSpanish‐speaking family caregivers of persons living with dementia (PLD) have limited resources in Spanish to aid in psychological coping with caregiver burden. They often have difficulty attending in‐person training due to barriers such as transportation costs, identifying substitute care, and ongoing COVID‐19 pandemic containment measures. There are few studies identifying Spanish language caregiver unique needs and preferences regarding desired caregiving skills and stress‐reduction interventions. In this study, we sought to identify the unmet needs of Spanish‐speaking family caregivers of PLD in the greater Boston area, as well as their preferences for virtual intervention frequency and duration.MethodsWe conducted two virtual focus groups with twelve Spanish language family caregivers of PLD (ages 37 to 87 years) recruited from the greater Boston area. Participants were asked semi‐structured questions regarding their unmet needs for caregiver skills training and stress reduction. We employed an inductive and deductive driven mixed method analytic approach. A taxonomy was created to organize results based on participant responses.ResultsThree major thematic clusters emerged. First, caregivers noted a desire to develop skills for managing stress, emotional reactivity, frustration, and grief. Second, there was an expressed need for education regarding disease‐specific knowledge such as stages of dementia, common manifestations, management of challenging symptoms and communication strategies with the PLD; how to navigate the health care system; and finding additional resources for care in the community. Third, there was an interest in learning about interventions for the PLD, such as specific activities to help keep them engaged and active. A particular interest was expressed in any interventions that might slow disease progression. Regarding frequency and duration for virtual intervention, caregivers most commonly preferred weekly sessions for 6‐10 weeks.ConclusionsUnmet needs of Spanish language family caregivers of PLD in the greater Boston area include education regarding disease‐specific symptoms and their management, and resources to enhance well‐being both in the caregiver and the PLD. Based on these results, we will develop a comprehensive virtual therapeutic intervention incorporating stress reduction techniques to facilitate emotion regulation, caregiver skills training, psychoeducation regarding dementia and caregiver resources, and healthful activities for the PLD.
TRIAD multi‐dimensional biobank for biomarker discovery
Authors: Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Stevenson Alyssa , Pallen Vanessa , Therriault Joseph , Lussier Firoza Z , Tissot Cécile , Bezgin Gleb , Pascoal Tharick A , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundThe Translational Biomarkers in Aging and Dementia (TRIAD) is a longitudinal, biomarker‐based cohort designed to study interactions between the pathophysiological processes driving to dementia. Currently, 50 million people worldwide have dementia [1]. PET and MRI imaging have been widely used to assess disease stage, though expensive and not readily accessible [2]. More recently though, breakthroughs in blood‐based biomarkers have proven a useful, available, and more cost‐effective way of evaluating amyloid and tau positivity. The TRIAD Biobank provides a unique framework to study disease stage using blood‐based biomarkers in conjunction with PET and CSF studies. Our cohort allows for validation of novel biomarkers as we simultaneously acquire gold standard second generation imaging acquisitions with full spectrum fluid biomarkers (CSF, saliva, plasma, urine). Importantly, the data acquired is integrated in a database compliant to multi‐dimensional biomarker analysis.MethodFigure 1 depicts the cohort's banked fluids by diagnostic group. Figure 2 depicts the cohort's banked fluids by sex grouping.ResultThe TRIAD Biobank stores 1,034 blood samples from 655 participants, 658 of these being follow‐up collections. Additionally, cerebrospinal fluid has been collected from 381 individuals accounting for 520 collections in the bank, 812 urine collections from 662 individuals and 591 saliva samples from 432 individuals.Additionally, the cohort has collected 761 tau PET scans using [18F]MK6240, 644 amyloid PET scans using [18F]AZD4694 and 804 MRI using 3 Tesla.ConclusionWith dementia being one of the leading, most costly causes of death, the need for early detection, more affordable, less invasive, and more readily available ways to determine disease stage is apparent [2]. The TRIAD multi‐dimensional biobank provides a wealth of resources to discover affordable biomarkers needed for early diagnosis and Alzheimer’s disease prevention.[1] Patterson, C. 2018. World Alzheimer Report 2018: The state of the art of dementia research, new frontiers. London, England: Alzheimer's Disease International.[2] Gauthier S, Rosa‐Neto P, Morais JA, & Webster C. 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
Lower synaptic density and higher neurofibrillary tau are associated with worse cognitive performance
Authors: DiFilippo Alexandra H , Xin Yangchun , Jonaitis Erin M. , Kohli Akshay , Ennis Gilda E. , McVea Andrew K , McLachlan Max , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Betthauser Tobey J , Barnhart Todd E , Engle Jonathan W , Johnson Sterling C. , Bendlin Barbara B. , Christian Bradley T 
