bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid and tau deposition influences cognitive decline in Down syndrome
Authors: Grigorova Monika , Mak Elijah , Beresford‐Webb Jessica , Brown Stephanie S G , Jones Elizabeth , Clare Isabel , Holland Tony , Hong Young T , Fryer Tim D , Coles Jonathan P , Williams Guy B , Aigbirhio Franklin I , Ances Beau M. , Christian Bradley T , Handen Benjamin L , Klunk William E , Laymon Charles M , Tudorascu Dana L , Zaman Shahid ,   NiAD (Neurodegeneration in Aging Down Syndrome)
Published: December 2021

Background

Amyloid‐β accumulation in the brain has been associated with decline in cognitive functioning in adults with Down Syndrome (DS). Despite the significant relationship between in vivo Amyloid‐β and tau pathology, no studies have assessed whether tau potentiates the relationship between amyloid‐β and cognitive decline in DS. Here we investigate whether (i) tau has an independent effect on changes in cognition; (ii) tau has a synergistic relationship with amyloid in the exacerbation of cognitive decline.

Method

A baseline cohort of 105 participants with DS underwent PET AV‐1451 and PiB scans to quantify tau and Amyloid‐β deposition. Neuropsychological assessment of participants included a test for episodic memory (Cued Recall), visuospatial ability (WISC‐IV Block Design and Haxby Extension) and global cognition (DSMSE). Cognition was re‐assessed at 16 (n = 105) and 32 months (n=26) after baseline. Amyloid‐β burden was quantified categorically as PiB+/‐ where PiB+ status was defined as PiB standard uptake value ratio (SUVR) above a defined threshold. Braak regions (2‐6) and the Striatum were used for generating the SUVR for AV‐1451. Linear Mixed Effects models were implemented to assess the independent effects of tau and PiB status on change in cognition. Additional models tested the 3‐way interactions between tau, PiB status and time for each ROI. P‐values were adjusted via the FDR method.

Result

For the memory outcome, the interactions between time and tau (with PiB status – time interactions also included in the model) were significant for all ROIs, except the Striatum, while Braak regions 3 to 5 were significantly associated with change in DSMSE scores. All ROIs’ tau showed a significant interaction with time for the Block Design task. The three‐way interaction between time, PiB status and striatal tau was significant in the models of memory change. Braak 5 and tau showed a significant interaction with time and PiB status for the visuospatial ability outcome (Fig 1‐4).

Conclusion

There was evidence for a significant independent effect of baseline tau on cognitive change, over and above the effect of amyloid status. We also found evidence for a synergistic relationship between PiB status and tau as predictors of change in memory and visuospatial ability.
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

Background

White 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.

Method

Six 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.

Result

Compared 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.

Conclusion

Regional 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

Background

In 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.

Method

DIAN‐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.

Result

Based 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.

Conclusion

Large 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

Background

Delirium 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.

Methods

We 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.

Results

Delirium 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).

Conclusions

Rates 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

Background

The 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.

Methods

GE 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.

Results

Four 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.

Conclusion

Requiring 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

Background

Subjective 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.

Method

Participants 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).

Result

A 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.

Conclusion

Our 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

Background

Frontotemporal 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.

Method

We 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.

Result

There 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.

Conclusion

Prior 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

Background

EXERT, 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.

Method

In 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.

Result

At 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%.

Conclusion

The 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

Background

Diet 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,

Method

We 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.

Result

Adherence 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)

Conclusion

Adherence 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

Background

Many 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.

Method

Data 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.

Result

During 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).

Conclusion

These 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.
Waist‐hip ratio as a moderator of the effects of hormone therapy on cognitive function in recently menopausal women
Authors: James Taryn T. , Dowling N. Maritza , Simó Carola A. Ferrer , Zuelsdorff Megan , Bouges Shenikqua , Lambrou Nickolas H. , Van Hulle Carol A , Johnson Adrienne L. , Wyman Mary F. , Salazar Hector , Umucu Emre , Kara Firat , Manson JoAnn E. , Brinton Eliot A , Cedars Marcelle I. , Lobo Rogerio A. , Neal‐Perry Genevieve , Santoro Nanette F , Naftolin Frederick , Harman Sherman M. , Pal Lubna , Miller Virginia M. , Kantarci Kejal , Gleason Carey E.
Published: December 2021

Background

Research on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer’s disease has been inconsistent. The Women’s Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog.

