bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results from the COVID caregiving project
Authors: Largent Emily A , Clapp Justin , Stites Shana D. , Peterson Andrew H , Abera Maramawit , Harkins Kristin , Karlawish Jason
Published: February 2022

Background

In the United States, family caregivers are the cornerstone of the support system for persons living with dementia (PLWD). This study examined how the coronavirus disease 2019 (COVID‐19) pandemic challenged caregivers’ capacity to deliver long term care services and supports to PLWD.

Method

Participants (expected N=40) in this qualitative study are family caregivers for PLWD who reside in either the community or a long‐term care facility. Family caregivers participate in semi‐structured, hour‐long telephonic interviews covering: (1) adequacy of caregiving supports; (2) social, emotional, physical, financial, and other effects of caregiving during the COVID‐19 pandemic on the caregiver; and (3) effects of the COVID‐19 pandemic on the person with dementia. Interviews are audio‐recorded, transcribed, and coded in NVivo. The University of Pennsylvania IRB approved this study.

Results

Preliminary results show that social distancing measures disrupted services and supports for PLWD (e.g., closure of adult day centers). Efforts to minimize the risk of COVID‐19 disease or death for the person with dementia increased caregiver work and feelings of burden. Many caregivers described making difficult tradeoffs. Some reduced their utilization of supports (e.g., forgoing having paid aides come into the home, limiting visits from other family members), but this has increased workload and limited opportunities for respite. Other caregivers reduced work hours or left the workforce entirely (e.g., because they deemed their risk of SARS‐CoV‐2 exposure on the job too high), but this has increased financial vulnerability and social isolation. A majority of caregivers expressed concern that social distancing has negatively affected the person in their care; many perceive a hastening of cognitive decline and feel their time with the person with dementia has been limited by the pandemic. Caregivers for long‐term care facility residents reported frustration with limited visitation opportunities as well as a perceived decrease in quality of care and lack of transparency.

Conclusion

Our results will help characterize the impact of the COVID‐19 pandemic on PLWD and their caregivers. They will inform ethical guidelines and policies to improve the delivery of services and supports for PLWD and the ability of people to perform the work of caregiving.
Effects of aerobic exercise on imaging biomarkers in Alzheimer’s disease
Authors: Yu Fang , Mathiason Michelle , Gunter Jeffrey L. , Jones David T. , Botha Hugo , Jack Clifford R.
Published: February 2022

Background

In animal models of Alzheimer’s disease (AD), aerobic exercise favorably modified the accumulation, degradation, and removal of Aβ and tau. However, human mechanistic randomized controlled trials (RCTs) are limited with mixed findings on hippocampal volume and biofluid Aβ and tau. Hence, an objective of the FIT‐AD Trial was to examine the effects of 6‐month aerobic exercise on magnetic resonance imaging (MRI) biomarkers in community‐dwelling older adults with AD dementia.

Method

The FIT‐AD Trial was a pilot RCT that first qualified participants for the main exercise study eligibility and then for MRI. Participants were randomized to moderate intensity cycling or low intensity stretching for 20‐50 minutes, 3 times a week for six months on a 2:1 ratio with three age strata (66‐75, 76‐85, and 85+ years of age) and followed up for another six months. MRI biomarkers included hippocampal volume, temporal meta‐regions of interest cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ) measured at baseline, six months, and 12 months.

Result

Sixty participants met MRI eligibility, but one was excluded when this participant’s baseline MRI failed quality control. Among the 59 remaining participants, 38 were randomized to cycling and 21 to stretching. The sample characteristics (n=59) were 77.3±6.3 years old with 15.6±2.9 years of education and 53% men. Both groups experienced significant declines in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and cortical thickness (0.94% vs. 1.54%) over six months and over 12 months (hippocampal volume: 4.47% vs. 3.84%; cortical thickness: 2.27% vs. 1.79%). These declines didn’t differ between groups. WMH volume increased significantly, but the cycling group increased >50% less than stretching (10.9% vs. 24.5% over six months [f=4.47, p=.04]; 12.1% vs. 27.6% over 12 months [f=5.88, p=.02]). NFQ didn’t change significantly over time nor differed between group.

