bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systolic Blood Pressure Levels and Probable Dementia : Secondary Analysis of a Randomized Clinical Trial
Authors: Jaeger Byron C , Gaussoin Sarah A. , Reboussin David M. , Rapp Stephen R. , Sachs Bonnie C. , Williamson Jeff D. 
Published: December 2023

AbstractBackgroundDespite a significant 19% reduction in risk for mild cognitive impairment, the primary Systolic Blood Pressure Intervention Trial (SPRINT) analysis lacked sufficient evidence to assert statistical significance for the 17% reduction in probable dementia alone in intensive blood pressure (BP) control, defined as a target systolic BP < 120 mmHg, compared to the standard target of < 140 mmHg (p = 0.10). However, early termination of SPRINT may have caused these analyses to be under‐powered. We applied the statistical framework of joint models for longitudinal data and time‐to‐event outcomes to analyze the effect of systolic BP levels on probable dementia using the SPRINT data.MethodsSPRINT was a multicenter randomized clinical trial that enrolled patients ≥50 years of age with hypertension and increased cardiovascular risk but without diabetes or history of stroke. In this secondary analysis, the primary outcome was occurrence of adjudicated probable dementia after randomization. Secondary outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. To analyze these outcomes, we applied joint longitudinal and survival models. In the longitudinal component of the joint model, systolic BP levels were modeled as a quadratic function of time since randomization, accounting for correlation in repeated measurements and for assignment to intensive BP control versus standard care. In the survival component, multi‐variable adjustment for race, education, and age at baseline was applied.ResultsOver a median follow up of 5.2 years, a total of 325 probable dementia and 640 mild cognitive impairment events occurred. After multi‐variable adjustment (as above), the hazard ratio per 10 mmHg decrease in systolic BP was 0.89 (95% confidence interval [CI] 0.79, 0.99) for probable dementia, 0.89 (95% CI 0.82, 0.96) for mild cognitive impairment, and 0.90 (95% CI 0.84, 0.97) for their composite outcome (Table). Dynamic predictions after 2 years of follow‐up provide a descriptive summary of systolic BP levels and predicted risk of probable dementia or mild cognitive impairment (Figure).ConclusionReducing systolic BP decreases the risk of both probable dementia and mild cognitive impairment.
Associations Among Depression, Stress, Resilience, and Alzheimer’s Disease Biomarkers in Older Adults Following a Major Societal Stressor
Authors: Burling Jessa , Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Quiroz Yakeel T. , Marshall Gad A , Vannini Patrizia , Gatchel Jennifer 
Published: December 2023

AbstractBackgroundBetter predicting depression following a stressor like COVID‐19 would help identify vulnerable individuals who might benefit the most from early intervention. We examined change in depressive symptoms relative to the onset of COVID‐19 and longitudinal trajectories of depressive symptoms post‐pandemic‐onset. As a secondary objective, we examined associations of these changes with stress, resilience, and in vivo AD biomarkers.MethodData were analyzed from 101 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study, a longitudinal observational cohort study. Depressive symptoms are assessed annually with the 30‐item Geriatric Depression Scale (GDS), and for these analyses, participants had no/mild self‐reported depression (GDS<11) at the last pre‐COVID examination. GDS‐delta scores were computed using the mean of the post‐COVID‐onset scores subtracted by the last pre‐COVID examination for participants. Levels of resilience (Connor‐Davidson Resilience scale) and stress (Perceived Stress Scale) were assessed within a year after pandemic onset. Cortical amyloid (PiB) and entorhinal (EC) and inferior temporal (IT) tau (FTP) were analyzed using pre‐pandemic acquisition (mean 1.6 years to pandemic onset). We used linear models to predict GDS‐delta and linear mixed effects models to predict GDS trajectory post‐COVID onset from resilience, stress, and the interaction of each with AD biomarkers (PiB and FTP).ResultsGDS‐delta was predicted by resilience (t = ‐4.69, p<0.001) and stress (t = 3.51, p<0.001) such that those with lower resilience and higher stress experienced higher GDS‐delta. EC tau, but not IT tau or cortical amyloid, interacted with stress to predict GDS‐deltas (EC tau*stress: t = 2.04; p = 0.04) indicating that those with higher levels of EC tau and stress experienced higher GDS‐delta. For post‐pandemic‐onset GDS trajectory, no significant longitudinal associations were observed, but there was a marginal interaction between EC‐tau*stress in predicting greater GDS trajectories (t = ‐1.79, p = 0.08).ConclusionResults suggest that change in depressive symptoms in elders following a societal stressor is associated with lower resilience and higher stress; this may be exacerbated by concurrent EC tau pathology. Moreover, elevated depressive symptoms in the years following onset of a societal stressor can be partially predicted by increased EC tau and stress, highlighting a vulnerable population who may benefit from preventive interventions throughout a major stressor.