Published: December 2022

AbstractBackgroundSynaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). PET radioligands for synaptic vesicle glycoprotein 2A (SV2A) provide an index for synaptic density in the brain. While development of these tracers is a major advance for the field of AD, little is yet known about regional synapse loss in AD or the extent to which synapse loss accounts for cognitive dysfunction in vivo. Here we tested whether regional synaptic density measured with [11C]UCB‐J is associated with cognition. Secondarily, we examined the association between tau, measured using [18F]MK‐6420 PET, and cognitive dysfunction.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study (Table 1). Cognitive functioning was measured using the Preclinical Alzheimer Cognitive Composite (PACC)(Donohue et al, 2014). Neurofibrillary tau in the entorhinal cortex (ERC) was detected using [18F]MK‐6420 SUVR. A global measure of synaptic density was calculated using volume‐averaged DVRs in the medial temporal lobe (hippocampus, entorhinal cortex, parahippocampus, and perirhinal cortex), superior and inferior parietal cortices, and the frontal lobe. Pearson’s correlations assessed the following relationships: PACC : ERC tau, PACC : global synaptic density, and PACC : regional synaptic density.ResultERC tau and PACC score showed a significant inverse relationship: r = ‐0.51, P = 0.004. While global synaptic density and PACC score were not significantly related, when individual regions were tested, hippocampal synaptic density showed a significant positive relationship with the PACC score (P = 0.05) (Figure 1A).ConclusionERC tau PET SUVR was robustly associated with poorer cognitive performance. While synapse loss has been observed among multiple regions in AD, our preliminary results suggest that synapse loss in the hippocampus is most closely associated with cognitive dysfunction. This preliminary work suggests that ERC tau is more strongly associated with Alzheimer’s‐related cognitive decline than global or hippocampal synaptic density in participants who are mostly cognitively unimpaired. Future work will include group comparisons between participants with and without significant amyloid and tau pathology, as well as exploratory analyses into which regions are most significantly affected by Alzheimer’s‐associated synaptic loss.
Baseline Reliability and Six‐Month Stability of a Remotely Administered Battery of Smartphone Cognitive Tests
Authors: Taylor Jack C , Clark Annie L , Heuer Hilary W. , Wise Amy B , Manoochehri Masood , Forsberg Leah K. , Mester Carly T. , Rao Meghana , Brushaber Danielle , Kramer Joel H. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M. 
Published: December 2022

AbstractBackgroundFrontotemporal dementia (FTD) is a collection of neurodegenerative diseases affecting behavior, cognition, and motor functions. FTD treatment trials will benefit from sensitive assessments capable of detecting and longitudinally tracking cognitive changes. Remote smartphone cognitive tests may improve the sensitivity to detect and monitor cognitive decline via novel methods of data capture and more frequent assessments within ecologically valid environments, while simultaneously reducing patient burden. The first step in determining the utility of these measures is establishing their reliability. We previously reported baseline reliability estimates for the ALLFTD Mobile App cognitive tests in a small pilot sample. Here we extend these results using a larger sample and evaluate six‐month stability.MethodWe enrolled a diagnostically mixed sample of 128 participants (CDR®+NACC‐FTLD = 0 [n = 84]; CDR®+NACC‐FTLD = 0.5 [n = 21]; CDR®+NACC‐FTLD≥1 [n = 23]) from ongoing studies of healthy aging (Hillblom Network) and frontotemporal dementia (ALLFTD). Participants self‐administered five cognitive tests from the ALLFTD Mobile App on their own smartphone; they were asked to complete each test three times within two weeks. Tests included gamified versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive short‐term memory test. We evaluated the internal consistency of each test’s first occurrence using Spearman‐Brown split‐half reliability (100 simulations). Test‐retest reliability over the first three baseline replicates (as available) was evaluated by calculating intraclass correlations (ICC). In a preliminary analysis, we tested the six‐month stability of test performance in nine functionally intact participants who completed baseline and follow‐up Flanker, N‐Back, and adaptive memory assessments by calculating Spearman’s rho.ResultSplit‐half reliability estimates were in the good to excellent range (r’s: 0.81–0.97). Test‐retest reliability estimates were in the adequate to excellent range (ICCs: 0.72–0.96). ICC estimates were comparable for participants with and without clinical impairment (CDR®+NACC‐FTLD = 0 (0.74–0.95) and CDR®+NACC‐FTLD >0 (0.67–0.95). Among functionally intact individuals, baseline and 6‐months scores were highly correlated (r’s: 0.76–0.93, p’s<.05).ConclusionOur findings of adequate to excellent internal consistency, test‐retest reliability, and 6‐month stability support the feasibility of remote, smartphone‐based cognitive testing among a diagnostically mixed sample typical of healthy aging and frontotemporal dementia research studies.
