bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal subfield volumes and memory performances: associations with stimulus modality and free recall or recognition
Authors: Aumont Etienne , Bussy Aurelie , Bezgin Gleb , Therriault Joseph , Savard Melissa , Arias Jaime Fernandez , Poltronetti Nina Margherita , Pallen Vanessa , Thomas Emilie , Vitali Paolo , Chakravarty Mallar , Bedard Marc‐Andre , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundAge‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual memory tasks in older adults without dementia.MethodWe selected 97 right‐handed participants without dementia aged 60 to 85, 42 males, from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. From T2‐weighted MRIs with 0.7*0.7*1mm voxel size, the hippocampi were segmented five subfields: 1) DG (DG); 2) CA2 with CA3 (CA2/CA3); 3) CA1; 4) strata radiatum, lacunosum and moleculare (SRLM); and 5) subiculum by using the MAGeT‐Brain algorithm. Memory was assessed with Rey Auditory Learning test for verbal free recall (RAVLT7) and recognition (RAVLT‐R), and with Aggie Figure Learning test for visual free recall (AFLT7) and recognition (AFLT‐R). Linear models were used to test the association between hippocampal subfield volumes and memory performances with age, sex and total intracranial volume as covariates (p<0.05, corrected for false discovery rate).ResultThe volumes of bilateral CA1 and SRLM were significantly associated with RAVLT7 and RAVLT‐R. The right DG volume was significantly associated with AFLT7 and RAVLT7. AFLT7 was also associated with the volume of right CA2/CA3 while AFLT‐R was not associated with any hippocampal subfield (see Figures 1 & 2).ConclusionOur results are consistent with the view that hippocampal subfields contribute differently to memory traces: CA1 for recollection that requires contextual information; the DG for pattern separation (creating new distinct representations of each stimulus); and CA3 for pattern completion (the recollection of a stimulus from a partial memory). Contextual information is more important when recollecting known words, while distinct and efficient encoding may be especially useful for search strategies inherent to free recall. Pattern completion could be particularly useful to efficiently recollect visual abstract figures based on visual features during free recall. Overall, this shows that hippocampal subfield segmentation offers a better understanding of their distinctive roles in cognition.
Feasibility of comprehensive heart‐brain MRI for investigating hemodynamic coupling in aging
Authors: Jarvis Kelly , Martersteck Adam , Richter Adam , Moore Jackson E. , Sridhar Jaiashre , Aristova Maria , Jin Ning , Schnell Susanne , Russell Eric , Markl Michael , Ragin Ann , Rogalski Emily J 
Published: December 2023

AbstractBackgroundCardiovascular risk factors have been linked with dementia risk in aging adults. However, mechanisms underlying heart‐brain hemodynamic coupling and effects on the brain remain unclear. 4D flow MRI is uniquely poised to systematically evaluate complex hemodynamics along the heart‐brain pathway. Owing to advancements yielding shorter scan times, 4D flow MRI can be acquired in approximately 7 minutes (heart) and 10 minutes (brain). This supports practical add‐on of 4D flow MRI to neuroimaging scans for comprehensive heart‐brain MRI evaluation in under an hour. We aimed to build a heart‐brain MRI acquisition and analysis framework to study relationships between hemodynamics and brain structure with age.Method17 healthy participants (age = 53.5±16.3[24‐76] years) underwent heart‐brain MRI at 3T (MAGNETOM Prisma, Siemens, Erlangen, Germany), including a free‐breathing whole‐chest 4D flow MRI research sequence, intracranial dual‐venc 4D flow MRI research sequence, and T1‐ and T2‐weighted structural neuroimaging. Participants were cognitively healthy and screened for history of cardiovascular and cerebrovascular problems that may influence blood flow. 4D flow MRI was used to evaluate blood flow velocities in the aorta and Circle of Willis (Figure 1: left). Mean velocity was determined on a voxel‐wise basis over the entire cardiac cycle. Volumetric and cortical thickness analysis was performed with FreeSurfer (v7.3; Figure 1: right). Left and right hippocampal and amygdala volumes were averaged and corrected for intracranial head size. We examined relationships between hemodynamics, volume and thickness measures, and age using Pearson correlations and multiple regression.ResultMean aortic velocity was associated with age (r = ‐0.59, p = 0.012), hippocampal volume (r = 0.68, p = 0.003), amygdala volume (r = 0.59, p = 0.012), and inferior temporal thickness (r = 0.49, p = 0.044). Figure 2. Mean velocity in the Circle of Willis (r = ‐0.49, p = 0.048), amygdala volume (r = ‐0.66, p = 0.004) and inferior temporal thickness (r = ‐0.60, p = 0.010) were also associated with age. Using multiple regression, mean aortic velocity was associated with hippocampal volume (p = 0.018) adjusting for age.ConclusionThis study demonstrates capture of comprehensive heart and brain data in a single imaging exam for assessment of age‐related relationships in hemodynamics and brain structure. Heart‐brain MRI is a promising tool for evaluation of hemodynamic coupling along the entire heart‐brain pathway.