Abeta and Tau impair retromer‐mediated cargo trafficking via distinct mechanisms
Authors: Ye Hui , Arya Vanuli , Shulman Joshua M 
Published: December 2023

AbstractBackgroundEvidence from neuronal pathology and experimental models suggest that endolysosomal dysfunction may contribute to Alzheimer’s Disease (AD) pathogenesis, however it is unclear how Aβ and Tau directly affect endolysosomal dynamics, partially due to a lack of reporters. The retromer, including VPS35, VPS26, and VPS29, is a conserved protein complex responsible for recycling proteins within the endolysosomal pathway. Retromer regulates Tau phosphorylation and pathogenic processing of the amyloid precursor protein. Cation‐independent Mannose 6‐phosphate receptor (CIMPR) is a well‐established retromer cargo, with a WLM motif recognized by the retromer for retrieval.MethodTo track retromer‐dependent protein trafficking in vivo, I have cloned the cytoplasmic tail of CIMPR carrying the WLM motif into a pUAST‐attb vector and generated a transgenic fly line (UAS‐CIMPR‐WLM). A transgenic line carrying CIMPR, but having WLM mutated to AAA, has also been developed as a negative control (UAS‐CIMPR‐AAA). I examined the CIMPR reporter in Vps35 and Vps29 mutants, as well as established Drosophila AD models during aging.ResultThe protein level of CIMPR‐WLM was reduced by genetic ablation of Vps35, possibly due to promoted degradation. Expressed in young Vps29 mutant brains, CIMPR‐WLM showed an increased colocalization with a late endosomal/lysosomal marker Arl8, indicating a promoted delivery of retromer cargoes into the lysosome. Further, neuronal expression of CIMPR‐WLM exhibited a punctate distribution, which was abolished when WLM was mutated to AAA. Altogether, my data suggested that CIMPR‐WLM worked as a retromer‐dependent reporter. While the reporter was broadly enriched within neuropil regions in control animals (Elav>CIMPR), neuronally expression of Aβ (Elav> Aβ+CIMPR) led to a striking redistribution of CIMPR, shifting from neuropil to enrichment in soma, and forming large perinuclear puncta. Moreover, the retromer reporter was mislocalized in brains from 1‐day‐old Elav> Aβ animals, and this result did not significantly change with aging. Interestingly, Elav>Tau+CIMPR animals showed no noticeable effects on the distribution of CIMPR‐WLM on day 1, but caused a similar redistribution of CIMPR‐WLM to the perinuclei region at day 30.ConclusionThe CIMPR‐WLM reporter requires the retromer for proper cellular localization. Our findings are consistent with the notion that Aβ and Tau affect endosomal sorting, but likely via distinct mechanisms.
