bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fiber density and cross‐section correlates with tau burden in entorhinal cortex in healthy older adults
Authors: Gazes Yunglin , Mensing Ashley , Luo Linggang , Razlighi Qolamreza , Kreisl William Charles 
Published: December 2020

AbstractBackgroundTau PET imaging, while highly predictive of the onset of dementia, requires injection of radioactive compound and costs much more than MRI scans. The goal of this study was to test whether multi‐shell diffusion MRI can generate diffusion measures that predict tau burden. While DTI measures such as fractional anisotropy (FA) and mean diffusivity have been examined in aging and dementia studies, the DTI model is now recognized as being too simplistic and has been shown to mistakenly calculated higher FA than controls in atrophied white matter. Multi‐shell diffusion MRI allows more accurate modeling of crossing fibers and has been demonstrated to detect atrophy in Alzheimer’s disease.MethodIn the current study, a sample of 14 healthy older adults was scanned with multi‐shell diffusion MRI and tau PET imaging using [18F]MK‐6240 tracer. For 10 of the participants, diffusion was obtained on average 222 days before tau PET while the 4 other participants were scanned with diffusion MRI 211 days after tau PET. Standardized uptake value ratio (SUVR) for the left and the right entorhinal cortex were quantified relative to the cerebellar mean uptake. Diffusion data were processed through MRtrix’s fiber‐based analysis pipeline to obtain the whole brain fiber density and cross‐section (FDC) measure. Using tracts connected to the parahippocampal gyrus as masks, we tested whether FDC of the fibers in the white matter tracts connected to the parahippocampal gyrus correlated negatively with the tau SUVR in the entorhinal cortex within each hemisphere, correcting for age.ResultAfter correction for multiple comparisons using family‐wise error approach, FDC for fibers connected to the left parahippocampal gyrus were negatively correlated with the left entorhinal tau SUVR as shown in figure attached. The mean FDC over the significant fibers and EC tau SUVR showed that r = ‐.707, p=0.007.ConclusionThe negative correlation supports our hypothesis that greater tau burden is associated with lower fiber density and cross‐section in white matter tracts directly connected to the parahippocampal cortex. This encouraging result demonstrates the potential for multi‐shell diffusion as an alternative to PET for early detection of tau burden in cognitively healthy older adults.
Evaluation of class C CpG ODN immunomodulatory potential in a non‐human primate model of sporadic CAA
Authors: Patel Akash G. , Nehete Pramod N. , Nehete Bharti P. , Guttman Daniel Ezra , Kwak Yena , Dowling‐Campbell Kathryn Leigh , Tibensky Miroslav , Williams Lawrence E. , Wisniewski Thomas , Scholtzova Henrieta 
Published: December 2020

AbstractBackgroundA number of studies have shown that the stimulation of innate immunity in transgenic mouse models can ameliorate AD‐related pathology. The failures of many immunotherapeutic clinical trials for AD has been related to poor translatability of promising transgenic mouse data to humans. Our recent data from a non‐human primate (NHP) model of sporadic cerebral amyloid angiopathy (CAA), squirrel monkey (SQM), indicate that treatment with TLR9 agonist, class B CpG ODN, results in reduction of CAA without toxicity. Here, we advanced our study using class C CpG ODN, which is currently being explored in a variety of human disease conditions and has shown favorable safety profiles. The present study is first to assess the effectiveness of class C CpG ODN to elicit an immune response in aged population whose immune system might be senescent.MethodElderly female SQMs received either CpG ODN or vehicle (saline) every 4 weeks as part of an ongoing chronic‐treatment study (14 injections so far). Phenotypes and frequency of lymphocyte/monocyte subsets were examined by flow cytometry (FC) in whole blood collected prior‐ and at multiple intervals post‐CpG ODN injection. SQM PBMCs were tested for functionality after incubation with CpG ODN (ELISPOT). Plasma taken at specific injection intervals was analyzed to identify cytokine/chemokine profiles and autoantibody responses toward Aβ40/42.ResultFC enumeration of major lymphocyte/monocyte populations revealed significant decreases in the absolute numbers across study days with days 3 and 7 being significantly lower than baseline. These results likely reflect transient redistribution of cells out of peripheral blood. Further validation of CpG ODN immunostimulatory potential was demonstrated by increased levels of plasma cytokines/chemokines in vivo, and an increase in the numbers of PBMCs producing IL12, IFNγ, and IFNα in vitro. CpG ODN did not lead to increased production of IgG/IgM autoantibodies against Aβ when assessed periodically. Additionally, longitudinal MRI monitoring for ARIA will enhance the evaluation of CpG ODN efficacy and safety.ConclusionOverall, the present study provides essential information regarding immune response patterns of CpG ODN in this NHP model, enabling potential future clinical applicability of CpG ODN for AD therapeutics.
HOPE4MCI trial: First trial targeting reduction of hippocampal overactivity to treat mild cognitive impairment due to Alzheimer’s disease with AGB101
Authors: Rosenzweig‐Lipson Sharon , Barton Russell , Gallagher Michela , Edgar Chris J. , Maruff Paul T. , Mohs Richard 
Published: December 2020