Examination of associations between female natural reproductive span and dementia risk
Authors: Saelzler Ursula G , Sundermann Erin E. , Karlsson Ida , Gatz Margaret , Pedersen Nancy L. , Panizzon Matthew S. 
Published: December 2022

AbstractBackgroundDespite substantial evidence for a greater prevalence of Alzheimer’s disease and related dementias (ADRD) among women, there is a limited understanding of sex‐specific mechanisms which may modify risk. Greater lifetime estrogen exposure (often approximated by the length of the reproductive span) is hypothesized to be protective, however, previous investigations into the relationship between the female reproductive span and ADRD have been mixed.MethodA series of Cox proportional hazards models were applied to data from 6,351 naturally post‐menopausal, exogenous hormone‐naive women from the Swedish Twin Registry. The age of dementia diagnosis (determined by clinical interview or approximated by an adjusted appearance of diagnostic codes in national health registries) was used as the event time, while the time of death or data aggregation were used as the time of censoring. Covarying for birth year, children, and education, stratifying by smoking history, and adjusting for the reduced sensitivity of dementia detection in health registries, the fit of three models, including either a linear, a quadratic, or a cut‐point reproductive span term, was compared and the reproductive span coefficients examined.ResultThere was a progressive improvement in model fit across the linear, quadratic, and cut‐point models. The linear term from the linear model was not significant (HR = 0.002, p = 0.752), while the linear and quadratic terms from the quadratic model were small, but significant predictors of ADRD hazard (HR = 1.016, p = 0.035 and HR = 1.004, p < 0.005, respectively). The optimal cut‐point model indicated that the length of the reproductive span is not predictive of ADRD hazard, until the span exceeds 44 years, at which point each 1‐year increase in reproductive span is associated with an 8.22% increase in ADRD hazard (below cut point term: HR = 0.988 p = 0.120; above cut‐point term: HR = 1.0822, p < 0.005).ConclusionIn contrast to the anticipated protective role of lifetime estrogen exposure, exceptionally long reproductive spans (i.e., those 1.77 SD or greater than the mean) are associated with increased ADRD hazard. The non‐linear nature of the relationship may contribute to the mixed findings in the literature.
Similar lysosomal abnormalities in cortex of patients with sporadic FTLD‐TDP type A and patients with FTD‐GRN
Authors: Davis Skylar E. , Cook Anna K. , Voskobiynyk Yuliya , Carullo Nancy VN , Hakim Ahmad R. , Anderson Kristian M. , Hobdy Kierra P. , Pugh Derian A , Murchison Charles F , McMeekin Laura J. , Simmons Micah S. , Cowell Rita M. , Li Alissa Nana , Spina Salvatore , Grinberg Lea Tenenholz , Miller Bruce L. , Seeley William W. , Arrant Andrew E. 
