bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal inflammation is associated with vascular dysfunction in middle aged Non‐Latinx Black APOE‐ε4 carriers
Authors: Igwe Kay C , Lao Patrick J. , Seblova Dominika , Swanberg Kelley , Rivera Andres M. , Giudicessi Averi , Tejeda Emely , Juchem Christoph , Mayeux Richard , Manly Jennifer J , Brickman Adam M. 
Published: December 2022

AbstractBackgroundNeuroinflammation may be associated with global vascular dysfunction and damage. APOE‐ε4, a major genetic risk factor for late onset AD, is expressed in neuroinflammatory cells and may lead to increased pro‐inflammatory cytokine and nitric oxide production in response to injury. We examined the relationship of vascular dysfunction and damage with a magnetic resonance spectroscopy (MRS) marker of neuroinflammation in APOE‐ε4 carriers and non‐carriers.MethodSingle proton MRS, pulsed arterial spin labeling (PASL), and T2 fluid attenuated inversion recovery (FLAIR) were collected in a sample of racially/ethnically diverse, middle‐aged adults (n=313, women=67%, age=55±11, years of education=13±3, 72% Latinx/22% Non‐Latinx Black/6% Non‐Latinx White) and used to derive hippocampal Inositol/creatine ratios (Ins/Cr) as a measure of neuroinflammation. Global cerebral blood flow (CBF) was used as a measure of vascular function, and white matter hyperintensity (WMH) volume as a measure of small vessel cerebrovascular damage. APOE genotype was categorized as the presence or absence of at least one ε4 alleles. We estimated general linear models to test main effects and the interaction of APOE‐ε4 and Ins/Cr on WMH or CBF, adjusting for age and stratified by race/ethnicity due to differential prevalence and effects of APOE ε4.ResultsIn the whole sample, being an ε4 non‐carrier (β=‐12.0 95%CI: [‐24.8, 0.83], p=0.067) and having greater Ins/Cr (β=‐1.1[‐2.2, 0.1], p=0.062) were associated with lower CBF. Within Non‐Latinx Black participants, being an APOE‐ε4 non‐carrier (β=‐40.2[‐73.3, ‐7.1], p=0.02) and having greater Ins/Cr (β=‐3.7[‐73.3, ‐7.1], p=0.007) were associated with lower CBF. The negative association with Ins/Cr was stronger in APOE‐ε4 carriers compared to non‐carriers (β=3.9[0.65, 7.1], p=0.02). No associations of Ins/Cr were observed with WMH.ConclusionGlobal vascular dysfunction, but not vascular damage, was related to hippocampal inflammation in APOE‐ε4 carriers among Non‐Latinx Black middle‐aged adults. Neuroinflammation may be linked to vascular brain health which is particularly important for groups with higher APOE‐ε4 prevalence or with greater exposure to social determinants of health that can lead to greater inflammation.
The Neurologist’s Role in Patients with Mild Cognitive Impairment and Mild Alzheimer’s Disease Dementia
Authors: Pruzin Jeremy J. , Brunton Stephen , Alford Susan , Hamersky Carol , Sabharwal Anup , Gopalakrishna Ganesh 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Mild cognitive impairment (MCI) affects >10% of US adults over the age of 70 and represents a transitional stage between healthy aging and dementia. Multiple factors influence the path to care through the health system. This study sought to better understand the medical journey of patients with all‐cause MCI and mild AD dementia (ADD) to identify opportunities for improvement.MethodAn anonymous online survey was conducted in a cross‐sectional US‐population of 103 patients with self‐reported diagnosis of MCI/mild ADD, 150 care partners of patients with MCI/mild ADD, and 75 neurologists.ResultIn the most common medical journey for patients (73% of patients), half of patients/care partners (51%) reported they received their diagnosis from a neurologist. The most common reasons patients/care partners initiated discussions with a healthcare provider were symptoms interfering with activities of daily life (51%), symptoms not resolving (46%), encouragement from family or friends (44%), and symptoms worsening in degree of discomfort/frequency (43%). Most patients/care partners (23%) reported receiving a misdiagnosis prior to receiving a formal diagnosis of MCI/mild ADD. Half of neurologists (52%) view themselves as the coordinator of care for patients with MCI/mild ADD; whereas 35% of patients/care partners view them as such.At the time of diagnosis, most neurologists (83%) reported discussing with patients the potential causes of MCI/mild ADD. Most neurologists (84%) reported following American Academy of Neurology guidelines (AAN) for treatment and management of patients with MCI/mild ADD. For ongoing care, treatments most commonly prescribed/recommended by neurologists included mental exercises (84%), general improvements in lifestyle (84%), acetylcholinesterase (AChE) inhibitors (78%), social interaction (75%), and NMDA antagonists (73%).ConclusionNeurologists are often the healthcare provider diagnosing MCI/mild ADD however patients frequently experience misdiagnosis in their medical journey. Neurologists are not viewed as coordinators of care by most patients. Positioning neurologists as coordinators of MCI/mild ADD care and equipping them with the right resources may help patients obtain a diagnosis and treatment sooner.