AbstractBackgroundEvidence from preclinical models and human patients demonstrates that neuronal circuits become hyperactive in prodromal AD contributing to the accumulation of Alzheimer’s pathology and subsequent cognitive decline. Such data support the hypothesis that neural overactivity in the medial temporal lobe/hippocampus is a critical driver of AD neuropathology, including the deposition of amyloid and spread of tau along connectional pathways. AGB101 (low dose levetiracetam) demonstrates efficacy on a range of molecular, synaptic, electrophysiological, functional and behavioral endpoints across models and species. In a Phase 2 study measuring hippocampal activity during a pattern separation memory test in patients with aMCI, AGB101 normalized hippocampal activity and improved performance on this specific memory assessment of hippocampal function. The HOPE4MCI trial is investigating the effects of AGB101 (220 mg) vs placebo in patients with MCI due to AD. The objective of the study is to assess the efficacy of AGB101 (low‐dose levetiracetam, 220 mg, extended release tablet) compared to placebo in subjects with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) scores as the sole primary outcome. A substudy will evaluate levels of tau protein in the brain using tau PET ([18F]MK‐6240) at baseline and end of protocol.MethodThis is a multicenter, randomized, double‐blind, placebo‐controlled, 78‐week, fixed‐dose study evaluating AGB101 versus placebo as a treatment for slowing the progression of MCI due to AD. Inclusion criteria: Subjects must meet the following inclusion criteria at screening: 1) Subjects between 55 and 85 years old; 2) Have MCI due to AD consistent with the NIA‐AA criteria: MMSE (24‐30); CDR (0.5); Impaired delayed recall on the ISLT; essentially preserved ADLs' 3) Evidence of an amyloid‐positive PET scanResultThe HOPE4MCI trial is currently underway. Sites are currently enrolling in the US and Canada with plans to expand to Europe. Up to date subject demographics, screen failure information, safety and dropout information will be presented at the meeting.ConclusionHOPE4MCI represents the first and only Phase 3 clinical trial targeting the reduction of hippocampal overactivity for slowing the progression of MCI due to AD.
Family quality of life in dementia and caregiver burden are associated with different caregiver personal characteristics
Authors: Pilonieta Giovanna , Jablonski Rita A , Winstead Vicki , Geldmacher David S 
Published: December 2020