Conclusion

Aerobic exercise may reduce hippocampal volume and cortical thickness declines during the intervention period; however, its effects are likely to be small and dose‐dependent and reverse after the intervention stops. Aerobic exercise is effective on reducing WMH progression but has no effect on NFQ.
Diffusion tensor imaging in mild cognitive impairment in community‐dwelling older adults in Taiwan
Authors: Chuang Yi‐Fang
Published: February 2022

Background

Most structural magnetic resonance imaging studies of Alzheimer’s disease and mild cognitive impairment (MCI) have focused on volumes of gray matter structures in the medial temporal lobe. This study aims to investigate white matter microstructures using diffusion tensor imaging (DTI) in MCI and different types of MCI in a community‐based cohort of older adults in Taiwan.

Method

The DTIs of 372 older adults at baseline from a community‐based prospective cohort study, the Epidemiology of Mild Cognitive Impairment in Taiwan (EMCIT) were used. Among them, 74 were ascertained as MCIs including 53 amnestic MCIs and 21 non‐amnestic MCIs. Tract‐based spatial statistics (TBSS) were used to compare voxelwise fractional anisotrophy (FA) differences between MCI, amnestic (aMCI), non‐amnestic MCI (naMCI) and cognitively normal (CN) older adults.

Result

Mean age of participants was 70.7± 5.3 years. Older adults with MCI were older, have lower education and higher prevalence of diabetes and depression. The pattern of white matter integrity disruption tends to follow an anterior to posterior gradient with greater damage noted in posterior regions in MCI (Fig. 1). On further analysis, participants with aMCI showed disrupted integrity in multiple white matter tracts across the whole‐brain when compared with CNs (Fig. 2) whereas only few white matter regions with diffusion changes were found in aMCI as compared to CNs and with less significance.

Conclusion

These findings indicate that the degeneration extensively exists in white matter tracts in MCI, especially naMCI. The results are consistent with the view that MCI is not a uniform disease entity and presents heterogeneity in the structural brain changes.
Characterizing white matter hemodynamic markers of lesion burden and cognitive function using arterial spin labeling MRI
Authors: Juttukonda Meher R. , Almaktoum Randa , Stephens Kimberly A. , Yochim Kathryn M. , Salat David H.
Published: February 2022

Background

White matter lesions (WMLs) have been linked to cognitive decline in Alzheimer’s disease (AD), but physiological mechanisms associated with microvascular dysfunction in white matter remain incompletely understood. The purpose of this study was to investigate associations between arterial spin labeling (ASL) magnetic resonance imaging (MRI) markers of white matter hemodynamics and aging, cognitive function, and WML burden.

Method

Study design. Participants (n=234) provided written consent for this IRB‐approved cross‐sectional study as part of the Human Connectome Aging Project. Participants underwent a range of health and cognitive assessments, including the Montreal Cognitive Assessment (MoCA), and 3 Tesla MRI.
Structural imaging. High‐resolution T1‐weighted images were acquired for co‐registration and were processed with FreeSurfer for calculation of white matter signal abnormalities as a measure of WML burden. Hemodynamic imaging. ASL data were acquired using a labeling duration=1500 ms and five equally spaced post‐labeling delays from 200‐2200 ms with spatial resolution=2.5x2.5x2.5 mm3. ASL images were corrected for distortion and for motion. Cerebral blood flow (CBF) and arterial transit time (ATT) were computed using a cross‐correlation approach and a two‐compartment model. Data analysis. Mean CBF and ATT values were calculated inside white matter masks derived using FreeSurfer for each subject and assessed as a function of age, WML burden, and MoCA score.

Result

We found an inverse association between white matter CBF and age (p<0.001) and a direct association between white matter ATT and age (p<0.001), where increasing age corresponded to lower CBF and longer ATT. After including age as a covariate, we found a trend for an inverse relationship between white matter CBF and WML burden (p=0.064), with lower CBF indicating higher WML burden (Figure 2). Lastly, we also found a trend for an inverse association between white matter ATT and MoCA score (p=0.097), with longer ATT indicating lower MoCA scores (Figure 3).

