bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Asian Cohort for Alzheimer’s Disease (ACAD) study
Authors: Wang Li‐San , Tee Boon Lead , Gu Yian , Li Clara , Vogel Briana , Reyes‐Dumeyer Dolly , Faber Kelley , Hsiung Ging‐Yuek Robin , Rosen Howard J , Schellenberg Gerard D , Varma Rohit , Foroud Tatiana M , Kukull Walter A , Henderson Victor , Lee Haeok , Yu W Haung , Peavy Guerry M , Feldman Howard , Mayeux Richard , Chui Helena C , Jun Gyungah R , Park Van Ta , Chow Tiffany W ,   The Asian Cohort for Alzheimer’s Disease Study
Published: December 2021

AbstractBackgroundAsian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. Roughly 21% of ASACs will be 65 years or older by 2060, underscoring the importance to understand how dementia and Alzheimer’s disease (AD) affect these large sectors of the populace. By comparison, ASACs are under‐sampled in AD research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed.MethodThe Asian Cohort for Alzheimer’s Disease (ACAD) will be the first large dementia genetics cohort to examine genetic/non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history, experience and leadership in AD research. The National Institute on Aging (NIA) has resourced our study, which will leverage national AD research resources and facilitate collaborations with international cohorts.ResultACAD consists of 8 recruiting sites (6 US and 2 Canada), a coordinating site, an analysis site, and 4 active workgroups. ACAD has developed a data collection packet (DCP) and pre‐screening/sample collection procedures. The Data Management Workgroup has implemented them into a central REDCap database. The Outreach Workgroup has translated the forms and are conducting an outreach campaign into Chinese (Mandarin and Cantonese), Vietnamese and Korean. The Training Workgroup has developed a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment. We will recruit cases of dementia, mild cognitive impairment, subjective cognitive complaint, and controls without cognitive impairment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. We will collect saliva or blood for DNA/genetics and biomarker studies.ConclusionAfter launching ACAD in November 2020, we built foundation materials to initiate recruitment in Spring 2021. ACAD will provide guidance for future studies to explore ASAC risk factors for AD and related dementias. In collaboration with ongoing consortium efforts in Alzheimer’s Disease Genetics Consortium, trans‐ethnic insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. Our long‐term goal will be to extend ACAD to South Asians, Filipinos, and Japanese.
Increased brain rewiring in patients with mild cognitive impairment
Authors: Li Yong , Butz‐Ostendorf Markus 
Published: December 2021

AbstractBackgroundDepending on disease progression, differentiation of patients with mild cognitive impairments from those with Alzheimer disease from structural MRI is often difficult as grey matter (GM) loss is not yet present in MCI patients. Therefore, we re‐assessed WM densities at the initial and changes between two measurements in 22 randomly chosen MCI patients from the ADNI3 cohort [Weiner MW et al. 2017] and compared them to 25 matched controls.MethodWe computed full brain probabilistic tractography by MrTrix3 [Tournier et al. 2019]. ROI to ROI connectivity (HCP MMP 1.0 brain atlas) was compared between groups for Superior Longitudinal Fasciculus (SLF) and Occipital Cortex networks in two longitudinal DTI scans with one year interval by the help of NICARA (www.nicara.eu) [Kopetzky, Butz‐Ostendorf, 2018].ResultSurprisingly, MCI patients showed an increase in brain connectivity of the SLF that was associated with an increased brain rewiring, which we did not observe in matched controls. By contrast, we did not find a similar pattern in WM connections of the visual cortex. This observation was seen in about 40% of MCI patients and did not correlate with age, nor with disease onset. Patients with increased connectivity did not show a decrease in MMSE scores over time whereas patients with a loss in connectivity were more likely to decrease in MMSE score.ConclusionThis study is the first that reports a pronounced brain [Van Ooyen, Butz‐Ostendorf 2017 (eds)] rewiring in association with WM hyperconnectivity [Delli Puzzi et al. 2019] in MCI patients. Phases of pronounced brain rewiring could be an expression of a compensatory response aiming at functional reorganization of brain networks. Our findings point to the urgent need for including longitudinal DTI tractographies in routine brain scans and clinical trials.
Mixed methods used in the refinement of an Alzheimer’s study registry to optimize recruitment of Latinx and Black individuals
Authors: Aggarwal Raj , Stowell Carter , Plant Aaron , Creech Deborah Neffa , George Sheba , Williams Emily , Fiore Nora , Langbaum Jessica B 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) disproportionately affects Latinx and Black individuals, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings. The purpose of this 2020 study was to improve an existing online AD participant registry to optimize recruitment of Latinx and Black individuals. Refinements were geared toward recruitment on mobile devices, as research suggests mobile‐first approaches may be more successful within these populations.MethodWe used an iterative, mixed methods approach to improve the registry with 45‐75‐year‐old Latinx and Black individuals who self‐reported no mild cognitive impairment, dementia, or AD diagnoses. Strategies included (in order): four focus groups (n=39); an online survey to assess attitudes and acceptability toward the existing registry (n=677); usability testing of existing registry (n=40); development of a refined registry prototype; qualitative (n=24) and quantitative (n=392) usability testing of refined prototype; a final online survey to assess attitudes and acceptability toward refined prototype (n=769). To assess acceptability of registry improvements, quantitative and qualitative data from the initial and final surveys were compared.ResultThere was an increase between the surveys in the percentage of Latinx and Black respondents who agreed that: they would likely sign up for the registry (48.2% to 54.1% and 42.1% to 53.4%); the registry was designed with people like them in mind (54.4% to 63.0% and 50.1% to 61.2%); and most of their family and friends would relate to the registry (41.2% to 51.9% and 36.8% to 49.4%). Survey participants responded favorably to specific content in the refined registry (e.g., discussing challenges of recruiting Latinx and Black individuals for AD studies and showing diversity of program staff). Qualitative responses in the final survey included that the refined registry was easy to understand and navigate, and was trustworthy. Nearly half of respondents (49.4%) said they would be likely to sign up for the registry using their smartphone or tablet.ConclusionRefinements to an online study recruitment registry aimed at improving participation among traditionally underrepresented populations were successful at increasing acceptability and sign‐up intentions. These findings have important implications regarding reaching underrepresented populations for participation in AD studies.
The impact of novel Xe delivery on Alzheimer‐related gene regulation
Authors: Yin Xing , Booher Keith , Peng Tao , Morales Rodrigo , Claypool Jonathan , McPherson David , Huang Shaoling 
Published: December 2021