AbstractBackgroundMost care for persons with dementia takes place in the context of family. Dementia is associated with diminished quality of life for both affected persons and their caregivers, as well as increased burden. There is a growing consensus in dementia care that service‐delivery models for persons with dementia need to be family‐centered, but few studies have explored the concept of “family quality of life” (FQOL) in dementia. As part of a planned coaching intervention to reduce burden in caregivers of people with behavioral and psychiatric symptoms of dementia (BPSD) associated with care resistance, we collected baseline data on factors that might influence burden, FQOL, and response to the intervention.MethodThe 42‐item Family Quality of Life in Dementia (FQOL‐D) questionnaire, Connor‐Davidson Resilience scale (CD‐RISC), Pearlin Mastery scale, and neuroticism items from Eysenck Personality Inventory(EPI) were collected from 26 family caregivers of people with AD who endorsed BPSD with care resistant behaviors. The Spearman correlation between caregiver personality traits and FQOL‐D was calculated. In addition, relationships between caregiver burden, measured with the Zarit Burden Interview (ZBI), and caregivers' personality characteristics were ascertained.ResultOf the 26 enrolled caregivers, 14 (53.85) were female, their mean age was 64.5 years and 24 (92%) were college‐educated. Their care recipients were 61% female, 77% white, mean age of 76 years, and college‐educated (88%). Mean scores were CDRISC 76.03 (+/‐12.05), EPI 6.30 (+/‐1.95), Pearlin 20.23 (+/‐3.26) and FQOL 173.80 (+/‐24.92). There were moderate correlations between FQOL and CDRISC (r=0.5). Secondary analysis showed moderate correlations between ZBI and Pearlin (r=–0.42) and EPI (r=0.48). All reported associations are P<.05ConclusionA relationship between Family Quality of Life and caregiver personal characteristics was identified. Higher baseline FQOL‐D was associated with greater self‐reported resilience. Similarly, higher mastery scores were associated with lower burden on the ZBI. Higher caregiver neuroticism was associated with higher reported burden. No relationships between mastery or neuroticism and FQOL‐D were established in this small sample. We identified that the positive construct of FQOL‐D may be associated with different caregiver characteristics than the negative emotional valance attributed to burden.
TOMM40 has genomic effects on hippocampal volume in mid‐life adults independent of APOE ε4 status
Authors: Pappas Colleen , Wang Qian , Lee Ling Yi , Le Scott T. , Klinedinst Brandon S. , Pollpeter Amy , Larsen Brittany , Willette Auriel A. 
Published: December 2020

AbstractBackgroundThe Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for developing late‐onset Alzheimer’s disease (AD). Part of this risk may be due to APOE ε4 carriers showing progressive hippocampal atrophy decades before disease onset. It is unclear if genes next to APOE, such as Translocase of Outer Mitochondrial Membrane 40 (TOMM40), exercise an APOE ε4‐independent effect on hippocampal volume, which could better identify asymptomatic adults at risk for AD.MethodWe leveraged participants from UK Biobank (N = 10,130) with complete genetic, brain magnetic resonance imaging (MRI), and sociodemographic data. ANOVA and multiple linear regression tested the relationship between a priori identified TOMM40 Single Nucleotide Polymorphisms and hippocampal volume. For preliminary data, we focus on rs2075650 (‘650) genotype of neutral vs. high risk (AA vs. AG + GG genotypes). Main effect and mediation‐moderation analyses were conducted across and within APOE ε4 vs. non‐APOE ε4 carriers. Specifically, mediation‐moderation included age, sex, and serum metabolic markers.ResultAmong APOE ε4 carriers, TOMM40 ‘650 did not exercise independent effects. For non‐APOE ε4 carriers, among women, TOMM40 AG and GG genotypes had 0.16% more atrophy in mid‐life but 1.8% less atrophy in late‐life. Among men, these genotypes showed 0.90% less atrophy in mid‐life but 4.5% more atrophy in late‐life. Biomarkers of energy metabolism and amyloid clearance mediated these associations.ConclusionAmong non‐APOE ε4 carriers, TOMM40 had an independent effect on hippocampal volume as a function of sex and age, acting as an ultimately protective factor in women but detrimental in men.
Cultural validity of cognitive markers for Alzheimer’s disease (AD): Evidence for global strategies
Authors: Parra Mario A. , Custodio Nilton , Montesinos Rosa , Pintado Caipa Maritza , Reynoso‐Guzman Wylliams , Slachevsky Andrea 
Published: December 2020

