bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased regional white matter hyperintensity volume in objectively‐defined subtle cognitive decline and mild cognitive impairment
Authors: Calcetas Amanda T. , Thomas Kelsey R. , Edmonds Emily C. , Holmqvist Sophia L. , Edwards Lauren , Bordyug Maria , Delano‐Wood Lisa , Brickman Adam M. , Bondi Mark W. , Bangen Katherine J. 
Published: December 2021

AbstractBackgroundWhite matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, less is known about the extent and pattern of WMH in pre‐MCI stages, such as among those with objectively‐defined subtle cognitive decline (Obj‐SCD). Therefore, we aimed to examine regional WMH volume in Obj‐SCD versus those who were cognitively normal (CN) and MCI.MethodSix hundred twenty‐one Alzheimer’s Disease Neuroimaging Initiative participants (182 CN; 96 Obj‐SCD; 343 MCI) underwent neuropsychological testing and MRI exams. Cerebrospinal fluid (CSF) data were available for ∼50% of the sample. MCI was classified using Jak/Bondi criteria and Obj‐SCD was classified using criteria proposed by Thomas et al. (2018, 2020). ANCOVA models were used to compare cognitive groups on regional WMHs adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 status. We also ran analyses stratified by CSF phosphorylated tau (p‐tau)/amyloid‐β (Aβ) ratio positivity versus negativity.ResultCompared to the CN group, those with Obj‐SCD had greater frontal (p=.036) and temporal WMH (p=.034) with a trend toward greater occipital WMH (p=.052). Those with MCI had greater frontal, temporal, parietal, and occipital WMH (p’s <.01). No significant differences in WMH volume were observed between Obj‐SCD and MCI (p’s >.05). Among p‐tau/Aβ negative individuals, those with Obj‐SCD showed a trend toward greater temporal WMH (p=.053) compared to CN individuals. In addition, the p‐tau/Aβ negative MCI participants showed significantly higher frontal (p=.001), temporal (p=.004), and parietal (p=.027) WMH relative to the CN group. Among p‐tau/Aβ positive individuals, there were no significant group differences in WMH volume.ConclusionRegional WMH vary across cognitive groups. Compared to the CN group, the Obj‐SCD group showed higher temporal and frontal WMH whereas the MCI group showed more widespread WMH increases affecting all lobes, which is in line with their greater cognitive impairment. Notably, these findings do not appear to be driven by p‐tau/Aβ positive individuals. Findings add to growing evidence of associations between Obj‐SCD and imaging biomarkers, providing support for utility of our criteria to capture very subtle cognitive changes.
Sample size estimation for clinical trials with tau‐PET SUVR as the primary outcome in dominantly inherited Alzheimer’s disease
Authors: Wang Guoqiao , Li Yan , Xiong Chengjie , Benzinger Tammie L.S. , Gordon Brian A. , Hassenstab Jason , Aschenbrenner Andrew J. , Fagan Anne M , Coalier Kelley , McDade Eric , Llibre‐Guerra Jorge J , Klein Gregory , Pontecorvo Michael J. , Galante Nicholas , Chatterjee Saptarshi , Bateman Randall J. 
Published: December 2021

AbstractBackgroundIn addition to anti‐Aβ immunization therapeutics completing phase II/III clinical trials1, drugs targeting tau, inflammation, and apolipoprotein E, are in clinical development. Due to its close association with cognitive and clinical impairment, tau is one of the most promising targets currently ready for phase II trials. In this study, using the longitudinal tau‐PET data from the DIAN‐TU‐001 trial in Dominantly Inherited Alzheimer’s Disease (DIAD), we estimated the sample sizes for clinical trials with Tau‐PET as the primary outcome.MethodDIAN‐TU‐001 is a phase II/III randomized, double‐blind, placebo‐controlled, cognitive endpoint, multicenter study of potential disease modifying therapies (gantenerumab or solanezumab) in individuals with DIAD. Sample sizes will be estimated using the longitudinal Tau PET with AV1451 from the placebo arm (N=40, mean (SD) of follow‐up: 2.6 (0.89) years, CDR 0 to 1 at baseline, No DIAN observational data) based on change from baseline for asymptomatic and symptomatic cohorts, respectively. To avoid bias from potential drug effect on Tau‐PET SUVR measurement, the Tau PET data from the active drug randomized participants were not used for sample size estimation, and only for comparison with the placebo arm.ResultBased on two‐sided two‐sample t‐test with type I error of 0.05, the estimated sample sizes for a 2‐year clinical trial enrolling only symptomatic participants with 1:1 randomization ratio and change from baseline as primary outcome was presented in Table 1 for several ROIs. Similar estimations will also be presented for the asymptomatic cohort and for several Tau PET SUVR composites.ConclusionLarge increases in Tau PET SUVR were observed in the placebo arm in many regions with inferior temporal region showing a very high effect size for both asymptomatic and symptomatic participants. Phase II clinical trials with Tau PET SUVR as the primary outcome in DIAD can be conducted with relatively small sample sizes for some ROIs or composite ROIs.
Delirium due to avoidable hospitalizations among older adults
Authors: Kennedy Richard E 
Published: December 2021

