bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations Between Brain Structure and Dual Decline in Gait and Cognition
Authors: Karunarathna Sadhani , Breslin Monique , Alty Jane E , Beare Richard , Collyer Taya , Srikanth Velandai K , McDonald Scott , Callisaya Michele L 
Published: January 2025

AbstractBackgroundDual decline in gait and cognition is associated with an increased risk of dementia, with combined gait and memory decline exhibiting the strongest association. However, little is known about the underlying brain correlates. Therefore, we aimed to examine the associations between measures of brain structure and dual decline in gait and cognition across several cognitive domains.MethodParticipants over 60 years were randomly selected from the electoral roll into the Tasmanian Study of Cognition and Gait. We used baseline MRI and three serial gait speed and cognitive assessments (memory, processing speed‐attention, verbal fluency) performed on average 2.5 years apart. Participants were classified into four groups depending on tertiles of annual decline in gait speed and each cognitive measure (non‐decliners, gait‐only decliners, cognition‐only decliners, and dual‐decliners). Dual decliners were defined as the participants belonging to the highest tertile of annual decline in both gait speed and each of the cognitive measures. Multinomial logistic regression was used to examine the associations of baseline brain volumes (gray matter, white matter, and hippocampal) and cerebral small vessel disease (white matter hyperintensities, subcortical infarcts, enlarged perivascular spaces, and microbleeds) with dual gait and cognitive decline for each cognitive domain.ResultThe mean age of participants was 70.9 ± SD 6.7 years (n = 267). Lower baseline gray and white matter volume and higher white matter hyperintensity volume increased the risk of being a dual decliner in gait and both the memory and processing speed‐attention groups (all p < 0.05). Lower hippocampal volume (p = 0.047) was only associated with increased risk of being a dual decliner in the gait and memory group. No significant associations were found between MRI measures and the gait and verbal fluency dual decliners.ConclusionNeurodegenerative pathology and white matter hyperintensities are involved in dual decline in gait and both memory and processing speed‐attention domains. Smaller hippocampal volume may also contribute to dual decline in gait and memory, but not dual decline in gait and other cognitive domains.
Correlations of antemortem [18F]MK‐6240 PET with ROI‐matched postmortem biochemical assessment of total tau and tau phospho‐epitopes pThr181, pSer199, pThr231, and pSer396
Authors: Betthauser Tobey J. , Abrahamson Eric E , Chavez Elena Ruiz De , Teague Jordan P , McVea Andrew K , Deming Yuetiva , Schroeder Brooke E , Barger Madeleine R , Johnson Sterling C. , Asthana Sanjay , Villemagne Victor L , Christian Bradley T. , Salamat Shahriar , Ikonomovic Milos D 
Published: January 2025

AbstractBackground[18F]MK‐6240 was developed for PET imaging of AD tau pathology, but the exact molecular signature of specific binding remains unclear. This study quantified levels of four phospho‐tau forms and total tau in postmortem brain tissues from [18F]MK‐6240 imaged cases to investigate associations with antemortem [18F]MK‐6240 PET.MethodsThis study included four participants from the Wisconsin ADRC or WRAP with antemortem [18F]MK‐6240 and [11C]PiB PET imaging and postmortem brain tissue obtained on average 32‐months after imaging (Table 1). Parametric SUVR were generated using T1‐w MRI to delineate regions matched to equivalent ROIs on fresh frozen brain tissue slabs. Tissue ROI dissected from ten brain regions per case were homogenized and ELISA was used to quantify concentrations of guanidine‐extracted total tau and tau phosphorylated at epitopes pThr181, pSer199, pThr231, and pSer396.ResultsMatched PET‐autopsy ROI analysis showed significant correlations of higher [18F]MK‐6240 SUVR with higher levels of all measured p‐tau forms or their ratios to total tau across all regions and cases. Analyses of two A+T+ cases with clinical AD dementia and postmortem Thal Phase 5/Braak NFT Stage VI showed higher [18F]MK‐6240 SUVR correlated significantly with higher levels of pThr181, pSer199, pThr231, and pSer396 tau or their ratios to total tau in a 79‐yo APOE‐ε4ε4 case, and with higher levels of pThr231 and pSer396 tau in a 78‐yo APOE‐ε3ε3 case. In two T‐ cases, we observed weak correlations of [18F]MK‐6240 SUVR with pThr181 and pSer396 tau in an A‐T‐ cognitively unimpaired case (Thal Phase 2/Braak NFT Stage II; 70‐yo; APOE‐ε3ε3), but no correlations in A+T‐ early‐onset AD dementia case with Thal Phase 4/Braak NFT Stage V (63‐yo; APOE‐ε4ε4). This latter case also had high [18F]MK‐6240 uptake outside the brain and a low tangle density outside the MTL.ConclusionsHigher [18F]MK‐6240 PET binding reflects high brain concentrations of pThr181, pSer199, pThr231, and pSer396 tau in AD dementia cases with high AD neuropathological change. Lack of associations between PET and p‐tau biochemistry in the T‐, Braak V early‐onset dementia case suggests that the T‐ PET status is more closely associated with p‐tau biochemistry than postmortem neuropathological staging, likely due to low tangle density.
An Ethnographic Analysis of The Black and African American Adult Male Perspective on Alzheimer’s Disease and the Social Determinants of Health
Authors: Williams Lilcelia A. , Lingler Jennifer H , Terry Melita H 
Published: January 2025