An accelerated rate of Beta‐amyloid Measured with [C‐11]PiB in Down Syndrome compared to Neurotypical Populations
Authors: McVea Andrew K , DiFilippo Alexandra H , McLachlan Max , Murali Dhanabalan , Zammit Matthew D , Johnson Sterling C , Betthauser Tobey J , Stone Charles K , Tudorascu Dana , Laymon Charles M , Klunk William E , Cohen Ann D. , Handen Benjamin L. , Christian Bradley T. 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is characterized by a higher risk and earlier onset of beta‐amyloid (Aβ) plaque accumulation and Alzheimer’s disease (AD). The triplication of chromosome 21 containing the amyloid precursor protein (APP) gene is implicated in this process and in this study we compare the accumulation rates of Aβ between DS and neurotypical (NT) populations quantified by longitudinal [C‐11]PiB imaged at the same site to minimize experimental variation.MethodsIndividuals with three or more [C‐11]PiB scans spanning eleven years our site with at least one Aβ+ (global SUVR>1.40) and Aβ‐ [C‐11]PiB scan were selected. 12 of 74 DS and 15 of 246 NT participants fit these criteria. An identical imaging procedure was conducted for all participants imaged on either an ECAT HR+ or Biograph mCT PET scanner 50‐70 minutes post‐injection. Reconstructed PET images were summed and spatially normalized into template space and converted into 50‐70min SUVR images using a cerebellar grey matter reference region. Global SUVR composed of grey matter regions from the AAL atlas was used as a metric for Aβ deposition. SUVR data were fit against age with a logistic growth curve (f(t) = NS+K/(1+e(‐r(t‐t50)))) to determine Aβ accumulation as subjects transitioned to Aβ+. The rate of accumulation was found using the slope of the curve at Aβ positivity threshold based on the model fit. Our model fixed NS = 1.12, the average baseline SUVR of all Aβ‐ subject scans (n = 491), and K = 1.28, the highest specific binding in any participant.ResultsPlotting [C‐11]PiB SUVR against age provides visual comparisons of cohorts (Fig 1) and transforming the x‐axis to amyloid chronicity (t = 0 at Aβ+) illustrates differences in accumulation rates between groups (Fig 2). The average rate of amyloid accumulation (ΔSUVR/yr) when becoming Aβ+ in the DS cohort is 0.071(0.021) versus 0.043(0.009) for NT (p = 4.31×10−4).ConclusionsAβ accumulation rate was higher in the DS cohort compared to NT. This is consistent with the additional APP gene copy in DS, and we observed an accumulation rate 65% faster in this cohort. There was a higher variability in the DS population requiring further investigation towards understanding the influence of genetic and lifestyle factors on Aβ deposition.
Association between military service identified through public data tracing and Alzheimer’s disease neuropathology at autopsy
Authors: Vilen Leigha H , Zuelsdorff Megan , Salamat Shahriar , Pfaff Alexandra , Rissman Robert A , Bendlin Barbara B , Kind Amy J. , Powell W. Ryan 
Published: December 2023

AbstractBackgroundMilitary veterans face increased risk of Alzheimer’s disease and related dementias (ADRD) compared to the general population, but the association between the military exposome and ADRD pathology is poorly understood. Existing biobanks rarely collect military service information, complicating efforts to characterize military risk factors. Public data tracing methods linking the military exposome to existing neuropathological data have the potential to catalyze research on the mechanisms driving brain health disparities.MethodSubjects were decedents from two Alzheimer’s Disease Research Center brain banks who died between 1986‐2018 and were characterized on neurofibrillary tangle burden (NFT‐B score, n = 1154). Military service was characterized through public data tracing (Figure 1): systematic extractions from public records including obituaries, newspapers, and enlistment records (Figure 2). NFT‐B score, per National Institute of Aging and Alzheimer’s Association guidelines for neuropathologic change, was extracted from the standardized Neuropathology Dataset form or from original autopsy reports. Generalized ordered logistic regression with site‐level clustered standards errors was used to model NFT‐B score, adjusting for age, sex, and year of death.ResultPublic data tracing identified 373 decedents (32% of the sample) with a history of military service. After adjusting for age, sex, and year of death, decedents with a history of military service had a 12% greater odds (OR = 1.12, 95% CI: 1.11–1.13) of a more severe NFT burden compared to those without a history of military service, which was proportional when comparing the odds at each increasing B score level (B score = (1,2, or 3), vs (0), B score = (2,3) vs (0,1) and B score = (3) vs (0,1,2)) (Table 1).ConclusionPublic data tracing offers a promising way to retrospectively add the military exposome into brain tissue biomarkers research. Military service was associated with more severe neurofibrillary tangle pathology, one of the primary neuropathological features of Alzheimer’s disease. Future research should explore the feasibility and validity of public data tracing for more detailed characterization of military service, such as length and branch of service, involvement in specific conflicts, or exposure to environmental toxins, which may elucidate mechanisms underlying its association with ADRD pathology.
