bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lowering Synaptogyrin‐3 Expression Rescues Tau‐Induced Memory Deficits and Synaptic Loss in the Presence of Microglial Activation
Authors: Largo‐Barrientos Pablo , De Strooper Bart , Spires‐Jones Tara L , de Wit Joris , Uytterhoeven Valerie , Verstreken Patrik 
Published: December 2022

AbstractBackgroundTau is implicated in multiple neurodegenerative disorders, including Alzheimer’s disease. Synaptic loss and neuroinflammation are characteristic feautures of tauopathies, but it is unclear if these pathological events are causally linked and whether they are relevant for cognitive decline. Mutations and/or hyperphosphorylation of Tau leads its accumulation at synapses, where Tau binds to synaptic vesicle‐associated protein Synaptogyrin‐3 resulting in clustering of vesicles and impaired synaptic function. Given that Synaptogyrin‐3 is uniquely present at pre‐synaptic terminals, this allows us to decipher the contribution of pre‐synaptic Tau to overall Tau‐induced pathology.MethodWe generated a synaptogyrin‐3 knockout mouse line using CRISPR‐Cas9 technology. Synaptogyrin‐3−/− and +/− mice are viable and fertile and do not show overt phenotypes. We bred synaptogyrin‐3+/− mice with human Tau P301S‐expressing mice (PS19 line) and aged the offspring. We used several techniques, including electrophysiology, behavioral tests, immunohistochemistry and electron microscopy, to determine the effects of lowering Synaptogyrin‐3 expression in a tauopathy mouse model.ResultWe found that heterozygous knockout of Synaptogyrin‐3 in Tau P301S mice was sufficient to rescue synaptic plasticity and working memory defects. Moreover, lowering Synaptogyrin‐3 expression prevented synaptic degeneration and loss of synaptic markers in Tau P301S mice. Interestingly, proliferation and activation of astrocytes and microglia are observed in Tau P301S; synaptogyrin‐3+/− mice to the same extent as in their Tau P301S littermates.ConclusionOur results indicate that Tau induces synaptic loss and neuroinflammation independently, and that neuroinflammation is not sufficient to cause synaptic loss. In addition, pre‐synaptic defects caused by Tau are enough to drive defects in working memory.
Alzheimer disease clinical trials in low and middle income countries: A call for globalization of clinical trials
Authors: Llibre‐Guerra Jorge J , Rodriguez‐Salgado Ana M , Hardi Angela , Heavener Anika , Behrens María Isabel , Brucki Sonia Maria Dozzi , Babulal Ganesh M , Nitrini Ricardo 
Published: December 2022

AbstractBackgroundIn the absence of clinically meaningful disease‐modifying treatments, the number of adults with dementia worldwide is projected to more than triple. Much of this increase will occur in low and middle‐income countries (LMICs); by 2050, 68% of adults living with dementia will be in LMICs. However, there is a gross under‐representation of LMICs in historical and contemporary AD clinical trial platforms.MethodsWe aimed to determine the global distribution of dementia clinical trials and identify existing barriers for conducting AD clinical trials in LMICs. Our primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform. Data analysis included number of clinical trials per country, regional distribution, funding source, study phase (1, 1/2, 2, 2/3, or 3), and annual growth rate by region relative to population density. An additional systematic review search and expert consensus was conducted to identify barriers for conducting clinical trials in LMICs.ResultAmong 1737 dementia interventional trials, only 17.2% have been or are conducted in LMIC (figure 1). LMICs trial sites participated/conducted 23.6% and 10.9% of phase 3 and phase 1 trials, respectively. We identified several limitations for trial implementation including lack of financial resources, low industry presence, regulatory obstacles and operational barriers, especially related to resources in neuroimaging. Two successful international trials platforms (Dominantly Inherited Alzheimer Network‐Trials Unit [DIAN‐TU] and Worldwide FINGERS) have been able to expand into Latin American countries creating a regional network for trial implementation.ConclusionAlthough LMICs bear the greatest burden of AD in the world, substantial development of clinical trial platforms to address this inequity is lacking. Ongoing LMICs regional trial platforms (e.g., DIAN‐TU and LatAm‐FINGERS) may shed light on alternative strategies to overcome existing barriers and highlight the need for a more thoughtful approach to increase diverse representation in AD clinical trials and expand access to LMIC.
Cognitive assessment in diverse populations: implications for Alzheimer’s disease clinical trials
Authors: Tsoy Elena , VandeVrede Lawren , Rojas Julio C. , Possin Kate L 
Published: December 2022