AbstractBackgroundBlack and African American adult males have the worst overall health than any other race or gender in the United States. The rate of Alzheimer’s Disease is twice as high for Black and African American adults. Yet, little is known about how Black and African American adult males perceive the relationship between the social determinants of health and Alzheimer’s Disease.MethodWe conducted a secondary analysis of ethnographic interview data from ten Black and African American adult male participants at an NIA‐funded Alzheimer’s Disease Research Center. Participants included both patients (n = 6) and study partners (n = 4) who were purposively sampled to ensure that a range of perspectives were represented in the parent study, Recruitment Innovations for Diversity Enhancement (RIDE) in Alzheimer’s Disease Research. Chronological age and education were self‐reported. For the present analysis, transcripts from semi‐structured participant interviews were first examined to organize the data within categories informed the Social Determinants of Health Model. Data within each social determinant of health category were then analyzed to identify themes and explore potential relationships within the data.ResultAll participants identified as male with a mean age of 75 (SD±13); 90% reported two or more years of post‐secondary education and 100% spontaneously mentioned elements of social determinants of health in response to questions about their experiences with dementia and motivations for participation in Alzheimer’s Disease research. A relationship between Alzheimer’s Disease and the social determinants of health was demonstrated by the study participants’ endorsement in across all domains. Locus of control, perception is reality, mistrust and othering are the thematic codes that consistently emerged from both the patient and caregiver interviews. The importance of having shared social characteristics (e.g., race) with clinicians, providers and staff members was a recurrent theme among the participants.ConclusionDespite the shared social characteristics of race and gender among the study participants, their perception of the relationship between Alzheimer’s disease and the social determinants of health was not monolithic. Findings support the need for additional research to examine the perceptions and lived experiences of Black and African American adult males as it relates to Alzheimer’s Disease.
Central Autonomic Dysfunction and Plasma Ab42/40
Authors: Lohman Trevor , Kapoor Arunima , Engstrom Allison C , Shenasa Fatemah , Nguyen Amy , Alitin John Paul M , Gaubert Aimée , Rodgers Kathleen E. , Bradford David , Mather Mara , Han Duke , Head Elizabeth , Thayer Julian F , Nation Daniel A. 
Published: January 2025

AbstractBackgroundHigher order regulation of autonomic function is maintained by cortical and subcortical interconnected regions within the brain, collectively referred to as the central autonomic network (CAN) (Benarroch, 1993). Despite the well‐established relationship between autonomic dysfunction and AD (Femminella et al., 2014) the relationship between CAN functional connectivity and biomarkers of AD, such as Ab42/40 ratio, remains unexplored.Methods76 independently living older adults were recruited from the community to undergo brain fMRI and venipuncture. Study exclusions were history of clinical stroke, dementia, major neurological or psychiatric disorder, current organ failure or other uncontrolled systemic illness. Resting state fMRI data were acquired and analyzed to quantify CAN functional connectivity from 3 previously described CAN networks with the CONN Functional Toolbox (Nieto‐Castanon, 2020). Default mode network connectivity was also included for analysis as a negative control. Plasma Aβ40 and Aβ42 concentrations were obtained by digital immunoassay with the Simoa Neurology 3‐Plex A (N3PA) Advantage Kit (Quanterix). Vascular risk factors were evaluated through interviews with the participant and informant, and included history of cardiovascular disease, hypertension, hyperlipidemia, type 2 diabetes, atrial fibrillation, and transient ischemic attack. The relationship between CAN functional connectivity and plasma Ab42/40 ratio was compared using linear regression adjusting for demographic covariates and vascular risk factor burden.ResultsCAN functional connectivity was positively associated with Ab42/40 for all three CAN models (CAN A (Beissner et al., 2013) P= .0001; CAN B (Monroe et al., 2020) P= .018; CAN C (Riganello et al., 2018) P= .006), and remained so after adjustment for age, sex, and vascular risk factor burden. Default mode network connectivity was not significantly associated with Ab42/40 (Figure 1).ConclusionOlder adults with decreased central autonomic network connectivity exhibit lower plasma Ab42/40, indicating greater cerebral Ab1‐42 retention. This correlation could not be accounted for by age, sex, or vascular risk factor burden, suggesting a direct relationship between central autonomic function and cerebral amyloidosis. Further studies should explore the implications of CAN dysfunction for autonomic changes during the early stages of AD pathophysiology.
Alzheimer’s disease as a primary pathology in logopenic variant of primary progressive aphasia
Authors: Nevzorova Kseniya , Shpilyukova Yuliya , Akhmadullina Diliara , Shabalina Alla , Fedotova Ekaterina 
Published: January 2025