Methods

KEEPS‐Cog randomized women less than 36‐months postmenopause to oCEE, transdermal 17‐β‐estradiol (tE2) or placebo for 48 months. Cognitive tests, completed at baseline, 18, 36, and 48 months post‐randomization were summarized as factor scores representing four cognitive domains: verbal learning and memory (VLM), auditory attention and working memory (AAWM), visual attention and executive function (VAEF), and speeded language and mental flexibility (SLMF). WHR, measured at screening and months 12, 36, and 48 was modeled as a time‐varying moderator of MHT on cognitive function over time. Education was included as a time‐invariant covariate.

Results

WHR decreased throughout the study in both the tE2 and oCEE groups compared to placebo. WHR was also inversely associated with all cognitive parameters at baseline. The inverse relationship of WHR on SLMF was significant at baseline and month 18, but decreased at month 48. The inverse relationship of WHR on VLM increased significantly over time. Models including interaction effects were significant for oCEE x WHR effects at months 18, 36, and 48 on SLMF, indicating better performance in MHT vs placebo arms. No other interaction effects were significant.

Conclusions

WHR decreased with MHT, and was consistently associated with VLM through 4 years of MHT. Further, women on oCEE performed better on SLMF tasks at a given WHR. Differences between KEEPS‐Cog and WHIMS findings may be related to the timing of MHT administration, and effects on central adiposity/insulin resistance/prediabetes.
Remote neuropsychological assessment using the UDS v3.0 T‐Cog: Preliminary data among participants at the Penn ADRC
Authors: Hackett Katherine , Ferrara Matthew J. , Newman Sidnei , Kelley Melissa , Schankel Laura , McCoubrey Hannah , Best Sharon , Peskin Sara Manning , O’Brien Kyra , Xie Sharon X , Wolk David A. , Mechanic‐Hamilton Dawn
Published: December 2021

Background

Due to the COVID‐19 pandemic, collection of the Uniform Data Set (UDS) at Alzheimer’s Disease Research Centers (ADRCs) transitioned to remote administration via the T‐Cog. Feasibility of data collection and dissemination of normative data in individuals across the cognitive spectrum will be necessary for accurate utilization of remotely‐captured neurocognitive performance and classification of cognitive function.

Method

Data was included from individuals who completed a remote T‐Cog protocol during their annual NACC evaluation. Additional data included demographics, informant‐reported functioning, self‐reported depression and consensus diagnosis. Descriptive and general linear model (GLM) statistics were used to characterize the overall sample and test for differences in performance across diagnostic groups.

Result

A total of 151 participants with normal cognition (NC; N=103), mild cognitive impairment (MCI; N=32) and Alzheimer’s disease (AD; N=16) were administered the T‐Cog (Age = 75.2+7.2, Education=16.3+3.1; 62% Female; 75% White). Data were collected via telephone (68%), video‐conference (29%), or a combination (3%). Time to completion ranged from 38‐120 minutes (M=58+14 minutes), with NCs showing a significantly lower (p<0.05) mean completion time (54 minutes) than those with MCI (65 minutes) and AD (69 minutes). Across the battery, 80% of responses were deemed “extremely valid”, 19% were “questionably valid” and <1% were “invalid”. Contributors to poor validity included hearing impairment (34%), distractions (16%), interruptions (6%), lack of effort/disinterest (9%), fatigue (3%), emotional issues (6%), or other reasons (25%). Diagnostic groups varied on tests of global cognition and functioning, as measured by the MoCA‐Blind and Global CDR, with the highest performance among NC, followed by MCI, and AD (p‐values<0.01). Nearly all T‐Cog measures of language, memory, and executive functioning abilities showed expected differences across diagnostic categories (covarying for age, sex and education; p<0.05). Comparisons to prior in‐person UDS neurocognitive testing across all diagnostic groups will also be presented.

Conclusion

Preliminary feasibility and performance data on the T‐Cog reveals expected differences in T‐Cog performance. Comparisons to within‐subject in‐person testing and deviations from in‐person norms will be presented to further explore the validity of remote cognitive testing and identify tests that show particular promise in discriminating between diagnostic groups.
Associations of TDP‐43 vs. Alzheimer’s disease neuropathology with brain atrophy in the oldest‐old: Initial imaging‐pathological results from The 90+ Study
Authors: Woodworth Davis C. , Nguyen Hannah L. , Phelan Michael J. , Greenia Dana E. , Corrada Maria M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2021

Background

Brain atrophy, particularly of the hippocampus and amygdala, is thought to reflect the effects of neurodegenerative proteinopathies such as TAR DNA‐binding protein‐43 (TDP‐43) and Alzheimer’s disease neuropathologic change (ADNC). We sought to test this hypothesis in a cohort of oldest‐old participants.