AbstractBackgroundDelirium is a common complication during the course of acute care hospitalizations in older adults, particularly those with pre‐existing dementia. A substantial percentage of these admissions are for ambulatory care sensitive conditions (ACSCs) or avoidable hospitalizations – conditions that might be treated early in the outpatient setting to prevent hospitalization and its complications. We sought to examine the incidence of delirium among older adults hospitalized for ACSCs.MethodsWe examined admissions for 37,346 older adults 65 years of age admitted from January 1, 2015 to December 31, 2019 to the general inpatient (non‐ICU) units of a large regional Southeastern academic medical center. The primary outcome was delirium defined as a score 2 on the Nursing Delirium Screening Scale (NuDESC) during hospital admission. Generalized linear mixed models were used to compare rates of delirium between hospitalizations with a primary admission diagnosis for an ACSC, using standardized definitions, versus hospitalization for other non‐ACSC diagnoses, adjusting for covariates and repeated observations for individuals with multiple admissions.ResultsDelirium occurred in 30.1% of admissions for older adults. Rates were lower for those admitted for ACSCs versus those admitted for other conditions. Older age, higher number of comorbidities, presence of dementia, lower baseline cognitive scores, and lower baseline functional scores were all associated with increased risk of delirium. After adjustment for covariates, risk of delirium was 51% lower for admissions for ACSCs versus admissions for other conditions (odds ratio [OR] = 0.49; 95% CI 0.43, 0.57).ConclusionsRates of delirium among older adults hospitalized for ACSCs were lower than rates of delirium during hospitalization for other conditions, but were still substantial. This indicates that treatment of ACSCs in the outpatient setting could be an important component of efforts to reduce delirium.
Effects of protocol and scanner changes on segmentation volume estimates in a dedicated crossover data set
Authors: Gunter Jeffrey L. , Wiste Heather J. , Kantarci Kejal , Weigand Stephen D , Vemuri Prashanthi , Schwarz Christopher G. , Mielke Michelle M. , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Jack Clifford R. 
Published: December 2021

AbstractBackgroundThe Mayo Clinic Study of Aging and Alzheimer’s Disease Research Center used GE scanners exclusively for MRI from 2005‐2017, employing consistent imaging parameters throughout. In 2017 the MRI protocol was updated and migrated to Siemens Prisma scanners; 113 participants were scanned with each configuration. The GE protocol included a 2D FLAIR. The Siemens protocol includes 3D FLAIR and T2‐weighted images. Both vendor protocols included a 3D T1. Experience with multi‐center trials suggests such changes may introduce systematic variations.MethodsGE scanning was carried out on 3T scanners with 12 channel phased array head coils. Siemens Prisma scanning was carried out with 64 channel head/neck coils. Imaging sequences and parameters are given in Table 1. We used the MCALT template and priors to perform standard six‐class segmentation on T1‐weighted (T1w) images. SPM12 unified segmentation supports the simultaneous use of multiple input contrasts; segmentation of multi‐contrast inputs was done using eight tissue classes including deep grey and white matter hyperintensity (WMH) priors. For a given MRI study (either GE or Siemens) all images were registered and resampled to the study’s T1w image. Two‐channel (T1+FLAIR) segmentation was performed on GE scans. Two and three‐channel segmentations were performed on Siemens scans. Comparisons included total intracranial volume, total tissue volume and total grey matter volumes, as well as hippocampal volumes and grey matter volume in a temporal lobe meta‐ROI.ResultsFour participants were excluded for poor image quality: one poor GE T1w quality, one poor Siemens T1, T2 and FLAIR quality, and two poor Siemens T2 quality. Comparisons were made among 109 participants aged 34–97 (Table 2). By visual assessment, adding T2‐weighted images always improved intracranial volume correctness. Using the combination of single‐channel GE and three‐channel Siemens generally improved cross‐vendor agreement on grey matter volumes with the exceptions of hippocampal and intracranial volume estimates.ConclusionRequiring multiple input channels increases the likelihood that the result of a study being excluded. Combining T1w, FLAIR and T2w images allows the delineation of WMH and deep grey matter probability outputs but may introduce differences in GM volumes.
Validation of a 4‐item subjective cognitive decline screening questionnaire in cognitively normal older adults
Authors: Strenger Jennifer , Alber Jessica , Arthur Edmund , Snyder Peter J , Sinoff Stuart , Correia Stephen , Salloway Stephen P. , Thompson Louisa I 
Published: December 2021