Conclusion

Preliminary results indicate that impaired hemodynamic properties (lower white matter CBF and longer white matter ATT) may be associated with elevated WML burden and poorer cognition. Further longitudinal studies are necessary to determine whether white matter hemodynamic may represent a prospective marker of WML burden and associated cognitive impairment.
The impact of APOE genotype disclosure on lifestyle behaviors and decisions about future directives
Authors: Popescu Dominique L , Alber Jessica , Thompson Louisa I , Arthur Edmund , Oh Hwamee , Correia Stephen , Salloway Stephen P. , Lee Athene KW
Published: February 2022

Background

Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well tolerated in cognitively unimpaired (CU) older adults. Genotyping can be valuable to modifiable lifestyle intervention studies as it provides important Alzheimer’s disease (AD) risk information. As such, the goal of this study is to examine the impact of the disclosure process itself on lifestyle behaviors and decisions about future directives in community‐dwelling CU older adults from the Butler Alzheimer’s Prevention Registry (BAPR).

Method

Cognitively unimpaired APOE ε4 non‐carriers (n= 106) and carriers (n= 80) aged 58‐78 from the BAPR first completed in‐person psychological readiness screening and genotyping followed by APOE disclosure. Follow‐up assessments were completed online 3 days, 6 weeks and 6 months post disclosure. The primary outcomes were scores on self‐reported measures of physical activity, diet, and decisions about future directives.

Result

Post‐disclosure, non‐carriers were more likely to report future directive change towards decisive action on will or estate planning at 3 days follow‐up, healthcare proxy and long‐term living arrangement planning at 6 weeks, and life insurance planning at 6 months. Further, non‐carriers were more likely to report having a long‐term planning discussion with their families at 6 months than carriers. No significant differences were found between non‐carriers and carriers on any of the self‐reported measures of modifiable lifestyle factors (all p> .10).

Conclusion

In a clinical research setting, APOE genotype disclosure has been shown to be safe, well tolerated, and in one study, to increase enrollment in ongoing clinical AD research studies. Disclosure led to more decisive actions on future directives in non‐carriers. Disclosure did not lead to changes in modifiable lifestyle factors, an indication that disclosure alone may not be sufficient to inspire behavioral change. Future work will investigate whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk‐lowering lifestyle modifications as an intervention approach engenders positive change.
Longitudinal [18F]flortaucipir PET: Comparison of quantitative and semi‐quantitative parameters
Authors: Visser Denise , Tuncel Hayel , Ossenkoppele Rik , den Hollander Marijke E. , Coomans Emma M. , Wolters Emma E. , Timmers Tessa , van der Flier Wiesje M. , Boellaard Ronald , Yaqub Maqsood , Van Berckel Bary N.M. , Golla Sandeep S.V.
Published: February 2022

Background

Dynamic [18F]flortaucipir PET imaging allows for more accurate quantification of specific binding compared to static imaging in Alzheimer’s disease (AD). Besides, with dynamic imaging flow is taken into account, which is especially important in longitudinal studies, because disease progression or drug intervention may lead to flow changes. We aimed to compare semi‐quantitative (SUVr) and quantitative (BPND) parameters for [18F]flortaucipir PET in a longitudinal study.

Method

We included subjects with subjective cognitive decline (SCD; n=38) and AD patients (n=24). All subjects underwent baseline (BL) and 2‐year follow‐up (FU) dynamic [18F]flortaucipir PET. BPND and R1 (relative cerebral blood flow) were calculated (RPM; reference region cerebellar gray). SUVr was derived 80‐100 min p.i.. (Trans)entorhinal, limbic and neocortical regions‐of‐interest (ROIs) were assessed. For each parameter %change was calculated (100*(FU‐BL)/BL). Regional SUVr was compared against respective DVR (BPND+1) using paired T‐tests. Additionally, simulations were performed to model effects of flow changes on BPND and SUVr in high, medium or low binding categories. For each category, R1 values were varied to mimic 5‐25% increase or decrease in flow. Thereafter, %bias for SUVr with respect to underlying binding and its association with respect to change in flow were evaluated.

Result

In SCD, there was a significant difference between %change in DVR (2.56%) and SUVr (1.85%) in the (trans)entorhinal ROI (p<0.05) only. In AD, differences in %change were found in the limbic ROI (DVR 6.61% vs. SUVr 7.52%; p<0.05) only. R1 changes were small (+0.7% in SCD and ‐1.6% in AD). Simulations showed varying %bias in SUVr depending on underlying binding. With increasing flow a decreased bias in low binding conditions was observed, whereas in high binding conditions an increased bias was seen. DVR remained relatively stable under different flow conditions, irrespective of underlying binding.