AbstractBackgroundBy 2060, racially/ethnically diverse individuals will constitute almost half of all older adults in the US and experience largest increases in dementia burden. Appropriate representation of diverse participants in clinical trials is critical to ensure generalizability of outcomes. Screening/inclusion criteria for trials often involve a brief cognitive assessment to indicate overall disease severity. We examined the Mini‐Mental State Examination (MMSE), the most widely used assessment, as a recruitment tool in diverse older adults.MethodData from 10,377 older adults (8,585 controls, 1,752 MCI; 232 Asian, 1,641 Black, 623 Hispanic, 7,841 White) were drawn from the National Alzheimer’s Coordinating Center (NACC) uniform data set. Only MCI participants for whom AD was presumed to be the primary etiology per NACC protocol were included. We performed logistic regressions to examine the likelihood of performing at/above a conventional MMSE cutoff of 24 in MCI participants. Multivariable regressions were performed to examine associations between 1) demographic variables and MMSE performance in controls, and 2) MMSE and CDR Sum of Boxes (CDR‐SB) in all participants.ResultCompared to White participants, Asian (OR = 0.46 [0.24‐0.99]), Black (OR = 0.53 [0.35‐0.80]), and Hispanic (OR = 0.38 [0.24‐0.61]) older adults with MCI were significantly less likely to perform at/above MMSE cutoff. Regressions in controls revealed a significant race/ethnicity by education interaction with greater magnitude of the association between education and MMSE in Black and Hispanic participants controlling for age, sex, and primary language. Associations between MMSE and CDR‐SB were significantly weaker in Black and Hispanic participants (Figure 1) and participants without high school education after controlling for age, sex, and primary language.ConclusionWe found that the MMSE has a greater education bias and weaker functional validity among Black and Hispanic older adults. Findings suggest that using an MMSE cutoff may be an inappropriate criterion for assessing disease stage among underrepresented participants. We discuss the implications of findings for the current state of diversity in clinical trials and for clinical diagnostic practice with diverse older adults. Focus points will include the need for culturally fair, sensitive, and psychometrically robust brief cognitive measures and the critical importance of incorporating social determinants of health into clinical and research practices.
How does APOE genotype moderate the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model
Authors: de Frutos Jaisalmer , Sewell Kelsey R , García‐Colomo Alejandra , Markovic Shaun J , Erickson Kirk I. , Brown Belinda M 
Published: December 2022

AbstractBackgroundEvidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD), while the Apolipoprotein E (APOE) ε4 allele represents the greatest genetic risk factor. Extensive research has thus far failed to establish whether frequent PA can mitigate the increased AD risk associated with APOE ε4. Studies looking at various AD‐related traits (e.g., amyloid beta burden or cortical atrophy) might show diverse results because the biological pathways involved are differentially influenced by PA, APOE ε4 carriage and their interaction. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model of how PA and APOE ε4 carriage, independently and in combination, may alter well‐established molecular mechanisms underlying AD pathogenesis.MethodAvailable literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response, and glucose metabolism.ResultWe have identified potential pathways through which the beneficial effects of PA might offset some of the detrimental outcomes of APOE ε4 carriage. Nonetheless, PA does not seem to be able to entirely prevent or revert the noxious effects of genetic risk. Our integrative model includes evidence‐based and theoretical synergistic interactions across mechanisms, and a proposal of testable hypotheses for future studies.ConclusionPA influences a wide array of molecular targets involved in AD neuropathology. A better understanding of where, when and most importantly, how, PA decreases AD risk in the presence of the APOE ε4 allele is essential to formulate combined therapeutic approaches.
Risk factors for loneliness in family caregivers of people with dementia and enduring mental health conditions during the COVID‐19 pandemic in Latin America
Authors: Leon Tomas , Miranda‐Castillo Claudia , Slachevsky Andrea , Tapia‐Muñoz Thamara , Olavarria Loreto , Castro Loreto , Pinto Alejandra , Chen Yaohua Sophie , Leroi Iracema , Lawlor Brian , Duran‐Aniotz Claudia , Grycuk Emilia , Beber Bárbara Costa , Peres Fernando Aguzzoli , Nubia Carla , Gaitan Pablo , Vilar‐Compte Mireya , O'Sullivan Roger 
Published: December 2022