Method

We used data from participants in The 90+ Study, a study of aging and dementia in individuals aged 90 and older, with both MRI during life and autopsy. Our outcome variables were hippocampus and amygdala volumes calculated from computational anatomy toolbox (CAT12, http://www.neuro.uni‐jena.de/cat/). Proteinopathy variables were dichotomized: TDP‐43 (presence in hippocampus/neo‐cortex), ADNC (NIA‐AA high severity), and Lewy bodies (LB, limbic/neocortical involvement). We examined the association between presence of the proteinopathies and gray matter atrophy using three different methods. First, we compared the volumes between those with vs. without each neuropathology. Then we studied the association between the volumes and proteinopathies in a model containing all neuropathologies, adjusting for age and intracranial volume. Lastly, we calculated voxel‐wise multiple linear regressions of gray matter atrophy across the whole brain (using CAT12) and report results for each proteinopathy. We also repeated the above analyses including cognitive impairment status for comparison.

Result

Table‐1 summarizes participant characteristics (N=64). Group differences in hippocampal and amygdala volumes were in the low‐to‐moderate effect‐size range for TDP‐43 (hippocampus d=0.40, amygdala d=0.33) and ADNC (hippocampus d=0.38, amygdala d=0.54, Figure‐1). For associations incorporating all three proteinopathies, semi‐partial correlations were low for TDP‐43 (hippocampus sr=‐0.15, amygdala sr=‐0.10) and ADNC except for the amygdala (hippocampus sr=‐0.12, amygdala sr=‐0.25, Table‐2). For the voxelwise analysis of gray matter atrophy, none of the proteinopathies displayed strong associations (Figure‐3). Generally, LB showed no discernible effect on gray matter atrophy. In contrast to the modest results for the proteinopathies, cognitive impairment was strongly associated with medial temporal atrophy (Figure‐4).

Conclusion

In this sample of oldest‐old participants, TDP‐43 and ADNC were only modestly associated with atrophy of the hippocampus and amygdala. While this finding may partly due to low number of participants, strong association of atrophy with cognitive status in the same sample suggests mere presence of degenerative proteinopathies might not be sufficient for brain tissue loss.
Development of voice digital biomarkers in AD, their associations with CSF amyloid beta (Aß1‐42) and their underlying neural representations
Authors: Hajjar Ihab , Choi Jinho , Moore Elliot , Calhoun Vince D. , Abrol Anees , Goldstein Felicia C.
Published: December 2021

Background

Subtle changes in connected speech may be detectable years before symptomatic phases of Alzheimer’s disease (AD). In this study we combine machine learning with innovative natural language processing (NLP) and automatic speech recognition (ASR) to develop digital voice biomarkers. We investigate their associations with levels of Ab (1‐42) and map the significant features to underlying brain networks.

Method

Data for the current case‐control analysis were drawn from participants in the Brain Stress Hypertension and Aging Research Program (B‐SHARP) at Emory University. B‐SHARP participants undergo cognitive assessments, neuroimaging, and lumbar punctures as well as annual audio recordings to capture connected speech. A picture description task was included for NLP analysis In addition, participants were asked to describe the room they were in and to list events they went through from the moment they arrived at the study site. Each audio recording went through 2 NLP pipelines to obtain lexical‐semantics and acoustic features.

Result

The sample included 206 B‐SHARP participants (age=65.1 years, 51% African Americans, 42% with mild cognitive impairment (MCI), 61% women, follow‐up period =2 years). NLP analysis and to a lesser extent acoustic analysis outperformed traditional cognitive screening in identifying MCI status. NLP based analysis outperformed other screening tools of Ab positive status (defined as <250 pg/ml) status especially in the MCI group. Area under the curve (AUC) for identifying MCI, Ab positive , and MCI/Ab positive and NC/Ab positive vs negative. Results are in the Table. We then assessed the association between baseline digital voice biomarkers and disease progression reflected by CDR‐SOB change/2 years. Both NLP‐based scores (Beta= ‐0.18;p=0.0097) and acoustic scores (beta=0.26,p=0.009) were associated with 2‐year change in CDR‐SOB after adjusting for baseline demographics. Finally functional brain connectivity, based on resting state MRI, was associated with digital voice NLP‐based scores in multiple brain networks (Figure).