AbstractBackgroundSubjective cognitive decline is an important factor in understanding AD risk and the progression of preclinical AD. Recent efforts have formalized a framework for defining and researching SCD, but significant variability still exists in the assessment and quantification of SCD (Jessen et al., 2014; Molinuevo et al., 2017). Including a uniform assessment of core defining SCD features in AD clinical research could help to overcome this problem and generalize research findings. We report preliminary data validating the novel Subjective Cognitive Decline Screen (SCDS), a 4‐item scale designed to assess key features of SCD in preclinical AD, as described by the Subjective Cognitive Decline Initiative (SCD‐I) Working Group.MethodParticipants were 97 cognitively unimpaired adults (ages 55‐80, 68% female, 93% White) pooled across two ongoing observational AD studies. The SCDS consists of 4 self‐report multiple choice questions assessing concerns about memory (0‐2 points), extent of memory decline (0‐2 points), and perceived memory change relative to peers (0‐1 point), with total scores ranging from 0 (no SCD) to 5 (high SCD).ResultA total of 67% of participants endorsed at least one SCDS item. Total scores ranged from 0 to 5 (M = 1.3, SD = 1.4) and did not vary significantly on the basis of sex, age, or education. The SCDS demonstrated fairly high internal consistency overall (4 items; Cronbach’s α = .79), with an average inter‐item correlation of r = .48. The scale was positively correlated with the self‐report form of the Cognitive Function Index (CFI; Amariglio et al., 2015), a 14‐item measure of SCD widely used in AD research (r = .68, p < .01). In sub‐analyses of participants with known APOE genotype (n = 46) and known amyloid PET status (n= 25), SCDS scores did not differentiate APOE e4 carrier or amyloid PET status, respectively.ConclusionOur initial evidence suggests that the SCDS is a convenient tool for brief SCD assessment with fairly high internal consistency, though the average inter‐item correlation suggests some overlap in item content. Further work is needed to validate the scale in more racially and culturally diverse samples and in individuals with biomarker defined preclinical AD.
MRI correlates of neuropsychiatric symptom progression in pre‐dementia GRN and C9orf72 mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Popuri Karteek , Beg Mirza Faisal , Mackenzie Ian R , Wittenberg Dana , Rademakers Rosa , Hsiung Ging‐Yuek Robin 
Published: December 2021