AbstractBackgroundThe logopenic variant of primary progressive aphasia (lvPPA) is a disorder centered on language impairment. Alzheimer Disease (AD) is one of the most common underlying pathologies in lvPPA. The aim of our study was to estimate frequency of AD in this phenotype and to analyze clinical features of AD‐lvPPA.MethodWe examined 20 patients (9 females and 11 males, 65.9±9.1 years) with the phenotype of lvPPA. The diagnosis was determined on clinical and imaging data according to the lvPPA criteria (Gorno‐Tempini et al., 2011). All patients underwent lumbar puncture. CSF biomarkers Abeta‐42 and p‐tau181 were analyzed. Based on the laboratory results and according to the recommendations of International Working Group (2021) we found 4 patients with established AD, 8 patients with probable AD and 8 non‐AD patients. Then we compared 2 groups (AD and non‐AD) on age of onset and cognitive features, assessed by Addenbrooke’s cognitive examination (ACE‐R) and Frontal Assessment Battery (FAB).ResultThe frequency of AD pathology in lvPPA group was 60% (20% for established diagnosis and 40% ‐ for probable). The disease onset was earlier in the group of AD lvPPA than in the non‐AD group (60.1 years vs. 65.4 years), but the difference was not statistically significant (p=0.175). We didn’t find significant differences between the groups in FAB, total ACE‐R. We revealed a higher median score in the speech ACE‐R subscale (18.5 vs. 14.5) and lower median score in the memory ACE‐R subscale (10.5 vs. 14.5) in patients with established AD group compared to non‐AD group.ConclusionIn our study we demonstrated a high prevalence of AD pathology in lvPPA. The results showed no specific differences, but some clinical findings may predict AD on pre‐laboratory stage (such as more severe memory impairment and less speech impairment). So, it is important to analyze AD biomarkers in CSF in all cases to establish underlying pathology and to prescribe specific treatment.The study was supported by RSF (#23‐25‐00483)
Brain structural changes in rural communities and disadvantaged neighborhoods: preliminary exploration in older adults from Southern Nevada
Authors: Zhuang Xiaowei , Cordes Dietmar , Caldwell Jessica ZK , Bender Andrew R. , Miller Justin B 
Published: January 2025