Conclusion

A brief voice recording analysis detected cognitive status, increased likelihood of identifying Abeta positivity, and predicted disease progression over 2 years. Our protocol for digital biomarkers had an underlying neural representation in language‐related neural networks. Our study provides multi‐faceted evidence for validity of using voice recording as a tool for biomarker and cognitive screening.
Meta‐analytic comparison of risk factors for mild cognitive impairment and Alzheimer’s disease between Hispanic and non‐Hispanic White subjects
Authors: Xiao Cally , Neu Scott C , Toga Arthur W
Published: December 2021

Background

Hispanic subjects have been found to have a higher risk for developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD) compared to non‐Hispanic white (NHW) subjects. In addition, having one or two copies of the APOEe4 risk allele, prior stroke, and a history of hypertension have also been shown to be risk factors for developing MCI or AD.

Method

In this meta‐analysis, we compared the differences of the risk factors contributing to MCI or AD between Hispanic and NHW subjects using data available in the Global Alzheimer’s Association Interactive Network (GAAIN), contributed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Alzheimer’s Coordinating Center (NACC).

Result

The odds ratio (OR) for developing a case outcome (MCI or AD) using Hispanic ethnicity as a risk factor is 1.49, which corroborated the existing trend. Interestingly, having one or two copies of the APOEe4 allele is more of a risk factor for NHW subjects (n = 23,148; OR = 2.78) than for Hispanic subjects (n = 2141; OR = 1.89). This OR difference between the two populations is statistically significant (p ≤ 0.001). Additionally, having had a prior stroke is more of a risk factor for NHW subjects, and having a history of hypertension is more of a risk factor for Hispanic subjects, though these differences are not statistically significant.

Conclusion

Having one or two copies of the APOEe4 risk allele, prior stroke, and a history of hypertension contribute differently to a case outcome when comparing between Hispanic and NHW subjects. A formal analysis to confirm these findings by matching for age, sex, and education level could further our understanding of the different risk factors that contribute to MCI or AD between Hispanic and NHW subjects.
Hidden objective test
Authors: Kim Ko Woon , Choi Jong Doo , Chin Juhee , Lee Byung Hwa , Choi Jee Hyun , Na Duk L.
Published: December 2021

Background

Alzheimer’s disease patients frequently complaint that they lose things and be unable to find them again because of deficit in visuospatial memory. In this study we aimed to develop a novel visuospatial memory tests called the Hidden Objective Test (HOT) based on the ideas of patients’ complaint. Virtual reality (VR) is an optimal tool for developing this visuospatial memory tests in that real‐life settings implementation.

Method

We designed a pleasant and cozy living room. The photorealistic virtual environment interface with 360‐degree panoramas was rendered through HMD. The VR system enables the users to turn their head, to walk around, to open and close the furniture doors using controllers, and to track their movement in the VR living room. When the participant starts the test, the VR living room is shown and instructions for the prospective memory test are given. Nine items appeared on the white panel in order, and one by one, the item moved to the each furniture space and were hided. Memory test composed of 1) Item Free‐recall test, 2) Place Free‐recall test, 3) Item Recognition test, 4) Place‐item matching test, and 5) Prospective memory test.

Participants were selected from those who visited the Memory Disorder Clinic at Samsung Medical Center in Seoul, Korea, between November 1st, 2019 and January 30th, 2020. This study group comprised 16 AD, 15 AMCI, and 15 NC participants.

Result

The performance of memory test was NC>AMCI (p<0.001), AMCI>AD (p<0.05), and NC > AD (p<0.001) in the Item Free‐recall test; NC>AMCI (p<0.01) and NC > AD (p<0.001) in the Place Free‐recall test; NC>AMCI (p<0.05), AMCI>AD (p<0.01), and NC > AD (p<0.001) in the Item Recognition test; NC>AMCI (p<0.001) and NC > AD (p<0.001) in the Place‐item matching test; NC > AD (p<0.05) in the Prospective memory test. Interestingly, the average movement path showed that NC participants went straight toward the target point whereas AD patients wandered to the target point when searching for hidden objects.