Translational potential of JAX humanized APOE mice: trajectories of resilient versus susceptible aging by sex and weight
Authors: Vitali Francesca , Wiegand Jean‐Paul L. , Tucker Allan , Merlini Simona , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundAging, chromosomal sex, and genetic risk factors interact to determine the trajectory of an individual’s age‐related biological changes and, in turn, may predispose individual risk or resilience to AD. To advance translational validity of the JAX humanized APOE (hAPOE) mouse model, we investigated whether a well‐documented preclinical AD symptom, inexplicable weight loss, was evident in our hAPOE mouse colony. Further we determined whether this hallmark symptom could be used to detect subpopulations of vulnerable vs resilient.MethodWe used an autoregressive hidden Markov model (AHMM) to identify trajectories of JAX humanized APOE mice based on their longitudinal weight data. We assumed 10 hidden states to estimate proper trajectories. We ran 10 AHMM models to ensure stability and each model was run with 1500 iterations to reach convergence. The AHMM with maximum trace value was selected as the main model. The key trajectories were then identified by clustering together mice ending in the same hidden state. Weight data were collected from November 2018 to September 2021 for 1196 hAPOE mice (652M, 544F) at different time points ranging from 5 to 28 months of age. Genotypes included APOEe3/3, APOEe3/4 and APOEe4/4.ResultAHMM results identified 5 main weight trajectories for mice ending in one of the 5 most probable ending states (formally named A,B,C,D,E). Of these, three states (A,B,D) captured weight loss trajectories for 426 (36%) mice, one state (C) was characterized by an increase in weight for 152 (36%) mice and 403 (13%) mice ending in a state stable (E) with no significant weight loss or increase. Weight loss was more apparent in female mice, while weight increase was more typical of male mice.ConclusionThis mouse cohort displays weight loss that may correspond to individuals exhibiting a hallmark inexplicable weight loss starting around 15/20 months (corresponding to human 50/55 years old) that can be symptomatic of the prodromal phase of AD.AcknowledgementsThis work was supported R01AG057931, RF1AG059093 and the Center for Innovation in Brain Science to RDB.