AbstractBackgroundRural‐dwelling older adults are at increased risk for Alzheimer’s disease (AD) and related dementia. Identifying how rural living and neighborhood disadvantage affect neurobiology may help to understand rural‐urban disparities in AD and promote healthy aging in rural communities. In this study, we characterize rural‐urban differences in cortical thickness (CT), and the association of regional CT with neighborhood disadvantage, using both clinically normal and impaired older adults.MethodWe assessed cross‐sectional data from 71 rural‐dwelling (61.97% women, 71.13±6.45 years old) and 87 urban‐dwelling (43.67% women, 72.16±6.88 years old) older adults from the Nevada Exploratory Alzheimer’s Disease Research Center and the Nevada Center for Neurodegeneration and Translational Neuroscience. The Rural‐Urban Commuting Area (RUCA) Codes score was used to determine rural‐urban residency status, and the Area Deprivation Index (ADI) was used to characterize neighborhood disadvantage. Clinical impairment status was determined by expert consensus review, and FreeSurfer‐derived CT measures were calculated from 3T structural magnetic resonance images (MRI). Analysis of covariance was used to test whether each CT measure was associated with rural‐urban living, clinical impairment status, or their interactions. Linear regressions were fitted to test the association between CT measures and ADI in clinically normal and impaired participants.ResultFor temporal and inferior frontal regions, rural‐dwelling older adults demonstrated a thinner cortex than urban older adults, and these rural‐urban differences were more pronounced in clinically normal than impaired participants. Cortical thinning of temporal regions was further correlated with advanced neighborhood disadvantages. In contrast, for superior frontal, parietal and occipital regions, rural participants showed thicker cortex than urban participants and these differences were greater in clinically impaired participants.ConclusionsWe observed extensive rural‐urban differences on CT measures with mixed directions, suggesting a complex interplay between community contexts and neurobiology in clinically normal and impaired older adults. More importantly, for regions involved in memory that are vulnerable to AD, our results suggest that living in rural areas and less advantaged neighborhoods might negatively affect subjects’ brain structures; but once clinical impairment onsets, impairment effect on these neurobiological measures tend be more dominant than the residency effect.
Genetic and Epigenetic Signatures for Cognitive Resilience in Neuropathologically Defined Alzheimer’s Disease Brains
Authors: Han Xudong , Li Donghe , Goldstein Daniel , Sahelijo Nathan J , Farrer Lindsay A. , Stein Thor D. , Mez Jesse , Jun Gyungah R 
Published: January 2025

AbstractBackgroundNot all people with neuropathological evidence of Alzheimer’s disease (AD) manifest clinical symptoms in life (cognitive resilience). We aimed to identify genetic and epigenetic signatures of cognitive resilience, utilizing data from brain donors with neuropathological evidence of AD who were either symptomatic or asymptomatic in life.MethodAmong brain donors with neuropathologically‐confirmed AD (364 asymptomatic/cognitively resilient and 490 symptomatic) from the Boston University AD Research Center, Framingham Heart Study—where we generated our own data—as well as the Religious Orders Study and Rush Memory and Aging Project, we utilized genome‐wide genetic array data, genome‐wide DNA methylation array data and RNA sequencing data. We conducted a genome‐wide association study (GWAS) and a methylation‐wide association study (MWAS) in each dataset and meta‐analyzed. Relationships between top‐ranked CpG sites, SNPs, and expression levels of the selected genes/isoforms were further evaluated.ResultMeta‐analysis of genome‐wide significant MWAS results revealed 3 CpG sites from 3 genes, ARHGAP22, UBAC2, and KANSL1 (top‐ranked= cg19832721: Log2 fold change [Log2FC]=‐0.12, P=2.5x10‐8). Meta‐analysis of GWAS findings identified significant ((P<1x10‐5) associations with 9 single nucleotide polymorphisms (SNPs) located in 9 different loci including APOE (top‐ranked=rs6917901 in TNFAIP3: odds ratio [OR]=0.53, 95% confidence interval [CI]=0.41‐0.67, P=3.8x10‐7). Expression of KANSL1 and its isoform ENST00000638269 were increased in symptomatic compared with cognitive resilient AD subjects (gene: Log2FC=0.082, P=5.95x10‐6; isoform: Log2FC=0.325, P=5.95x10‐4). The methylation level of cg19832721 was negatively correlated with expression of the KANSL1 isoform (Beta=‐27.13, P=0.002) but not with the gene (P>0.05). SNP rs4586175 located in the ROBO3‐ROBO4 locus was significantly associated with symptomatic AD (OR=0.58, CI=0.45‐0.74, P=9.89x10‐6) and increased expression of the ROBO3 isoform ENST00000543966 (Beta=2.72, P=0.03). A CpG site cg08770647 located 773 bp from rs4586175 was nominally associated with symptomatic AD (Log2FC=0.06, P=1.52x10‐4) and its methylation level was correlated with increased expression of the ROBO3 isoform (Beta=83.26, P=0.01).ConclusionOur study suggests that interactions between genetic and epigenetic signatures contribute to cognitive resilience in persons with pathologically confirmed AD. Our findings also provide insight about genetic mechanisms that could be targeted to retard or prevent onset of AD clinical symptoms.
Cross‐Cultural Adaptation of the Pool Activity Level (PAL) Checklist: From UK English to U.S. English for Enhanced Dementia Care
Authors: Gholizadeh Shadi , Sudberry Liz , Popolizio Elizabeth M. , Merz Erin L , Daniels Damaris , Pool Jackie 
Published: January 2025