Conclusion

Compared to BPND, SUVr provided a good estimate of specific binding for [18F]flortaucipir over a two‐year follow‐up. However, simulations showed that [18F]flortaucipir SUVr is subject to variable bias in case of larger flow changes, which seemed to be depending on underlying tau load. Therefore, BPND should be preferred over SUVr, especially in the context of pharmacotherapeutic interventions that could induce significant changes in flow.
snoRNAs in plasma extracellular vesicles of AD patients are differentially associated with APOE genotype
Authors: Fitz Nicholas F , Nam Kyong Nyon , Koldamova Radosveta , Lefterov Iliya
Published: February 2022

Background

Standardized disease specific PET patterns correctly classify 95% of AD MCI patients. The cost of PET, however, is still prohibitive as a widespread AD diagnostic test. Diagnostic tests using CSF have also been established to measure the levels of Aβ and hyperphosphorylated tau for early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. CSF biomarkers show a good agreement with amyloid imaging and a combination of CSF Aβ42/Aβ40 increases the agreement between markers of amyloid pathology. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently found small nucleolar non‐coding RNAs (snoRNAs) of box C/D (SNORDs), transcribed from imprinted chromosomal domains SNURF‐SNRPN at human chromosomal region 15q11q13 and DLK1‐DIO3 at region 14q32, highly enriched in plasma EVs of AD patients compared to non‐demented individuals.

Method

During the discovery phase of the study, using RNA‐seq we profiled four major classes of ncRNAs in EVs isolated from early stage AD patients and control non‐demented individuals: miRNAs, snoRNAs, tRNAs and piRNAs. We verified the results by Digital Droplet PCR in plasma samples of independent group of AD and control plasma samples.

Result

We report a significant enrichment of SNORDs in AD samples compared to controls. Through verification assays we confirmed these results and identified SNORD115s & SNORD116s with the highest discriminatory power to differentiate AD samples against Controls.

Conclusion

The results of our study present evidence that AD is associated with changes in enrichment of SNORDs, transcribed from imprinted genomic loci, in plasma EVs and provide a rationale to further explore validity of snoRNAs as plasma biomarkers for AD.
Compensation training and lifestyle modifications to promote healthy aging in persons at risk for Alzheimer's disease: A digital application supported intervention
Authors: Farias Sarah , Weakley Alyssa , Chan Michelle L , Beech Brooke F , Luna Catherine , Schmitter‐Edgecombe Maureen
Published: February 2022

Background

The protocol for ‘Brain Boosters’, a novel combined compensatory training and lifestyle modification intervention aimed at Alzheimer’s disease (AD) risk reduction is presented. Training in compensation will focus on a calendar and tracking system, organizational strategies, and goal setting, all aimed at supporting independent function. These same compensatory tools will be employed to facilitate adoption of lifestyle changes that support brain health (e.g., physical exercise, cognitive exercise, wellbeing exercise) through behavioral monitoring and feedback. A comprehensive suite of digital tools encapsulated in the Electronic Memory and Management Aid (EMMA), an easy to use, interactive application, will be used to facilitate behavioral change and enhance participant motivation. EMMA also allows collection of real‐time data to track intervention adherence and factors that influence adherence.

Methods

To capitalize on a critical window of opportunity to intervene, we will target cognitively normal older adults with subjective cognitive concerns (SCC), an established risk for AD and cognitive impairment. The trial will enroll 200 older adults with SCC who will be randomized to our digital application‐supported compensation training and lifestyle modification intervention or to an education only control group that will not use the EMMA app or be taught how to implement the educational material into their daily lives. Both intervention arms will be delivered in a group setting over 6 months, followed by 12 months of unsupervised follow‐up.

Results

Specific aims of the project include to: 1) evaluate intervention efficacy on primary outcomes (global cognition and everyday function); secondary outcomes focus on indicators of well‐being, cognitive domains (memory and executive function), physical function, compensation, and health behaviors; 2) evaluate characteristics of treatment responders; 3) evaluate adherence and identify the effective components of the target intervention using a mixed‐method approach; and 4) design machine learning algorithms that use patterns of change in real‐time data metrics to identify incipient declines in treatment adherence and changes in health status.