Allopregnanolone as a Regenerative Therapeutic for Alzheimer’s Disease: Phase 2 proof‐of‐concept clinical trial using hippocampal volume as a surrogate endpoint
Authors: Hernandez Gerson D , Lopez Claudia M , Raikes Adam C. , Rodgers Kathleen E. , Matthews Dawn C , Cutter Gary R , Schneider Lon S. , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundGiven that hippocampal volume is a well‐established imaging biomarker predictive of cognitive decline although not itself a measure of cognition, we propose its use as a surrogate endpoint to test the efficacy of allopregnanolone as a regenerative therapeutic for mild AD.MethodPhase 2 multi‐center, double‐blind, parallel‐group, randomized‐controlled clinical trial. A total of 20 sites will recruit 200 participants with mild AD, 100 participants per treatment arm. Eligible participants are male or female, age 55 to 80 years old, diagnosed with probable AD, with a MMSE between 20‐26 and APOE ε4 genotype (3/4 and 4/4). Participants will be randomized to 4 mg Allo (administered intravenously over 30 minutes, once per week) or matching placebo, 1:1 allocation, for a 12‐month period. After 12 months, all participants in the placebo group will be crossed‐over to receive Allo for the remainder of the study (6 month open‐label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months. A critical component of this trial is that all imaging sites participating in the trial are capable of performing both basic and advanced MRI sequences required in the protocol.ResultPrimary Endpoint is Mean rate of change in hippocampal volume at 12 months. Secondary Endpoints include mean rate of change in cognitive outcomes (CANTAB‐PAL, ADAS‐Cog11), functional outcomes (ADCS‐iADL) and safety outcomes at 12 months. Exploratory endpoints include other imaging outcomes (regional brain volumes, white matter fiber tract diffusion measures as determined by DTI, average intrinsic connectivity as determined by resting state fMRI, and cerebral region cerebral blood flow); blood‐based biomarkers of target engagement; other cognitive and functional outcomes (CDR‐SB score, ADAS‐Cog14 score, MMSE score, NPI‐Q score, EuroQol 5‐Dimension / 5‐Level (EQ‐5D‐5L) health‐related quality of life scale scores, QoL‐AD score, Zarit Burden Interview Questionnaire score at 12 and 18 months. Additionally, change from baseline to 6, 12 and 18 months in open‐label treatment participants switching from placebo to Allo at 12 months in the above endpoints.ConclusionResults from this study will validate previous findings indicating that allopregnanolone may exert both regenerative and neuroprotective effects on structure and connectivity in the Alzheimer’s brain.
The Association of Pain and Dementia among Mexicans aged 50 and older from 2001 to 2018
Authors: Milani Sadaf Arefi , Samper‐Ternent Rafael , Downer Brian 
Published: December 2022

AbstractBackgroundFindings on pain and dementia are mixed. While some studies document an increased odds of dementia among those with pain, others have found that pain that limits a person’s ability to do daily activities (i.e., pain interference) is a stronger risk factor for dementia, rather than pain presence or severity.MethodWe used data from five waves of the Mexican Health and Aging Study (2001 to 2018), a nationally representative survey of Mexican adults aged 50+. Pain and dementia status were measured at each wave. Pain was defined as frequent pain (yes/no), pain severity (none, mild, moderate, severe), and pain interference (none/non‐interfering, interfering), defined as pain that limits daily activities. Dementia was defined as impairment on two or more cognitive domains and limitation with one or more instrumental activities of daily living. Multilevel mixed logistic regression was used to model the association between pain and dementia among those without dementia at baseline, adjusting for sociodemographic and health characteristics.ResultsOur analytic sample (n = 10,819) was 54.4% female with a mean age of 61.6 [standard deviation (SD): 9.1]. At baseline, 40.5% of participants reported frequent pain, 11.6% reported mild pain, 16.8% reported moderate pain, 10.1% reported severe pain, and 18.4% reported pain interference. The proportion of participants with dementia ranged from 3.5% in 2003 to 12.9% in 2018. Those with frequent pain had higher odds of dementia [odds ratio (OR): 1.59; 95% confidence interval (CI): 1.21, 2.09], compared to those without. Compared to those with no pain, those with moderate (OR: 1.45; 95% CI: 1.04, 2.02) or severe (OR: 2.26; 95% CI: 1.55, 3.29) pain had higher odds of dementia. Those with pain interference had higher odds of dementia (OR: 2.35; 95% CI: 1.77, 3.11) compared to those without.ConclusionIn our sample of community‐dwelling Mexicans, we found that those with frequent, moderate, and severe pain, as well as pain interference had higher odds of dementia, compared to those without pain. Further work is needed to establish the temporality of the pain and dementia relationship. This is particularly needed in Mexico, where many individuals requiring pain relief have their needs unmet.