AbstractBackgroundDuring the COVID‐19 pandemic, loneliness has increased in the general population due to government measures to contain the spread of the disease. In Latin America (LA), caregiving is most often delivered informally by family members Family caregivers often face mental health challenges linked to their caregiving role and their social context. Pandemic‐related social restrictions have been especially detrimental for older people with dementia or other brain health challenges, as well as their family caregivers. We aimed to investigate the associations of loneliness, social isolation and care burden in these family caregivers.MethodWe undertook a cross‐sectional survey of over 300 informal caregivers of people with dementia or enduring mental health problems living in 4 Latin American countries, Mexico, Brazil, Chile, and Peru. We categorized loneliness into 3 groups ‘low’, ‘moderate’ and ‘severe loneliness’. Here, we analyzed factors related to changes in the prevalence of moderate and severe loneliness before and during the pandemic using a longitudinal multinomial logistic regression model.ResultDuring the pandemic, there was a significant increase in loneliness prevalence (p<.001) among caregivers in Latin America, with more people having moderate (6.25% pre‐pandemic; 17.67% mid‐pandemic) and severe loneliness (2.78% pre‐pandemic; 15.19% mid‐pandemic). Gender differences in the prevalence of loneliness or higher levels of loneliness among dementia caregivers compared to caregivers of other conditions were not seen. The regression model revealed that the increment in risk for moderate loneliness during the pandemic was related to caregivers' age, level of education, and social contact/isolation. Increased risk for severe loneliness was related to caregivers' social contact during the pandemic and perceived mental health.ConclusionPublic health interventions regarding COVID‐19 pandemic should consider increased loneliness in Latin‐American caregivers. This population will need both, short and long‐term mental health and practical support. Next steps include gathering more evidence on specific risk factors for loneliness and its impact on caregivers’ physical and mental health.
Toward a statistical foundation for brain signatures of behavioral outcome
Authors: Fletcher Evan M , Gavett Brandon E , Farias Sarah , DeCarli Charles S. , Widaman Keith F. , De Leon Fransia S. , Mungas Dan M. 
Published: December 2022

AbstractBackgroundThe “brain signature of cognition” concept has garnered interest as a data‐driven, exploratory approach to better understand key brain regions involved in specific cognitive functions, with the potential to maximally characterize brain substrates of clinical outcomes. However, to be a robust brain phenotype, the signature approach requires a statistical foundation showing that model performance replicates across a variety of cohorts. Here, we outline a procedure that provides this foundation for a signature models of episodic memory and extend this to a measure of functional everyday memory.MethodUniversity of California, Davis (UCD) and ADNI provided imaging and memory data. For cognitive and ECog memory, we derived regional brain gray matter (GM) cortical thickness (CT) measures, testing for replicability (Fig. 1). Signature model generation used two steps in each cohort: 1) Randomly select 40 discovery subsets of size N = 400. In each subset, use voxelwise regression to compute the CT signature regions for outcome at three t‐values of association. 2) Compile frequency maps of region selection across all 40 discovery sets and designate regions with selection frequency >70% as “consensus” signature masks for each cohort. Model validation used regressions of outcomes on consensus masks: 1) Compare adjusted R2 fits of both consensus signature models in 40 discovery sets in each cohort (thus, symmetrically compare same and oppositely generated models). 2) In each full cohort, compare signature model fits with competing models.ResultSpatial replications produced strongly convergent consensus signature regions derived from UCD and ADNI (Fig. 2). Consensus model fits were highly correlated in 40 random subsets of each cohort (Fig. 3 top) indicating high replicability, with tight (∼80%) ratios of within/outside cohort model fits (Fig. 3 bottom), indicating low bias. In comparisons over each full cohort, signature models outperformed other models with one exception (Fig. 4).ConclusionMultiple random model generations, followed by consensus selection of regional brain substrates, produced signature models that both consistently replicated model fits to memory and outperformed other commonly used measures. Results support consensus signature models as robust biomarkers of cognition and everyday function across imaging cohorts with differing demographic composition (see Table).
School‐Based Brain Health Curriculum: Teaching the skill of advocacy through the lens of brain health for middle and high school students
Authors: Felten Kristen M. , Smith Kathleen O'Toole 
Published: December 2022

AbstractBackgroundIt is estimated that 250,000 children and young adults in the U.S. provide care to family members with dementia, according to the Alzheimer’s Association Facts and Figures from 2015. Research increasingly demonstrates that lifestyle choices throughout life affect later brain health. This knowledge provided the impetus for the Wisconsin Departments of Health Services and Public Instruction to develop the Advocacy for Self or Others: Brain Health curriculum. The purpose of this presentation is to describe the curriculum and discuss implications for the future.MethodIn partnership between these two state agencies, this unit was created to help youth learn the skill of advocating for themselves or another person, an important skill for life and in caregiving. Students in middle or high school will apply this skill to one of eight areas of brain health that were developed for the curriculum. The curriculum intends to reduce the stigma around dementia, promote awareness of brain health strategies, and increase understanding of caregiving for a person with dementia. The unit also includes information on the effect of music on the brain, and how a love of music can be a connection between generations.ResultsThe Department of Public Instruction will make the curriculum available on their website, where anyone is welcome to access and use it. Five Wisconsin schools will receive funding to pilot the material to demonstrate student learning and achievement with the material, as well as usability for educators. The units covering brain health material include: Overall Brain Health• Keeping your Brain Healthy• Aging and the Brain• Music and the Brain• Concussion & Brain Injury Awareness• Reducing Stigma and Providing CareConclusionIt is possible for school systems to become involved in promoting brain health, reducing stigma around dementia through promoting understanding, and supporting students who are providing care at home. Partnerships between experts in curriculum development for youth and content around dementia and brain health can be brought together to offer a new topic to educators for use in health classes, physical education, consumer education, psychology, student health associations, and more.
Research Inclusion Supports Equity (RISE): Building Community and Research Engagement among Sexual and Gender Minority Adults at Risk for Alzheimer’s Disease and Related Dementias
Authors: Wharton Whitney , Anderson Joel G , Verble Danielle D , Likos Kelly D. S. , Flatt Jason D. , Kittle Krystal R. 
Published: December 2022