Safety and pharmacokinetics of single ascending doses of TAK‐594/DNL593, a brain‐penetrant progranulin replacement therapy, in healthy volunteers: Interim results from Part A of a Phase 1/2 clinical trial
Authors: Berger Amy Chang , Cohen Isaac , Jafarnejad Mohammad , Chiu Chi‐Lu , Bhalla Akhil , Damo Lorna , Shanbhag Niraj M , Simen Arthur , Lu Hong , Zicha Stephen , Bednar Martin , Troyer Matthew D. , Ho Carole , Tsai Richard 
Published: December 2023

AbstractBackgroundLoss of function mutations in the granulin (GRN) gene, which encodes the lysosomal protein progranulin (PGRN), account for 5‐10% of frontotemporal dementia (FTD‐GRN). Deficiency of PGRN in neurons and microglia results in lysosomal dysfunction, which in turn leads to neuroinflammation and neurodegeneration. TAK‐594/DNL593 is a novel PGRN replacement therapy that has been engineered to deliver PGRN across the blood brain barrier (BBB) and into lysosomes. In PGRN‐deficient mice, TAK‐594/DNL593 corrected age‐dependent elevations of disease biomarkers that are also observed in patients with FTD‐GRN (Logan et al. 2021).MethodsStudy DNLI‐H‐0001 (NCT05262023) is a Phase 1/2 randomized, placebo‐controlled study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TAK‐594/DNL593 in 3‐parts. Part A evaluated single ascending doses of TAK‐594/DNL593 in healthy participants (randomized 6:2 drug to placebo). Part B, currently enrolling, will evaluate multiple doses of TAK‐594/DNL593 for 6 months in participants with FTD‐GRN (randomized 2:1 drug to placebo) and will be followed by Part C, an 18‐month open‐label extension.ResultsPart A enrolled 35 healthy participants. Single doses of intravenously administered TAK‐594/DNL593 were generally safe and well tolerated. There were no discontinuations related to drug. The majority of treatment emergent adverse events (TEAEs) were mild to moderate, and no infusion related reactions were observed. TAK‐594/DNL593 serum exposures increased in a greater than dose‐proportional manner with low to moderate variability in PK parameters. Cerebrospinal fluid (CSF) total PGRN concentration, sampled 24 hours post‐infusion, also increased dose dependently above baseline levels.ConclusionSingle dose safety and PK of TAK‐594/DNL593 in healthy participants support initiation of the multiple dose study in participants with FTD‐GRN. The dose‐dependent increase in CSF PGRN is consistent with delivery of TAK‐594/DNL593 across the BBB and supports the potential of TAK‐594/DNL593 to treat FTD‐GRN.
References
Logan, Todd, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, et al. 2021. “Rescue of a Lysosomal Storage Disorder Caused by Grn Loss of Function with a Brain Penetrant Progranulin Biologic.” Cell 184 (18): 4651‐4668.e25. https://doi.org/10.1016/j.cell.2021.08.002.
Practice effects on cognitive testing and amyloid status
Authors: Duff Kevin , Dixon Ava , Embree Lindsay , Hoffman John M. 
Published: December 2023

AbstractBackgroundPractice effects are improvements in cognitive test scores due to repeated exposure to the same or similar test materials. Reduced practice effects have been reported in older adults with impaired cognition (e.g., Mild Cognitive Impairment, Alzheimer’s disease). However, to our knowledge, practice effects have not been examined in those who are classified as being amyloid positive or negative. Such information could be useful for screening individuals for clinical trials in these conditions.MethodOne hundred fifty‐five older adults with either intact (n = 63) or impaired (n = 92) cognition completed a brief battery of neuropsychological tests twice across one week and an amyloid positron emission tomography (PET) scan. Based on FDA approved prescribing and visual interpretation information, the amyloid PET scan was classified as positive (n = 95) or negative (n = 60). Practice effects across one week were quantified using regression‐based change scores from an independent sample.ResultOn a composite of seven neuropsychological test scores, those who were classified as amyloid positive showed significantly smaller practice effects than those classified as amyloid negative. Similar results were seen on practice effects for 6 of the 7 individuals tests, with smaller practice effects being seen in the amyloid positive participants.ConclusionPractice effects across one week were related to amyloid status in this sample of older adults. As such, these short‐term changes in scores on cognitive tests may be useful for enriching samples for future clinical trials in Alzheimer’s disease.