AbstractBackgroundAvailability of culture‐free cognitive tests with marker properties for AD has proved a barrier to global harmonization strategies. The European Neurodegenerative Diseases Working Group suggested that the Short‐Term Memory Binding Test (STMBT) and the Free and Cued Selective Reminding Test (FCSRT) are useful tests for the early detection of AD (Costa et al., 2017). Yassuda et al. (2019) showed that STMB is insensitive to age and education among healthy Brazilian adults. Parra et al. (2019) suggested that these tests should enter global strategies to aid the early detection of AD. Evidence is still needed to ascertain that such a validity translates to the assessment of affected individuals from underrepresented populations. The current study aimed to shed new light on such an outstanding question.MethodsWe recruited 64 healthy controls (HC), 60 patients with Mild Cognitive Impairment (MCI), and 63 patients with mild AD from Lima, regional area health clinics (DIRESA) between 06/2018‐05/2019. They were all illiterate. We considered Illiterate individuals who (1) attended no school or were enrolled for less than one year and (2) could not read or write (a booklet was given which showed a simple sentence). We assessed them with the STMBT, the visual FCSRT, and a brief clinical‐neuropsychological protocol.ResultsThe assessment confirmed the healthy (CDR=0.0, pFAQ=2.2, BDI=5.9), MCI (CDR=0.5, pFAQ=3.7, BDI=6.2), and dementia (CDR=1.3, pFAQ=16.5, BDI=7.2) status of our groups. Significant between‐group differences were found with both the STMBT (F(2,184)=590.1, p<0.001) and Free Recall during the visual FCSRT (F(2,184)=3936.2, p<0.001), with HC>>>MCI>>>AD. ROC analysis with STMB revealed AUC=0.98 for HC vs. MCI, AUC=1.00 for HC vs. AD, and AUC=0.97 for MCI vs. AD. For the visual FCSRT, an AUC=1.00 was found for HC vs (MCI & AD), and AUC=0.99 for MCI vs AD.ConclusionThe two cognitive markers recently recommended for harmonisation of neuropsychological assessment in neurodegenerative dementias in Europe seem suitable to support such practices in illiterate populations. Parra et al. (2019) recently suggested that only global strategies will help meet global challenges. Here we provide evidence of cognitive markers for AD that can reliably enter such strategies.
Performance comparison of automated white matter lesion segmentation algorithms in the DELCODE Study
Authors: Gaubert Malo , Zimmermann Isabella , Lange Catharina , Dyrba Martin , Li Hongwei , Duering Marco , Ziegler Gabriel , Teipel Stefan J. , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Bürger Katharina , Laske Christoph , Spottke Annika , Jessen Frank , Düzel Emrah , Wirth Miranka ,   the DELCODE Study Group
Published: December 2020

AbstractBackgroundWhite matter hyperintensities (WMH), derived from T2‐weighted MRI, represent a sensitive imaging marker of cerebrovascular disease. To investigate WMH in large‐scale multicenter clinical studies, appropriate automated WMH segmentation algorithms are required. Therefore, prior evaluation of these methods is important, especially due to additional challenges posed by the multicenter acquisition. We assessed performance of different WMH segmentation algorithms compared to manual segmentation (reference) in the multicenter DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE).MethodWMH segmentations were performed on a preliminary randomly‐selected dataset of 20 participants that included FLAIR images from different diagnostic groups across the AD continuum, various study sites and Siemens 3T scanner models. We used freely‐available and fully‐automated WMH segmentation methods, i.e. LST‐LGA, LST‐LPA, and Sysu_Media, the winner of the MICCAI WMH segmentation challenge. Performance of the algorithms was compared to reference segmentation using volumetric and spatial correspondence indices, intraclass correlation coefficient (ICC), Dice’s similarity coefficients (DSC), recall (sensitivity), and precision (positive predictive value), across the whole brain and with respect to the number of detected clusters.ResultPreliminary analyses (n=20, example in Fig.1) indicated that mean WMH volumes, estimated by the algorithms, were lower compared to reference, except for Sysu_Media. Volumetric agreement with reference segmentation was moderate‐to‐high across methods (best: Sysu_Media, ICC=0.9). Mean global DSCs were moderate (best: Sysu_Media, DSC=0.6±0.2), with better performance for larger compared to lower WMH load. Mean number of clusters, detected by the algorithms, was lower compared to reference, except for Sysu_Media that overestimated this value. Mean DSCs for clusters were also moderate for all algorithms (best: Sysu_Media, DSC=0.5±0.2). Mean precision of detected WMH load and number of clusters was higher than mean recall (sensitivity) across all methods, except for Sysu_Media.ConclusionThese preliminary findings show that performance of different automated WMH segmentations is relatively similar. Although most algorithms correctly identify WMH (higher precision), the methods underestimate total WMH load (lower sensitivity). The Sysu_Media algorithm performs best in many indices, however, it yielded lowest precision in number of clusters. Results of the final sample (n=40) will be presented, intended to serve as a method guide for conducting WMH segmentations in the multicenter DELCODE study.
Global Council on Brain Health: Recommendations to promote brain health through music enrichment
Authors: Lock Sarah Lenz , Chura Lindsay Rachel , Parkes David ,   Global Council on Brain Health
Published: December 2020