AbstractBackgroundEffective treatments for Alzheimer’s disease (AD) are classically designed to canonical disease players (e.g., misfolded proteins, neurodegeneration, and brain inflammation). Importantly, treatments must be able to cross the blood‐brain barrier (BBB) to cause meaningful therapeutic effects. Sufficient evidence has demonstrated that xenon (Xe), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the BBB into hypoperfused brains without side effects. For chronic use, a long‐term and effective Xe delivery method is needed. Here, we present novel Xe formulations with effective cerebral delivery strategies for extended endogenous neuroprotection and neurorestoration.MethodOrally deliverable Xe cyclodextrin (Xe‐CD) and intravenous deliverable Xe‐liposome were prepared. Xe‐CD was orally administrated in aged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks. The brain and blood amyloid‐β (Aβ) levels were measured by ELISA. To extend therapeutic effects, Xe‐liposomes were intravenously administrated using an intermittent repetitive administration strategy in a rat stroke model. Xe effects on epigenetic regulation were evaluated in this rat stroke model using Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses. Neurocognitive recovery was also evaluated.ResultAged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks developed high Ab expression levels in the brain and blood. However, Xe oral administration for 6‐week prevented the high‐fat diet‐induced Aβ elevation. Repetitive intermittent administration of Xe formulations extended the protective effects over time as long‐term memory restoration post stroke was observed. Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses revealed enrichment of differential methylation in multiple biologic pathways associated with growth factor response, memory consolidation, synaptic plasticity, and brain aging in the hippocampus. Of interesting, Xe regulated endogenous β‐secretase (BACE1), and low‐density lipoprotein receptor‐related protein 1 (LRP1), both of which are known to be associated with Ab. Xe also regulated memory and age related genes such as Gadd45b, DMNT3a, and HDAC9; and growth factor related genes NTrK2 and NGF. Gadd45b and PFAa also regulate long‐term memory consolidation.ConclusionWe have developed a novel Xe formulation and delivery strategy for long‐term neuroprotection that stabilizes the brain through multiple pathways.
A 10‐year behavioral and social sciences research agenda for ADRD: Reflections on a new national academies report
Authors: Powell Patricia , Yaffe Kristine , Mor Vincent , Checksfield Molly 
Published: December 2021