AbstractBackgroundAn important aspect of quality of life is engagement in meaningful and purposeful activities. For people living with dementia (PLwD), opportunities to engage in purposeful activities can be vastly diminished. Successful engagement of individuals with dementia typically hinges upon selecting engagement targets and activities that are appropriate to the individual’s level of cognitive functioning. The Pool Activity Levels (PAL) Checklist, a strength‐based, person‐centered 9‐item checklist tool for nonclinical caregivers to assess cognitive, physical, and sensory abilities in PLwD in order to guide activity planning and engagement strategies, was originally developed in British English. The increasing use of the measure in the United States necessitates a translation into American English to ensure cultural and linguistic appropriateness. Back translation (BT) is a commonly‐used methodology of questionnaire translation. However, several problems with BT have been highlighted, including its reliance on perfect equivalence and prioritization of literal translation over conceptual and cultural equivalence. Alternatives to BT include engaging professionals with expertise in translation and the subject matter to translate the assessment and to then submit the translation to a review by an expert panel and field test or using an iterative, team based approach that involves translation, review, evaluation, pretesting, and documentation.MethodAdopting a multidisciplinary approach, the PAL Checklist was translated from British to U.S. English. This process involved a team of professionals, including collaboration with the original author of the PAL, from various U.S. regions with expertise in care planning and assessment. The translation methodology aligned with the ISPOR Quality of Life Special Interest Group guidelines, incorporating steps like forward translation, reconciliation, back translation, cognitive debriefing, and finalization.ResultThe translation retained the original checklist’s conceptual integrity while adapting linguistic differences, such as “flannel” to “washcloth/sponge” and “cupboards” to “drawers/closet.”ConclusionThis preliminary translation of the PAL into U.S. English lays the groundwork for future research to assess its psychometric properties in American settings. Future research will focus on extensive validation to meet psychometric criteria (e.g., internal consistency reliability, structural validity), ensuring its efficacy and reliability in the United States.
Evaluating the impact of empathy loss on caregiver burden in behavioral variant Frontotemporal degeneration (bvFTD)
Authors: Fisher Lauren , Cousins Katheryn A Q , Rhodes Emma , Irwin David J , Massimo Lauren 
Published: January 2025

AbstractBackgroundBehavioral variant Frontotemporal Degeneration (bvFTD) is a common form of early onset dementia characterized by prominent behavioral change, including loss of empathy. Research has demonstrated that caregivers of persons living with bvFTD (PLwFTD) are more burdened, stressed, and depressed than other dementia caregivers, and that empathy loss may contribute to this high level of burden. However, it remains unclear if empathy loss contributes to caregiver burden above and beyond other neuropsychiatric symptoms. Understanding the contribution of empathy loss in the PLwFTD to caregiver burden is important for supporting caregivers. The purpose of this study is to evaluate the impact of empathy loss on caregiver burden in the context of other common neuropsychiatric symptoms.MethodsParticipants included 111 caregivers to PLwFTD who were enrolled in research at the University of Pennsylvania Frontotemporal Degeneration Center and completed caregiver questionnaires that assess cognitive and emotional empathy (Interpersonal Reactivity Index [IRI]– Perspective Taking (PT) and Empathic Concern (EC) subscales, respectively), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), dementia severity (Clinical Dementia Rating Scale global score [CDR]), and caregiver burden (Zarit Burden Inventory [NPI]). Linear regressions were performed to evaluate the relationship between IRI subscales and caregiver burden, adjusting for dementia severity and NPI total score.ResultsFor PLwFTD (n = 111), mean age was 62.8 (SD = 8.74) and predominantly white, non‐Hispanic (94.6%, 99.1% respectively), and male (59.5%). Caregiver reports of lower EC (β = ‐0.80, 95% CI: ‐0.6227806 to 0.4829205, p< 0.001) and PT (β = ‐1.29, 95% CI: ‐1.8700469 to ‐0.5882883, p<0.001) were associated with increased caregiver burden. After covarying for other neuropsychiatric symptoms (NPI total score: β = 2.28, 95% CI: 1.2032696 to 3.3532612, p<.001) and dementia severity (CDR: p = 0.25), decreased PT remained significantly associated with increasing caregiver burden (β = ‐0.77, 95% CI: ‐1.4041703 to ‐0.1321910, p<0.05), but EC was no longer significant (p = 0.57).ConclusionsEmpathy loss is a common behavioral symptom in PLwFTD that contributes to caregiver burden, even after accounting for other neuropsychiatric symptoms. In particular, we found that cognitive empathy or the inability of PLwFTD to understand their caregiver’s viewpoint is a major source of burden. These findings can inform interventions to support caregivers of PLwFTD.