APOE4 copy number‐dependent Complement Pathway Dysregulation
Authors: Berger Miles , Morshed Nader , Stevens Beth 
Published: December 2022

AbstractBackgroundComplement has been implicated in the pathophysiology of AD based on human genetic studies, human post‐mortem pathology, and mouse genetic studies. However, the relationship between complement activation and other AD risk factors (such as the APOE4 allele) remains unclear.MethodWe used pathway analysis of the ADNI targeted proteomics dataset to identify protein clusters highly correlated with each other, including a complement pathway cluster. We then developed a hybrid proteomics platform, which allows for both discovery proteomics (via LC‐MS/MS) and precise quantitation of complement protein‐derived peptides via Stable Isotope Labelled (SIL) internal control peptides for the complement proteins. We then tested this hybrid proteomics platform on over 130 CSF samples from cognitively normal older adults (ages 60‐80), together with assays for CSF amyloid beta, tau and p‐tau‐181p. Spearman correlation tests were used to evaluate correlations between protein pathway expression and demographic variables, such as APOE4 allele number.ResultPathway analysis of the ADNI targeted proteomics dataset identified a cluster of complement proteins whose levels were highly correlated with each other in the CSF; this cluster included peptides from C1QB, C2, C3, C4A, C5, C6, C8B and CRP and several additional proteins. Across ∼300 individuals (including cognitively normal controls, MCI and AD patients), expression of this complement protein cluster was inversely correlated with APOE4 allele count and gender (with lower expression in females), and a positive correlation with age (P<0.05 for each). To further study complement protein levels in human CSF across the AD spectrum, we developed a hybrid proteomics platform for precise quantitation of complement proteins and for unbiased discovery proteomics. In 130 CSF samples from older adults, we were able to detect ∼9,000 different peptides from 884 different proteins, and to precisely quantitate all proteins in the classical, alternative and mannose binding lectin complement pathways using the SIL peptide internal controls. Here we report data on APOE4 copy number dependent changes in quantified CSF complement protein levels, and on APOE4 dependent changes across the human CSF proteome.ConclusionAPOE4 is associated with a reduction in CSF complement protein levels, which may reflect increased complement pathway activation and ensuing degradation of these proteins.
Trusted Partnerships in the Faith Community Facilitate Awareness and Recruitment of African Americans for Alzheimer’s Disease Studies
Authors: Williams Kelvin , Henderson Shelby , Lloyd Shawnta' , Caban‐Holt Allison M , Starks Takiyah D. , Martin Patrick McPhail , Bozoki Andrea C. , Price Stephen Russ , Plassman Brenda L , Welsh‐Bohmer Kathleen A. , Byrd Goldie S. 
Published: December 2022

AbstractBackgroundHistorical mistrust in medical systems has resulted in low Alzheimer’s disease (AD) research participation among African Americans (AA). However, the faith community remains a trusted institution among many AAs and can be a major facilitator for increasing AA AD awareness and research. To better understand the health needs of AAs and build relationships with faith organizations in the Triad area of North Carolina, we conducted a community needs assessment (CNA) among local faith leaders.MethodA mixed‐methods CNA was conducted. Quantitative data was collected from 44 pastors of AA churches via surveys that assessed resources, church demographics, and health topics of concern. Descriptive statistics were conducted for survey data. Qualitative data was collected during “listening tours” among pastors, with specific emphases on healthy aging, trust in medical systems, and research perceptions. Data from “listening tours” were analyzed using thematic analysis.ResultOur CNA indicated that AD was a common health topic of concern among pastors and their congregations. This is likely influenced by the composition of the churches, given that more than half of the pastors reported that at least 30% of their congregation was 65 years of age or older. During 2021, collaborations between MACHE and faith leaders produced 3 webinars, 13 food distributions, and 4 community outreach events. Over 40,000 people were provided AD and brain health education; 1,961 community members expressed interest in AD research opportunities; and 580 AAs enrolled in the NC Registry for Brain Health over an 8‐month period in 2021, during the COVID‐19 pandemic.ConclusionThrough a 3‐year partnership, the TPN and MACHE have significantly increased brain health awareness and AA participation in AD research through grassroots community engagement and outreach. Investments in trusting and sustained partnerships between an academic institution and faith communities demonstrated efficacy in increasing opportunities for providing service, access to research, and health education opportunities to communities that are typically underrepresented in research.