AbstractBackgroundThe Global Council on Brain Health (GCBH) is an independent collaborative of scientists, clinicians, scholars, and policy experts convened by AARP to provide evidence‐based advice on what people and professionals can do to maintain and improve brain health. The Council translates scientific research into actionable recommendations for the public that will help drive behavior change in individuals across communities and cultures. In 2020, the Council will focus on the topic of music specifically as it relates to brain health. Music offers natural and accessible strategies for older adults who wish to exercise their full creative potential or cope with issues related to dysfunction or isolation.MethodExperts from around the world were brought together to analyze the body of evidence on the impact of music and brain health, build consensus, and issue recommendations. AARP’s original research captures data from surveys highlighting adult engagement with music as it relates to their brain health.ResultThis presentation will feature consensus on whether and how music impacts cognitive health. Recommendations and practical tips based on the latest research advancements will also be showcased to help the public understand the potential that music holds for supporting and enriching brain health. Data from surveys fielded by AARP research, developed in consultation with the GCBH, will be featured.ConclusionThis presentation highlights findings from the Council’s examination of the impact of music on brain health. Music and dance/movement interventions can positively impact health outcomes, including cognition, quality of life, psychological impact, mental well‐being, etc. Participation in music therapy and experiences can regulate stress and arousal, thus affecting overall health. The scientific and policy dimensions of music and brain health on aging adults will also be addressed.
Associations among family stigma, type of dementia, caregiver burden and other negative psychological outcomes
Authors: Velilla Lina M , Acosta‐Baena Natalia , Calle Andres , Allen Isabel Elaine , Lopera Francisco , Kramer Joel H 
Published: December 2020

AbstractBackgroundThere is very little research about the impact of family stigma and the type of dementia on the mental/physical health, and Quality of life (QoL) in early‐onset Alzheimer's disease (EOAD) and Frontotemporal dementia (FTD) caregivers. Thus, we aimed to address the question of whether family stigma and the type of dementia are predictors of depression, QoL and caregiver burden.MethodsThis is an analytical study with a cross‐sectional design. 140 Participants who are family caregivers of patients with the diagnosis of EOAD, FTD and late‐onset AD (LOAD) completed questionnaires about family stigma, caregiver burden (Zarit Burden), depression (CES‐D), anxiety (STAI), and QoL (SF36). Multivariable linear regression models were used with LOAD as a reference category to examine associations between depression, QoL and caregiver burden as outcomes predicted by family stigma and type of dementia.ResultsAfter adjusting by age and patient’s dementia stage, the cognitive component of family stigma (Cog‐stigma) and type of dementia were good predictors of role limitations due to emotional problems (EOAD type b= ‐0,34 p<0,001; FTD type b= ‐0,36 p<0,001; Cog‐stigma b= ‐0,23 p<0,001), general health performance (FTD type b= ‐0,25 p=0,007; Cog‐stigma b= ‐0,34 p<0,001), energy/fatigue (EOAD type b= ‐0,27 p=0,003; FTD type b= ‐0,27 p=0,001; Cog‐stigma b=0,38 p<0,001), emotional wellbeing (EOAD type b= ‐0,28 p=0,004; Cog‐stigma b= ‐0,38 p<0,001), depressive mood (EOAD type b= 0,22 p= 0,028; Cog‐stigma b= 0,35 p<0,001), and depression (EOAD type b=0,24 p=0,018; Cog‐stigma b= 0,35 p<0,000). The Cognitive aspect of stigma was a good predictor of role limitation due to physical problems (b= ‐0,31 p<0,001) and caregiver burden (b=0,51 p<0,001).ConclusionsThe cognitive aspect of stigma (negative self‐attribution about the caregiver role or the own perception of been treated as less worthy by others) and the type of dementia are significant predictors of higher caregiver burden, greater depression and reduced QoL among caregivers. The EOAD caregivers showed a higher occurrence overall of negative caregiver outcomes. Family stigma should be addressed as a potential risk factor for both emotional and physical health among caregivers and as a potential factor that increases the burden among early‐onset dementia caregivers.