Brain Health PRO: An Interactive, Online, Educational Program for Dementia
Authors: Belleville Sylvie , Chertkow Howard , Feldman Howard H. , Nygaard Haakon B. , Montero‐Odasso Manuel , Anderson Nicole D. , Bherer Louis , Ferland Guylaine , Camicioli Richard , Chan Senny , Cuesta Marc , Dwosh Emily , Fiocco Alexandra J , Gilbert Brigitte , Itzhak Inbal , Jarrett Pamela , Laurin Danielle , Liu‐Ambrose Teresa , Lupo Jody‐Lynn , McGibbon Chris A , Middleton Laura E , Murphy Kelly J , Phillips Natalie , Pichora‐Fuller M. Kathleen , Revta Carolyn , Savundranayagam Marie Y. , Sexton Andrew , Smith Eric E. , Speechley Mark R. , Trigui Amal , Wittich Walter ,   CCNA‐CAN‐THUMBS UP Study Group
Published: December 2023

AbstractBackgroundThe Intervention mapping framework was used to plan and develop Brain Health PRO (BHPro), a 45‐week, theory‐ and evidence‐based online educational program co‐created with users in English and French. The goal of the program is to improve dementia literacy, self‐efficacy, and attitude toward dementia and ultimately have a positive impact on the dementia risk profile. A pilot study evaluated usability and acceptability using a shorter version of the online program, which informed changes for a full efficacy trial.MethodA group of over 100 researchers contributed expert content targeting seven modifiable risk factors (physical activity, nutrition, cognitive engagement, sleep, social and psychological health, vascular health, vision and audition). 181, ten minute chapters were created in total. All chapters were reviewed and edited by the Citizen’s Advisory group, consisting of older adults in the community. Information and recommendations for lifestyle improvement are delivered incrementally through weekly email interactions, and the platform is designed based on e‐learning principles. Participants complete online questionnaires to assess usability (eg: ease of use, ease of navigation, access, complexity), acceptability (eg: whether the program is interesting, whether they would use it again or recommend it) and level of risk at baseline for each of the seven modifiable risk factors.ResultA pilot study of Brain Health PRO was conducted, including 20 older adults, 13 women and 7 men. They had 16.75 years of education on average and their mean score on Logical Memory Scale II was 10.90. Two focus groups were conducted with a randomly selected group of participants to inform about the usability and acceptability of the program. The focus groups along with user experience questionnaires indicated excellent usability, with all dimensions rated in the positive range. Feedback from the end users were incorporated into the program prior to the main efficacy study.ConclusionBHPro was designed out of necessity to pivot in the changing environment brought by COVID‐19. Early data indicate that the BHPro program meets the needs and abilities of older adults in a virtual setting. The platform is easy for older adults to learn and use and is considered relevant.
Synucleinopathy in Alzheimer’s disease: role of the alpha‐synuclein seed amplification assays
Authors: Bellomo Giovanni , Toja Andrea , Ma Yihua , Farris Carly , Chipi Elena , Wojdala Anna , Paoletti Federico Paolini , Gaetani Lorenzo , Chiasserini Davide , Parnetti Lucilla , Concha Luis 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent proteinopathies of the central nervous system. Alpha‐synuclein seed amplification assays (αS‐SAA) are the most promising techniques for the in vivo detection of synucleinopathies, ie, PD and DLB. In neuropathological studies, Lewy Bodies (LBs) have been found in 50‐60% of AD patients. In AD, concomitant LB pathology could lead to parkinsonism and to a more aggressive course of the disease. Whether concomitant LBs could be related to some clinical aspects of AD, i.e., clinical variants or clinical progression, remains to be assessed. In our work, we applied αS‐SAA to determine whether the rate of assay positivity differs in AD vs controls (CTRL), and among AD clinical variants.MethodWe used αS‐SAA to test 457 CSF samples from a cohort of AD, CTRL, and patients with PD and DLB. Classical AD CSF biomarkers were used to select CTRL and AD patients according to the A/T/(N) system. All CTRL showed a CSF A‐/T‐/N‐ profile while all AD patients were A+T+. Details of the subjects included are reported in Table 1. Fisher’s Exact test for count data and logistic regression (by assuming age and gender as covariates) were used to evaluate the significance of the different prevalences observed.ResultWe observed significantly higher αS‐SAA positivity in PD/DLB (86%) and AD patients (30%) with respect to CTRL subjects (13%, 7% in CTRL CN and 16% in CTRL MCI subjects) (Fig‐1A). Among the AD clinical variants, patients with posterior variant exhibited significantly higher αS‐SAA positivity (Fig‐1C). Interestingly, αS‐SAA positivity increased in the diagnostic groups as they progressed to later stages of AD, with the highest percentage in the AD at dementia phase (AD‐dem) group (36%) (Fig‐1B).ConclusionOur results show that a large portion of AD cases have concomitant synucleinopathy and αS‐SAA could allow stratification of AD cases, as assay positivity was associated with AD subtypes and progression. Further evaluation of cross‐sectional and longitudinal clinical data is needed to determine potential prognostic value of αS‐SAA in AD. Early detection of synucleinopathy in AD patients will be increasingly important for design of personalized disease‐modifying therapies.