Grant support: NIH NIA P30AG059988, P30AG072977, K01AG080070; NINDS R21NS122511
ARKD‐104, A Potential Treatment of Frontotemporal Dementia and Other Neurodegenerative Disorders
Authors: Hung Serena W , Hurst Raymond S. , Blain Jean‐François , Holler Christopher J. , Chen Angela Y.P. , Brand Morgan A. , Alves Anna M , Astarita Giuseppe , Gallegos Richard , Greenberg Gennifer , Henry Shawna , Koenig Gerhard , McTighe Stephanie , Peng Xiaowen , Ross John , Thompson Bonne M , Watters Katherine , Wozniak Mary , Lanter James C. , Burnett Duane A. 
Published: December 2023

AbstractBackgroundHeterozygous mutations in the gene encoding progranulin (GRN) that lead to haploinsufficiency of the progranulin protein (PGRN) cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). A promising treatment approach for FTD‐GRN is to restore PGRN to levels detected in healthy individuals. In pursuit of this objective, Arkuda Therapeutics is developing brain‐penetrant, orally bioavailable small molecules that increase PGRN levels within the central nervous system (CNS).MethodA functional cell‐based assay was utilized to identify novel compounds that stimulate PGRN secretion from a murine microglial cell line. Compounds with good in vitro potency were further optimized through an iterative series of selectivity, ADME, pharmacokinetic (PK), safety and pharmacology assessments.ResultWhen applied to cells, ARKD‐104 increased PGRN and PSAP secretion and engaged lysosomal pathways as evidenced by intracellular changes in granulins, saposins, and lysosomal lipids including bis(monoacylglycero)phosphate (BMP). Oral administration of ARKD‐104 to cynomolgus monkeys resulted in a dose and exposure‐dependent increase in PGRN measured in cerebrospinal fluid (CSF). The exposure‐response relationship demonstrated that a systemic exposure of 8 nM ARKD‐104 in plasma (unbound) doubled the amount PGRN in CSF. PGRN levels were further increased to more than 4‐times pre‐dose levels at the highest tested dose. Elevation of PGRN levels was sustained with repeat dosing of ARKD‐104. ARKD‐104 was characterized for CNS drug‐like properties including PK, metabolism, brain penetration, selectivity, and safety. In these assessments, ARKD‐104 demonstrated a profile suggesting that beneficial increases in PGRN can be achieved with once daily oral dosing in human.ConclusionARKD‐104 has excellent CNS drug‐like properties, increases PGRN in the CNS of non‐human primates and increases important cofactors of lysosomal enzymes, . ARKD‐104 is therefore a promising candidate for continued development as a treatment for FTD‐GRN, Parkinson’s disease and other neurodegenerative disorders exhibiting lysosomal dysfunction.