AbstractBackgroundAn estimated 2.7 million U.S. older adults self‐identify as a sexual and/or gender minority (SGM; i.e., lesbian, gay, bisexual, transgender, and/or queer), a numbers that will increase to 4 million by 2030. SGM adults age 50+ experience a higher prevalence of chronic disease and disability and poorer mental and physical health. About 27‐45% of SGM adults provide informal care for family and friends, taking on caregiving roles at a higher rate (one in five) than the general population (one in six). Little is known about the health‐ and caregiving‐related needs of SGM adults living with ADRD and SGM caregivers of people with ADRD.MethodA concerted, national effort to recruit SGM people into ADRD‐related research does not exist. Our recently funded NIA R24 award titled “Research Inclusion Supports Equity (RISE)” will increase research inclusion and engagement of SGM adults living with ADRD or caring for someone living with ADRD to allow for future development of targeted interventions and prevention studies in this under‐resourced community.ResultWe will present the rationale, design, best practices, and progress to date including: 1) our community‐based participatory research protocol for national and SGM‐community‐led engagement and outreach activities, 2) details of our RISE recruitment registry of SGM adults with ADRD and SGM caregivers for people with ADRD), and 3) development of a replicable model for recruitment and retention of SGM adults with ADRD and SGM ADRD caregivers in aging‐related research.ConclusionsOpportunities for investigator / physician / Center collaboration and utilization of the RISE Research registry will be discussed.
The relationship between plasma matrix metalloproteinase‐9 and cerebrospinal fluid biomarkers of tau is sex‐dependent
Authors: Tsiknia Amaryllis A. , Sundermann Erin E. , Edland Steven D. , Reas Emilie T. , Brewer James B. , Galasko Douglas R. , Banks Sarah J. 
Published: December 2022

AbstractBackgroundMatrix metalloproteinase‐9 (MMP‐9) is a proinflammatory, proteolytic enzyme that is dysregulated in Apolipoprotein (APOE) ε4 carriers, patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and has been shown to accelerate tau oligomerization, blood‐brain barrier breakdown and amyloid‐β (Aβ) accumulation. Evidence suggests that MMP‐9 activity may be regulated by sex hormones, yet it is unknown whether the association between plasma MMP‐9 and cerebrospinal fluid (CSF) AD biomarker levels varies by sex.MethodIn 335 ADNI participants (128 women, mean age 74.8±7.4), including 56 cognitively normal adults, 183 MCI patients and 96 AD dementia patients, we examined whether sex modulates total and free plasma MMP‐9 associations with CSF total tau (t‐tau), tau phosphorylated at threonine 181 (p‐tau181) and Aβ42.ResultFree and total plasma MMP‐9 levels were not associated with sex, age, APOE ε4 status or cardiovascular disease risk (CVDR). Total plasma MMP‐9 levels were higher in AD dementia patients versus MCI patients but did not differ between normal controls and MCI or AD patients. Free and total MMP‐9 levels were not associated with CSF Aβ42 regardless of sex. There was a sex × total plasma MMP‐9 interaction on CSF t‐tau (β=24.7; 95% CI, 82.5 to 355.2; P=0.002) and p‐tau181 (β=24.7; 95% CI, 8.9 to 40.4; P=0.002). Higher total MMP‐9 correlated with higher t‐tau and p‐tau181 levels in women, but with lower levels in men. There was a sex × free plasma MMP‐9 interaction on CSF p‐tau181 (β=19.5; 95% CI, 6.0 to 33.1; P=0.005) and t‐tau (β=147.8; 95% CI, 30.2 to 265.3; P=0.01). Higher free plasma MMP‐9 correlated with lower CSF p‐tau181 and t‐tau in men, but not women. These relationships were independent of age, education, diagnosis, CVDR, and CSF Aβ42 levels, and were likely driven by APOE ε4‐carriers as free or total MMP‐9 levels were not significantly associated with CSF biomarkers among non‐carriers regardless of sex.ConclusionOur findings provide preliminary evidence of sex differences in associations between MMP‐9 and CSF tau biomarkers, particularly among APOE ε4‐carriers. Compared to male ε4‐carriers, female ε4‐carriers might be more vulnerable to MMP‐9 activity, possibly promoting higher levels of AD‐related tau pathology.