Socioeconomic Status Moderates the Effect of Inflammation on Whiter Matter Hyperintensity Burden and Neurodegeneration in Hispanic Older Adults: A Healthy Aging Brain Study‐Health Disparities
Authors: Clark Alexandra L , Haley Andreana , Evangelista Nicole D. , Ortega Nazareth , Dekhtyar Maria , Foret Janelle T 
Published: December 2022

AbstractBackgroundHispanic/Latino (H/L) older adults are at increased risk for AD, demonstrate an earlier age of dementia onset, and are more likely to experience delays in AD diagnosis and treatment relative to Non‐Hispanic Whites. These racial/ethnic disparities are the consequence of structural inequities and socioeconomic disadvantages (e.g., income, education) that disproportionately affect H/Ls and promote pathologic inflammatory cascades. Although low socioeconomic status (SES) and inflammation have independently been linked to poor cognitive outcomes, their effects on neural markers of brain health in older adults have yet to be fully examined. Therefore, the present study examined the independent and interactive effects of inflammation and SES on brain markers of neurodegeneration in Hispanic older adults.MethodData from 524 H/L (428 = cognitively normal; 105 = mild cognitive impairment) older adults enrolled in the Health Aging Brain Study‐Health Disparities were included. Z‐scores for income and years of education were averaged to estimate SES. A principal component analysis was used to create a composite measure of inflammation from serum markers (IL‐6, TNFα). MRI brain scans characterized intracranial volume, white matter hyperintensity (WMH) burden, and neurodegeneration of an AD‐signature meta‐ROI. Multiple linear regressions were used to examine (1) the independent effects of inflammation and SES and (2) inflammation x SES interactions on brain MRI markers.ResultRegression analyses controlling for age, intracranial volume, sex, and vascular risk revealed that inflammation and SES were not significantly associated with WMH burden (ps >.15) or neurodegeneration (ps >.35). However, results revealed significant SES x inflammation interactions on WMH (p = .02) and neurodegeneration (p = .004); examination of simple main effects revealed that inflammation was associated with higher WMH burden and neurodegeneration in individuals from a lower SES, but not in those from a higher SES.ConclusionInflammation negatively impacts brain health in H/Ls from a low SES. Results suggest that inflammation is a potentially modifiable point of prevention and intervention underlying poor brain health in H/L older adults from a lower SES. Importantly, results provide a foundation for further characterization of the contributions of systemic racism and barriers to brain health equity in minoritized and marginalized community members.
White Matter Correlates of Spoken Discourse in Cerebrovascular Disease
Authors: Broberg Dana N , Haddad Seyyed Mohammad Hassan , Aveni Katharine , Havens Alexander , Orange Joseph B , McLaughlin Paula , Binns Malcolm , Roberts Angela C , Bartha Robert ,   ONDRI Investigators
Published: December 2022

AbstractBackgroundSpoken discourse (language beyond single words or sentences) performance can be used to detect cognitive impairment in cerebrovascular disease (CVD) [Roberts A, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and indicators of white matter microstructural integrity provided by diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered spoken discourse.MethodSpoken discourse and 3T DTI data (30‐32 directions, b=1000) were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n=133). Spoken discourse analyses were completed previously [Roberts, 2021]. A DTI analysis pipeline [Hassan SMH, et al. (2019) PLoS One 14(12):e0226715] was used to generate brain maps of fractional anisotropy (FA) and mean diffusivity (MD) and calculate mean FA and MD values for the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculi (UNC) in each hemisphere. Canonical correlation analyses examined associations between DTI metrics and 10 spoken discourse measures separately for FA in left hemisphere, MD in left hemisphere, FA in right hemisphere, MD in right hemisphere.ResultCanonical correlations were significant in the left hemisphere (FA: r=0.47, p<0.05; MD: r=0.51, p<0.01) but not the right (FA: r=0.34, p=0.90; MD: r=0.40, p=0.15)(Figure 1). Among the white matter tracts, the strongest canonical loadings were seen for the SLFp (FA: 0.81; MD: ‐0.59) and SLFt (FA: 0.71; MD: ‐0.40) compared to the ILF (FA: 0.44; MD: 0.03) and UNC (FA: ‐0.34; MD: 0.10). Higher FA in the SLFp and SLFt was associated with better performance on measures of fluency and information content. Lower MD in these tracts was associated with better performance on measures of fluency, information content, and syntax.ConclusionSpoken discourse performance was associated with white matter microstructural integrity in the left hemisphere of the brain. Of the white matter tracts investigated in this study, impaired spoken discourse performance in CVD was most strongly linked to altered tissue microstructure in the parietal and temporal endings of the superior longitudinal fasciculus.