Conclusion

The Hidden Objective Test (HOT) developed in this study, which incorporated virtual reality to experience real‐life events, showed potential to be used as a new memory screening test.
Clinical characterization of a large Caribbean Hispanic family linked to chromosome 9 without ApoE4
Authors: Tejada Sergio J , Mena Pedro Ramon , Silva‐Vergara Concepcion , Adams Larry D. , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E.
Published: December 2021

Background

The ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to discovering ancestry‐specific genetic factors in Alzheimer's disease. As part of the Puerto Rican Alzheimer Disease Initiative (PRADI), we ascertained 80+ multigenerational families with multiple AD family members and reported linkage to 9p21. Here we present the clinical phenotype of the largest 9p21 linked family.

Method

The 18 members of this family were screened using neuropsychological test (e.g., CDR, 3MS), history of medical conditions, Apolipoprotein e4 were obtained and AD diagnosis was done by a panel of experts. Results were reported as frequencies and percentage and the associations were determined using Chi‐square.

Result

The family consisted of 17 participating family members, 76% females, a mean age of 70 years (SD=14 years). 1 participant was diagnosed with Parkinson’s disease, 6 with AD possible diagnosis, 1 as MCI and 6 were cognitively normal. No known causal genes for AD were observed through whole genome sequencing. The prevalence for APOE genotypes, 2/2, 2/3, 2/4 and 3/3, were 6%, 47%, 6% and 41% respectively. None of the AD cases in the family had an APOE4 allele. The average age of onset of AD cases was 79 years (SD=12 years) with a minimum of 60 years and maximum of 90 years. The average 3MS score for the cases was 49/100 (SD=33) and 90/100 (SD=4) for controls. CDR scores for all controls were 0 and between 2 and 1 for all cases. Depression was present in 33% of the participants, 22% diagnosed with diabetes, 25% with high cholesterol and 44% with hypertension.

Conclusion

In this family, 8 individuals had neurodegenerative disorders, 5 of which had at least 1 APOE2 allele. The only APOE4 carrier is a unaffected participant (APOE 2/4) whose age at exam was 57 years. This supports a novel AD risk factor segregating in this family. Pedigree studies remain a useful tool to help unravel the pathophysiologic pathways involved in neurodegeneration.
Randomized controlled trial of gamma sensory stimulation treatment maintains functional ability and decreases sleep fragmentation in Alzheimer’s disease patients
Authors: Cimenser Aylin , Hempel Evan , Travers Taylor , Strozewski Nathan , Malchano Zach , Hajos Mihaly
Published: December 2021

Background

Daily, at‐home gamma sensory stimulation consisting of EEG‐calibrated auditory and visual stimuli is a new therapeutic approach for the treatment of Alzheimer’s Disease (AD). Based on experimental studies demonstrating that sensory‐evoked gamma oscillation halts or reverses AD‐related pathology, improves cognitive function, and normalizes circadian rhythm in transgenic mice carrying human AD pathological genes, this clinical trial evaluated the effects of 40Hz sensory stimulation on functional ability and sleep quality of AD patients.

Method

Patients with mild‐to‐moderate AD (MMSE 14‐26, inclusive; n=74) were randomized to receive either 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Functional abilities of patients were measured by Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale at baseline and every four weeks during the study and follow‐up period. Sleep quality was assessed from nighttime activities of a subgroup of patients (n=7 in treatment, n=6 in sham groups) who were monitored continuously via a wrist worn actigraphy watch throughout the 6‐month period.

Result

Adjusted ADCS‐ADL scores from beginning and end of the trial were compared in patients who completed the trial. Over the 6‐month period, patients in the sham group (n=19) showed the expected decline, a 5.40‐point drop in ADCS‐ADL scores, whereas patients in the treatment group (n=33) receiving therapy exhibited only a 0.57‐point decline. Changes in ADCS‐ADL scores were statistically significant between the sham and treatment groups (P<0.01). Nighttime active durations in the treatment group were significantly (p<0.03) reduced in the second 3 months compared to the first 3 months but the opposite change was observed in the sham group. After normalizing the active durations by the corresponding nighttime period of each patient, the analysis confirmed opposite changes in nighttime active durations between the two groups (p<0.001).

Conclusion

Patients in gamma sensory stimulation therapy maintained their activities of daily living and showed an improved sleep quality over a 6‐month treatment period; two outcome measures, functional ability and sleep quality known to be strongly linked in AD. Maintenance of functional ability represents an important treatment and management goal for AD patients, reducing formal and informal care, and delaying time to institutionalization.