AbstractBackgroundFrontotemporal dementia (FTD) patients with mutations in the C9orf72 or the GRN genes frequently exhibit neuropsychiatric symptoms (NPS), which may precede the onset of dementia. We hypothesized that the burden and progression of NPS in pre‐dementia mutation carriers are associated with structural abnormalities detectable in brain MRI.MethodWe analyzed data from 42 participants before onset of dementia (11 C9orf72+ mutation carriers, 8 GRN+ mutation carriers, and 23 non‐carrier family members (NCs); mean±SD age: 46y±11, 50y±9, and 53y±8 respectively) recruited through the University of British Columbia FTD Study. Participants were assessed longitudinally for NPS with Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI) and Iowa Scale of Personality Change (ISPC) (mean follow‐up: 8.4y). Participants also underwent 1.5T MRI at the first and third annual visits (mean interval: 28±8m). If a participant developed FTD during the follow‐up (N=2), we only analyzed observations collected before the conversion. We processed T1‐weighted MRI to calculate annualized volumetric changes in the grey‐matter, the white‐matter and the hypointense white‐matter signal‐abnormalities (WMSA), within the entire brain and lobar region‐of‐interests. We applied a random‐slope model to the NPI, FBI and ISPC scores to estimate subject‐specific slopes of their progression. Then, we applied a linear model to evaluate the association between the estimated slopes and the MRI measures, among the genetic groups. Covariates included sex, age, baseline assessment scores, baseline WMSA and total white‐matter volumes.ResultThere were non‐significant baseline group differences in the MRI or NPS measures. Overall, a higher rate of frontal lobar WMSA accumulation was associated with a higher rate of NPI score increase. However, GRN+ carriers had a faster progression of NPS compared to NCs, and the higher NPI slope was associated with a higher rate of frontal lobar white‐matter volume loss. The FBI and ISPC slopes were not significantly associated with the MRI measures.ConclusionPrior to the onset of FTD, the emergence of NPS in mutation carriers may be correlated with the degree of frontal lobar white‐matter lesions. In GRN+ carriers, the progression of NPS, as represented by NPI score increases, may also be associated with frontal white‐matter volume loss.
EXERT: Impact of COVID‐19 on retention and intervention delivery of a large multisite exercise trial in adults with MCI
Authors: Baker Laura D , Cotman Carl W , Morrison Rosemary H , Katula Jeffrey A , Chmelo Elizabeth , Hodge Heather , Johnson Cara , Kipperman Sean A , Matthews Genevieve , Bennett Daniel , Mason Jennifer , LaCroix Andrea Z , van Dyck Christopher H , Okonkwo Ozioma C , Tam Steven P , Fairchild Jennifer Kaci , Li Clara , Welsh‐Bohmer Kathleen A , Feldman Howard ,   the EXERT Study Group
Published: December 2021

AbstractBackgroundEXERT, a multisite 18‐month RCT, is testing the effects of aerobic exercise vs. stretching on cognition and AD biomarkers in sedentary adults with MCI. In the first 12 months, participant exercise 2x/week under the supervision of YMCA trainers, and 2x/week on their own. In months 13‐18, participants continue to exercise 4x/week but without supervision. Here we describe the impact of the COVID‐19 pandemic on delivery of this support‐intensive intervention that involved many challenges but also opportunities for innovation.MethodIn February 2020, EXERT met the recruitment goal with 296 enrolled. In March 2020 when COVID‐19 incidence rates began to climb in the US, study assessments and per‐protocol intervention delivery were paused. During the pause, all YMCAs were closed, and the majority of study‐certified YMCA trainers were furloughed.ResultAt the time of the pause (March 23), 153 participants were in the supervised phase of the study, and 65 participants were in the unsupervised phase. To keep participants engaged and encourage adherence to the intervention, sites initiated weekly calls with active participants to provide support, address barriers to exercise and collect self‐report adherence data. By September, 7 of 14 sites resumed study activities. Weekly call completion rates during the pause exceeded 85%, and participants reported completing a mean of 3.3 40‐minute exercise sessions per week. On these calls, participants frequently expressed gratitude for the regular contact. By February 2021, all sites resumed activities despite COVID infection rates that have continued to climb across the US. In response, supervised exercise for the majority of participants was transitioned from in‐person to web‐conferencing. Even with this change that can be challenging for MCI, supervised session adherence rates are 72% for the aerobic group and 79% for the stretching group. Retention has remained high at 87%.ConclusionThe COVID‐19 pandemic presented unprecedented challenges, but it also provided unique opportunities to adapt intervention delivery so that a community‐based exercise trial could continue – even during a debilitating global health crisis. EXERT’s adaptations may ultimately impact resilience of the intervention to even the most challenging of circumstances that older adults with MCI will face now and in the future.
Effects of the MIND diet and physical activity on cognitive domains in the elderly
Authors: Holland Thomas Monroe , Agarwal Puja , Dhana Klodian , Halloway Shannon , Desai Pankaja , Wang Yamin , Aggarwal Neelum T , Barnes Lisa L , Rajan Kumar B 
Published: December 2021