Published: December 2022

AbstractBackgroundLoss‐of‐function mutations in progranulin (GRN) are an autosomal dominant cause of frontotemporal dementia (FTD). Progranulin is critical for maintenance of lysosomal function. Patients with FTD due to GRN mutations (FTD‐GRN) exhibit signs of lysosomal dysfunction, which may contribute to FTD‐GRN pathogenesis. To assess the potential involvement of lysosomal dysfunction in FTD of sporadic origin, we investigated whether the lysosomal abnormalities of FTD‐GRN are also present in patients with sporadic frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) type A, the same FTLD subtype found in patients with FTD‐GRN.MethodWe used enzyme activity assays, western blot, immunostaining, and Nanostring analysis to assess changes in lysosomal protein and gene expression in orbital and occipital cortex of patients with FTD‐GRN, sporadic FTLD‐TDP type A, or controls. We measured lipofuscin using autofluorescence and staining with Sudan Black B. In follow‐up studies, we assessed these lysosomal markers in a transgenic mouse line expressing wild‐type human TDP‐43 under the Thy1 promoter.ResultWe found similar lysosomal abnormalities in orbital cortex of patients with FTD‐GRN or sporadic FTLD‐TDP type A. Both FTD patient groups exhibited elevated levels of lysosomal enzymes and membrane proteins, higher expression of many lysosomal genes, and greater lipofuscin accumulation than controls. These changes were largely absent in occipital cortex from both groups. Analysis of frontal cortex from a transgenic mouse model of TDP‐opathy also revealed elevated levels of some lysosomal proteins and elevated lipofuscin levels.ConclusionThese studies indicate that the lysosomal abnormalities of patients with FTD‐GRN may be more closely associated with TDP‐opathy or neurodegeneration than with progranulin insufficiency. Orbital cortex, an affected brain region in FTD‐GRN, exhibited elevated lysosomal protein levels and lipofuscin accumulation, which were also found in patients with sporadic FTLD‐TDP type A. In contrast, the occipital cortex, a relatively spared brain region in FTD‐GRN, exhibited much milder lysosomal abnormalities. Future studies will assess signs of lysosomal dysfunction in patients with other classes of FTLD pathology to determine whether these changes are limited to patients with FTLD‐TDP or may be found throughout the FTLD spectrum.
Genetically diverse mouse models of Alzheimer’s Disease reveal an association between amyloid deposition and glycan metabolism in the brain
Authors: Uyar Asli , Elk Kevin J , Garceau Dylan , Bednarczyk Daria , Sasner Michael , Carter Gregory W , Howell Gareth R 
Published: December 2022

AbstractBackgroundVarying degrees of cerebral amyloid angiopathy (CAA) co‐occur with parenchymal amyloid deposition in majority of Alzheimer’s Disease (AD) cases. However, common mouse models of familial AD generated on a single inbred strain do not recapitulate the spectrum of parenchymal and vascular amyloid pathogenesis in the brain. To better represent phenotypic diversity in AD, we generated a panel of genetically diverse Collaborative Cross (CC) mouse strains harboring APOE4 allele and amyloidogenic mutations.MethodFive CC strains (CC002, CC006, CC013, CC037 and CC041) were selected for maximal genetic and transcriptional variation in AD‐relevant genes. Selected CC strains were crossed to C57BL/6J (B6J) mice homozygous for humanized APOE4 allele and carrying mutant APP and PS1 alleles (APPswe
, PS1de9
). Cohorts of male and female B6JCCnF1.APOE4.APP/PS1 mice and controls were aged to 8 months, and brain hemispheres were processed for RNA‐Seq transcriptomics and neuropathological assessment. Weighted Gene Co‐Expression Networks Analysis (WGCNA) and gene set enrichment analysis were performed to identify gene modules and biological pathways associated with plaque deposition and CAA in CC strains.ResultNeuropathological assessment revealed significant strain and sex‐dependent differences in both parenchymal and vascular amyloid pathology. Highest levels of plaque deposition in cortex and hippocampus was observed in female CC002 mice. Female mice had higher plaque load compared to male mice in all strains, whereas CAA score was higher in males and in CC037 strain. CC006 represented lowest levels of plaque deposition and CAA at comparable levels with B6J mice. RNA‐Seq data revealed a common microglia/neuroinflammation related transcriptional response observed in all strains and both sexes. On the other hand, gene expression signatures associated with varying levels of plaque deposition and CAA revealed alterations in metabolic pathways, in particular glucose, lipid and glycan metabolisms.ConclusionOur results suggest that major genetic diversity modulates distinctive parenchymal and vascular amyloid phenotypes, and differentially impacts transcriptomic signatures in the mouse brain. Overall, CC lines mouse models better represent the spectrum of neuropathological and molecular phenotypes associated with AD.