AbstractBackgroundThe National Academies of Sciences, Engineering, and Medicine was charged with developing a ten‐year agenda for research in the behavioral and social sciences that would substantially contribute to reducing the burden of ADRD.MethodThe report was developed by a committee of individuals with expertise across a range of disciplines and fields, including dementia research. The committee was charged with assessing the role of the social and behavioral sciences in reducing the burden of dementia. The committee held several evidence‐gathering sessions, reviewed published literature, commissioned several papers, and engaged individuals living with dementia and caregivers as a part of an Advisory Panel to the committee.ResultThe committee’s report will be published in spring 2021, after undergoing the National Academies' rigorous review process. The report will include conclusions and recommendations about the following topics: (1) research using the methods of behavioral and social sciences on the burden of AD/ADRD on individuals, families, medical and long‐term care systems; (2) challenges associated with AD/ADRD care; (3) intervention development for persons with dementia and their caregivers at different stages of illness; (4) cognitive and AD/ADRD epidemiology; (5) factors affecting AD/ADRD prevention, leveraging basic and translational research on behavioral and social pathways to AD/ADRD and cognitive decline; (6) detection of AD/ADRD‐related change; (7) causes and consequences of AD/ADRD health disparities; and (8) AD/ADRD data infrastructure needs.ConclusionThe report will include conclusions and recommendations to guide behavioral and social science research in the coming decade that could reduce the burden of ADRD.
Increasing fasting glucose is associated with Alzheimer’s disease–related neuropathological and structural decline in older adults
Authors: Honea Robyn A. , Greene Zachary D. , John Casey S. , Kueck Paul J. , Kamat Ashwini , Taylor Matthew K. , Lepping Rebecca , Vidoni Eric D. , Burns Jeffrey M. , Morris Jill K. 
Published: December 2021

AbstractBackgroundResearch on risk factors for dementia and in preclinical populations has shown that glucose regulation may be involved in amyloid synthesis, cognitive processing, and neurodegeneration; however, the extent to its involvement is unclear. Fasting glucose is a straightforward measure that could be a window into metabolic changes either associated with or preceding dementia.MethodWe sought to test whether a change in fasting glucose over one year was related to multi‐modal brain imaging measures of neuropathological changes in the brain associated with dementia. We leveraged longitudinal biospecimens and neuroimaging measures collected during the Alzheimer’s Prevention through Exercise (APEX) trial (n=109) to examine the longitudinal relationship between change in fasting glucose and change in neurodegeneration and cerebral amyloid over 1 year of follow‐up.ResultThe group of individuals with stable or improving fasting glucose (n=65) exhibited less atrophy and regional amyloid accumulation compared to the group whose fasting glucose worsened over 1 year (n=44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus, reduced diffusion in limbic white matter, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by APOE4 carrier status. Increasing fasting glucose may reflect changes in cellular bioenergetics associated with Alzheimer’s disease neuropathophysiology.ConclusionDysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine if treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.
Inhibitory control deficits in vascular cognitive impairment revealed using the Multi‐Item Localization (MILO) task
Authors: Richards Emma V , Thornton Ian M , Bayer Antony , Tales Andrea 
Published: December 2021

AbstractBackgroundReaction time (RT) in Vascular Cognitive Impairment (VCI) is particularly slowed when assessed using tests of executive function, however, these tests do not reveal the integrity of specific functional subcomponents of information processing related to RT that are affected by VCI, thus limiting understanding of behavioural change, symptoms and disease progression. Pathological changes in white matter can be ‘silent’, on routine neuroimaging, and not all clinical tests may be sensitive to such effects, highlighting the importance of using of a wider range of tests than may be used at present. The Multi‐Item Localization (MILO) task is used to characterise the performance of mild/moderate VCI and is designed to explore the temporal context of visual search, in addition to measuring overall completion time, it provides a profile of serial reaction time (SRT) patterns across all items in a sequence. MILO assesses how well participants plan ahead during search, and whether items that have already been located can be effectively ignored (i.e., inhibited) identifying deficits in inhibitory control during search.MethodParticipant groups: VCI patients (n =26); cognitively healthy (CH) older adult control group (n=23); young adults (n=26). The MILO iPad app consisted of the digit sequence 1‐8, presented as red/white pool balls. Participants were required to tap each ball in consecutive order, quickly and accurately. In the Vanish condition, items were removed from the screen following the response. In the Remain condition, items were unaffected when touched and the set size were the same throughout a trial. Participants completed two blocks of 20 correct trials, one block of Vanish trials followed by one block of Remain trials.ResultsThe performance of VCI participants was characterised by overall slowing, increased error rates, and crucially, a compromised ability to use inhibitory tagging. Performance was compromised when items remained visible and have already been responded to, resulting in detrimental slowing of processing.ConclusionThe MILO task could be a useful tool for identifying non‐age‐related changes in behaviour with patient populations, and clearly hints at a specific inhibitory deficit in VCI.
Tau pathology mediates the effects of amyloid on cerebral blood flow and propagation of tau
Authors: Bilgel Murat , Wong Dean F. , Resnick Susan M. 
Published: December 2021