Afternoons can be a critical time of the day that reflects associations between life‐space mobility and loneliness among living alone older adults: longitudinal analyses with motion sensor data
Authors: Yu Kexin , Wu Chao‐Yi , Barnes Lisa L. , Silbert Lisa C , Beattie Zachary T , Dodge Hiroko H , Kaye Jeffrey A 
Published: December 2023

AbstractBackgroundDaily activity patterns of life‐space mobility can serve as indicators for loneliness and subsequent cognitive change. Assessment of life‐space mobility often uses self‐reported data, and the measurement intervals are often less frequent than needed to capture change over time. This study examined whether the life‐space mobility changed when loneliness was reported weekly.MethodsParticipants were 139 older adults who lived alone (age = 78.1±8.6, 103 (74%) were female, 32 (23%) were African Americans, 19 (14%) had MCI diagnosis) and were enrolled in ORCATECH (ORegon Center for Aging & TECHnology) longitudinal aging studies and Minority Aging Research Study. Passive infrared motion sensors were placed in common rooms of each participant’s home (bathroom; bedroom; kitchen; living room). Time spent in each room across the day (morning; afternoon; evening; night) and out‐of‐home were used as indicators of life‐space mobility and were derived from home sensor data. Participants reported whether they felt lonely on a weekly basis using an online survey sent via email. Generalized estimating equations were used to correlate the time spent in each room and out‐of‐home and the likelihood of feeling lonely. Age, gender, education, race, cognitive status (MCI/ non‐MCI), and average daily time out‐of‐home were controlled in the model.ResultsWe analyzed 4994 weeks of data; 232 weeks had an incidence of loneliness (5%). Spending an additional hour in the bedroom in the afternoon (noon‐6 pm) was associated with a 21% increase in the likelihood of experiencing loneliness (p = .03). Spending an additional hour out‐of‐home in the afternoon was associated with a 13% decrease in the likelihood of experiencing loneliness (p = .02). Time spent in the kitchen, bathroom, and living room in a day was unrelated to weekly loneliness.ConclusionTime spent outside the home may suggest an expansion of life‐space, while spending time in one’s bedroom may indicate contraction of life space. Our findings suggest carefully monitoring a person’s location in the afternoon might help detect loneliness in this population. Frequent and objective measurements of life‐space mobility can produce renewed insights into the experience of loneliness among older adults who live alone, and thus, inform timely interventions for loneliness and prevent cognitive decline.
Are Current International Pricing Paradigms for an Efficacious Disease‐Modifying Anti‐Alzheimer’s Treatment Equitable? Are Quality‐Adjusted Life‐Years Worth Considering?
Authors: Wilcox Charles S 
Published: December 2023

AbstractBackgroundThe June 2021 approval of aducanumab [Aduhelm], initially priced at $56,000/year, followed by the January 2023 approval of lecanemab [Leqembi], initially priced at $26,500/year, generated renewed debate over reasonable and appropriate pricing for disease‐modifying anti‐Alzheimer’s treatments. For equitable pricing of an anti‐Alzheimer’s treatment, what are the optimal patient‐centered pricing paradigms?MethodA literature search of pricing models for anti‐Alzheimer’s, plus other, medicines indicates there are (at least) seven drug pricing models, with value‐based pricing being the most popular. In many countries new medicines are only compared within a certain indication, which may lead us to unknowingly pay substantially more for equal benefit in one disease versus another(1).ResultIn tandem with Leqembi’s expedited review and approval, there was substantial discussion as to what would be reasonable and appropriate pricing. Analysts at the Institute for Clinical and Economic Review [ICER] reported the drug would be cost‐effective at the $8,500 to $20,600 range; their analyses were based on preliminary data. Eisai analysts reported that lecanemab has a societal medicinal value of approximately $37,000, noting that it slowed cognitive decline by 27% over eighteen months(2). The top five selling drugs for multiple sclerosis have an average annual price of $64,760; the average annual cost for the top five cancer drugs is > $165,000.Measurement of outcomes and costs are essential for value‐based pricing. For dementia, the International Consortium for Health Outcomes Measurement [ICHOM] notes that patient‐centered outcome measures represent the ultimate measure of quality and they are always multidimensional. Quality‐adjusted life‐years [QALYs] seem to be absent from the computation of pricing for anti‐dementia treatments. Although consensus on QALY calculations is evasive, currently extant data are compelling. In Australia, the 2023‐adjusted QALY range is $32,618 to $55,415; United Kingdom $49,631 to $98,158, Germany $25,562 to $82,079, Sweden $51,494 to $59,416 and in Japan $56,819 to $67,643(3‐5). Utilizing an 18‐month treatment‐period, a range of QALY valuations will be presented, plus comparisons with the two other clinical indications.Conclusion
The inclusion of QALYs for valuation of Alzheimer’s disease medicines warrants consideration; and,
The full value of anti‐dementia treatments may be understated in current pricing models.