AbstractBackgroundDiet and physical activity (PA) are important for cognitive health, but few studies have examined whether there is a synergistic relationship with cognitive decline in older adults. In this study, we investigated whether the combination of a high MIND diet score and high, device‐measured, PA has a stronger relationship with global cognitive decline and specific cognitive domains when compared to other combinations of MIND diet score and PA levels,MethodWe examined the association of MIND diet and PA interactions on global cognition and five cognitive domains in 264 participants without cognitive impairment from the Rush Memory and Aging Project. Diet was assessed using a validated 144‐item food frequency questionnaire with objective physical activity measured by Actical. Cognition was assessed using a 19‐test cognitive battery from which a global composite score and 5 domains were derived. Participants (mean age = 79± SD 7.7 years; 75% female) were followed for an average of 6.3 ± SD 2.7 years and separated into 9 categorical combinations of MIND diet score and PA (high, moderate, low for MIND diet x high, moderate, low for PA), with low MIND diet and low PA serving as the reference. Linear mixed models adjusted for age sex, education, ApoE‐4, late life cognitive activity, self‐reported physical activity, smoking, and caloric intake.ResultAdherence to a high MIND/high PA regimen over time versus low MIND/low PA was associated with a 62.5% slower rate of decline in global cognition (β=0.12, p=0.0001). We also found similar associations for episodic memory (β=0.13, p=0.0006), semantic memory (β=0.1, p=0.005), perceptual speed (β=0.05, p=0.03), and working memory (β=0.08, p=0.006) but not visuospatial ability (β=0.05, p=0.15.). Further, it was determined that the high MIND/high PA combination improved a broader range of cognitive domains over time, than either the high MIND/low PA, or low MIND/high PA, versus low MIND/low PA. (Figure 1)ConclusionAdherence to a high MIND diet/high PA regimen has a greater impact on cognitive decline and specific cognitive domains versus alternate combinations of MIND diet and Physical Activity.
Novel biomarkers in healthy aging: Tongue and jaw kinematics as a potential way to further explore Alzheimer’s‐induced biological changes
Authors: Luckas Jared , Laurence‐Chasen J.D. , Fereira Hernando , Arce‐McShane Fritzie 
Published: December 2021

AbstractBackgroundMany age‐related oral health problems, such as masticatory dysfunction and dysphagia, have been associated with Alzheimer’s Disease (AD). However, how oromotor dysfunctions in healthy aging differ from those found in AD is still largely unknown. Here, we aim to assess changes in tongue and jaw kinematics in healthy aging to understand how these biomarkers may provide early signatures of AD.MethodData were collected from two male monkeys (Macaca mulatta), one young (8 years) and one older (20 years). Using high‐resolution bilateral videoradiography (200 frames/s) and the X‐Ray Reconstruction of Moving Morphology (XROMM) workflow, we quantified the 3D position of tongue and jaw radio‐opaque markers while monkeys engaged in a natural feeding behavior. To evaluate age‐related changes, we analyzed tongue and jaw kinematics relative to specific events in the feeding cycle during 10‐s feeding trials (20‐60 trials). All protocols were approved by the University of Chicago Animal Care and Use Committee and complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
ResultDuring chews and swallows, both monkeys exhibited cyclical tongue motions, however, the tongue motions in the older monkey were substantially less stereotyped. The distributions of x‐y‐z positions of the tongue during start/end of chews and swallows were tightly clustered in the young monkey but were more spread out in the older (Fig. 1). In addition, tongue movements in the rostro‐caudal direction lagged behind jaw movements to a greater degree in the older monkey than in the younger (Fig. 2). Indeed, in the young monkey, tongue movements in the rostro‐caudal direction were highly correlated with supero‐inferior jaw movements, with peak correlations occurring at zero lag (Fig. 3).ConclusionThese results show that tongue and jaw kinematics may change with age, particularly with regards to stereotypy of tongue movement and tongue‐jaw coordination. Understanding oromotor changes in healthy aging may serve as diagnostic measures that may be helpful in treating or delaying AD progression and in reducing the severity of debilitating oromotor dysfunctions.