AbstractBackgroundAmyloid is associated with greater tau pathology and is thought to facilitate the spread of tau from the medial temporal lobe (MTL) to the neocortex. The extent to which amyloid versus MTL tau is involved in propagating tau remains unclear. Given the potential role of cortical tau in early neurodegeneration, understanding the contributors to its spread might inform preventative strategies.MethodWe acquired 18F‐flortaucipir (FTP) PET scans to measure tau pathology in 113 non‐demented Baltimore Longitudinal Study of Aging participants. To assess if amyloid facilitates the spread of tau from the MTL to the neocortex, we investigated whether amyloid moderates the association between tau in the entorhinal cortex (EC) and the inferior temporal gyrus (ITG). To quantify the involvement of amyloid versus MTL tau in propagating tau, we investigated whether EC tau mediates the association between amyloid and ITG tau. Finally, we investigated the local relationship between ITG tau and cerebral blood flow (CBF), an indicator of neurodegeneration, quantified as the relative radiotracer delivery parameter R1
computed from dynamic Pittsburgh compound B (PiB) PET scans. We used robust linear regression for all statistical models to mitigate the influence of the few outlying tau data points on the estimates, and included age, sex, race, and education as covariates.ResultAmyloid positive (A+) participants had higher FTP‐SUVR in the EC and ITG. Higher FTP‐SUVR in the EC was associated with higher FTP‐SUVR in the ITG. This association was steeper among A+ individuals (amyloid and EC FTP‐SUVR interaction β=0.269, p=0.023). EC FTP‐SUVR mediated the association between amyloid and ITG FTP‐SUVR (indirect effect=0.136, p=0.043).Higher ITG FTP‐SUVR was associated with lower PiB‐R1
(β=‐0.277, p=0.039). The direct association between amyloid and PiB‐R1
was not statistically significant (direct effect=‐0.366, p=0.192), but there was an indirect effect via ITG FTP‐SUVR (indirect effect=‐0.14, p=0.015).ConclusionOur findings suggest that both amyloid and MTL tau pathology are involved in the spread of tau into the neocortex. Tau accounted for 28% of the amyloid‐CBF relationship, indicating its role in early neuronal hypoactivity. Therapeutics may need to target both amyloid and tau early to prevent neocortical involvement.
Gamma frequency sensory stimulation prevents brain atrophy, improves sleep and memory in probable mild Alzheimer’s patients
Authors: Chan Diane , Suk Ho‐Jun , Jackson Brennan L , Milman Noah , Stark Danielle , Fernandez Vanesa , Banerjee Arit , Kitchener Erin , Klerman Elizabeth B , Boyden Edward S , Brown Emery N , Dickerson Brad C. , Tsai Li‐Huei 
Published: December 2021

AbstractBackgroundNon‐invasive gamma frequency light and sound stimulation at 40Hz reduced Alzheimer’s disease (AD) pathology and improved performance during behavioral testing in mouse models of AD (Iaccarino et al., Nature, 2016; Martorell et al., Cell, 2019; Adaikkan et al., Neuron, 2019). Sensory stimulation inducing 40Hz entrainment reduced amyloid and hyperphosphorylated tau burden and prevented brain atrophy in different mouse models of AD. Performance on tasks testing short‐term memory and spatial learning improved after 6 weeks of daily 40Hz stimulation. We therefore hypothesized that translation of gamma entrainment with light and sound can be used as a disease‐modifying therapeutic for AD.MethodsWe conducted a placebo‐controlled, randomized control trial (n = 15) in volunteers with probable mild AD to use our light and sound device at home for one hour daily (NCT 04042922). Control devices delivered constant light and white noise while devices with the active setting produced patterned and synchronized light and sound at 40Hz. Electroencephalogram (EEG) was used to evaluate for safety and entrainment when using the 40Hz stimulation. Weekly phone questionnaires were used to assess safety. Magnetic resonance imaging was used to evaluate brain structure and actigraphy was used to record sleep. Face‐name association delayed recall was done to assess changes in cognition.ResultsWe report interim results after 3 months of daily 40Hz stimulation. Mild AD patients were highly compliant with usage in both the control and active groups. EEG data show that our novel light and sound device safely and effectively induced 40Hz entrainment in subjects with mild AD. After 3 months of daily stimulation, 40Hz entrainment prevents both hippocampal atrophy and ventricular enlargement and the extent of ventricular change differs between groups (p = 0.034, p = 0.024, p = 0.043, respectively). Circadian rhythmicity also improved with 40Hz stimulation (p = 0.03). Performance on the face‐name association delayed recall test improved in accuracy (p = 0.004).ConclusionsGamma frequency light and sound stimulation can be used safely daily for 3 months and prevents AD‐related degeneration. Induced entrainment using sensory stimulation at 40Hz shows promise as a novel disease modifying therapeutic for Alzheimer’s dementia.