An implementation evaluation of the Driving and Dementia Roadmap (DDR) in Alzheimer Society organizations
Authors: Naglie Gary , Stasiulis Elaine , Sandhu Harvir , Gallucci Christina E. , Rapoport Mark J. 
Published: December 2023

AbstractBackgroundIn response to the immense challenges that people with dementia (PWD) and family/friend carers (FCs) face in the driving cessation process, we developed the Driving and Dementia Roadmap (DDR). The DDR is a web‐based resource comprised of information and tools to support PWD, FCs and healthcare providers in the decision‐making and transition to non‐driving. To understand the factors (i.e., barriers and facilitators) that influenced the DDR’s implementation in Alzheimer Society (AS) settings, we conducted an implementation evaluation.MethodThe DDR was implemented by AS staff in six organizations in four Canadian provinces. Nineteen AS staff were interviewed after a three to six month period of delivering the DDR to their clients. Participants also recorded details about each interaction involving the DDR (e.g., setting, mode and rationale). Data were examined using a thematic analysis approach guided by the Consolidated Framework for Implementation Research (CFIR), which is a meta‐theoretical framework comprised of constructs organized into five domains (e.g., user characteristics, intervention characteristics and process).ResultThe DDR was implemented mainly via individual consultations by telephone/email to FCs who expressed concern about driving issues. Main factors that facilitated the DDR’s implementation were related to the characteristics of the DDR, such as its perceived evidence strength (e.g., research‐based) and quality (e.g., variety of tools, association with reputable organizations), superiority to other resources (e.g., more in‐depth, comprehensive and user friendly) and its ease of delivery (e.g., via telephone/email with minimal instruction required by clients). AS staff characteristics’ that facilitated implementation included their enthusiastic and favorable views about the DRR’s potential to be an empowering resource that could facilitate conversations and early planning for driving cessation. Barriers to implementation included clients’ lack of computer skills as well as competing priorities for AS staff such as other projects and tasks, and attending to issues related to the COVID‐19 pandemic (e.g., isolation, caregiver burnout, staying safe).ConclusionThis study highlights how the perceived strengths of the DDR resource itself and AS staff’s favourable beliefs about the DDR facilitated its successful implementation in AS settings. Strategies to address implementation barriers include offering a print‐based version of the DDR.
Cognitive Change in a Diverse Group of Individuals Aged 90+: The LifeAfter90 Study
Authors: Meunier Claire C. , Corrada María M. M. , Gilsanz Paola , George Kristen M , Glymour M. Maria , Kawas Claudia H. , Decarli Charles , Whitmer Rachel A. 
Published: December 2023

AbstractBackgroundThe oldest‐old are the fastest growing segment of the elderly population but very little is known about cognition in this age group; particularly in diverse populations. Our goal was to evaluate if domain specific cognitive change was different across different ethnoracial groups in those aged 90+.MethodLifeAfter90 (LA90) is an ongoing cohort of participants aged 90+ who are long‐term members of Kaiser Permanente Northern California participants. Participants (n = 984) were interviewed every 6 months for up to 3.5 years (1‐7 visits). Executive Function (EF) and Verbal Episodic Memory (VEM) were measured every six months using z‐standardized Spanish English Neuropsychological Assessment Scale. Racial/ethnic identify (Asian, Black, Latino, or White participants) was used in linear mixed models with random slopes and intercepts adjusting for baseline age, gender, education, interview mode, and practice effects.ResultParticipants were 20% Latino, 23% Black, 24% Asian, 27% White, and 7% other individuals with a mean age of 92.4 (SD = 2.3) and a mean follow up time 1.1 years (Table 1). 39% of the cohort were men, 35% were college educated, and 29% were high school or less educated. Average annual change in EF was ‐0.06 (95% CI: ‐0.12, ‐0.00). Stratified models with Latino as the reference group showed White participants had significantly greater decline in EF (β = ‐0.13; 95%CI:‐0.20,‐0.06), followed by Asian participants (β = ‐0.09; 95%CI:‐0.17,‐0.01). EF scores among Black participants and participants who identified as other declined at a similar rate as Latino participants (β = ‐0.03; 95%CI:‐0.11,‐0.05; β = 0.00; 95%CI:‐0.10, 0.11; respectively) (Table 2: model 2). VEM had an annual change of ‐0.26 (95%CI: ‐0.40, ‐0.13), but there were no significant differences across ethnoracial groups in rate of decline.ConclusionIn this population of individuals aged 90+, decline in EF over the study period varied across ethnoracial group with White participants experiencing the fastest decline and Black, Latino, and other participants experiencing the slowest decline. Continued follow up will identify if there are differences in risk of cognitive impairment in this diverse population of oldest‐old. The results suggest the disparities in cognitive aging for those aged 90+ don’t mirror disparities seen in younger‐elderly ages.
Characterizing structural neuroimaging biomarker changes in the canine model of Alzheimer’s disease
Authors: Noche Jessica A. , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , McCarty Katie , Meacham Beverly , Smiley Jeffrey , Puskas Laszlo G. , Powell David K , Sordo Lorena , Bailey Stasia A. Bembenek , Phelan Michael J. , Norris Christopher M. , Head Elizabeth , Stark Craig E.L. 
Published: December 2023

AbstractBackgroundThe aging beagle is an exceptional model for longitudinal preclinical studies of Alzheimer’s disease due to their endogenous accumulation of beta‐amyloid plaques linked to cognitive impairment in aging, human‐like metabolisms, and ability to undergo serial neuroimaging. However, studies that use standardized analysis methods for evaluating longitudinal changes to neuroimaging biomarkers in this model are lacking. Here, neurostructural changes were characterized from longitudinal neuroimaging of middle‐aged beagles under chronic calcineurin inhibitor (CNI) treatment.MethodT1‐weighted structural images were collected from 3T MRI at baseline and annually for 3 years from 43 middle‐aged beagles (6.47 +/‐ 1.1 years old) in an environmental enrichment paradigm under a chronic low dose of Tacrolimus (n = 15), Q134R (n = 14) or placebo (n = 14). Tissue segmentation and normalization to a group template for atlas‐based statistics were performed using Advanced Normalization Tools (ANTs) where atrophy rates were assessed from 27 bilateral cortical and subcortical regions of interest (ROIs). The auxiliary log‐Jacobian determinant images derived from non‐linear timepoint‐to‐template warps in ANTs were used to conduct whole‐brain, deformation‐based morphometry in AFNI.ResultAmong the brain structures examined with both ROI‐based and voxel‐based measures, the pregenual gyrus within the frontal lobe exhibited a distinct acceleration in atrophy. In contrast, the volume of the hippocampus was selectively preserved over the three years. Neither atrophy rate nor the preservation of hippocampal volume was modified by chronic CNI treatment.ConclusionStructural analysis from serial MRI in the beagle model of AD revealed that age‐related brain atrophy is accelerated within the frontal lobe, an area susceptible to early beta‐amyloid deposition in canines, and is unaltered by CNI treatment. Furthermore, the maintenance of hippocampal volume over time across all groups warrants further investigation into the effects of environmental enrichment on altering the trajectory of hippocampal structural decline. The novel application of robust longitudinal neuroimaging analysis methods in canines offers a novel framework for evaluating canine brain aging characterics and for monitoring treatment‐related structural alterations in preclinical intervention studies.