Conclusions

The project is expected to expand understanding of factors that may impact adherence to and outcomes of a preventative intervention leading to optimization of a scalable intervention to reduce dementia risk applicable to diverse populations.
Spousal caregiver burden in patients with cognitive impairment: Effects on nutrition and other related factors with cognition
Authors: Jeon So Yeon , Kim Jeong Lan
Published: February 2022

Background

With the rapid aging process, the number of elderly couple househol is increasing. Accordingly, when a patient with cognitive impairment occurs, the elderly spouse tends to take care of patient, and undergoes physical and psychological stress and changes in nutritional status due to the care, which can be a risk factor for cognitive decline.Therefore, this study aims to evaluate the spousal caregiver`s lifestyle, psychosocial factors and nutritional status related with cognition according to the burden of care for elderly couples.

Method

From May to December 2020, clinical evaluation and blood tests were conducted for patients who visited Chungnam National University Hospital Geriatric Neuropsychiatric Clinic with their spouse. A total of 39 subjects were included in the analysis. As clinical assessment, we evaluated the care burden(Zait burden interview), depression(Geriatric‐Depression‐Scale), sleep quality (Pittsburgh‐Sleep‐Quality‐Index), cognitive function(Mini‐Mental‐state‐exmination) and subjective cognitive decline, physical activity(International‐Physical‐Activity‐Questionnaire), and dietary habits(Mini‐Nutrional‐Assessment). And, serum total protein, albumin, Hemoglobin and Lipid pannel was measured.

Result

As the patient's cognitive function declined, the burden of care increased(p<0.001). In univariate analysis, the spousal caregiver`s burden was significantly associated with the worse the dietary habits(p=0.003) and increased level of depression(p=0.001) and subjective cognitive decline(p=0.038). The spousal caregiver`s burden showed trend level association with sleep quality(p=0.074), but there was no significant relationship with physical activity(p=0.653). When the age, sex, and caring assistant type were adjusted, dietary habits (p=0.002), depression(p=0.003), and sleep quality(p=0.023) worsened as the spousal caregiver`s burden increased.

Conclusion

Even if cognitive function in the older adult was normal, the higher the burden among spousal caregivers of patients with cognitive decline, the lower the diet habit and sleep quality, and the higher the level of depression. All of these factors could lower cognitive function. Early intervention on these factors is necessary to prevent the cognitive impairment in spouse due to the burden of care.
Technology‐assisted caregiver matching to address isolation and stress
Authors: Lunde Angela M , Forsberg Leah K , Seifert Sara J , Kramer Kevin M , Knutson Matthew , Lunde Angela , Miller Joel K , Melius Jodi L , Knopman David S , Boeve Bradley F , Petersen Ronald C , Fields Julie A
Published: February 2022

Background

Caregiving for persons with dementia negatively impacts physical and mental health, including increased risk for chronic loneliness and isolation. This Phase I study aimed to recruit former and current dementia caregivers as engaged partners in the design of a unique, technology‐assisted pairing platform to match caregivers to one another for meaningful connection and support based on characteristics chosen by the caregivers themselves.

Method

We recruited thirty‐two caregivers to participate in two semi‐structured focus groups (audio recorded for qualitative analyses) and complete a survey to understand the characteristics desired in another caregiver for the purpose of emotional support. Participants interacted with a website prototype on their personal device and completed a user experience feedback form. An iterative process was used to design the website and matching questionnaire allowing participants to validate preferences and concerns. Website analytics were captured (e.g. time to answer each question, total time spent on the website).

Result

The efforts culminated in a website ‘look and feel’ that addressed the preferences and criticisms of study participants. Figure 1 shows the home page slider inviting caregivers to join (images 1‐3) and describes the matching process (4); the caregiver answers up to 34 questions to create a profile (5‐7) and the website provides a list of caregivers that best match criteria (8). Overall, 87% of study participants rated a high level of comfort with completing the personal profile questions; 82% felt confident the questions asked would lead to a good match. An algorithm to match caregivers was created using the profile questions which asked participants to self‐select and then rank the characteristics of highest importance. Good and poor matches are scored by the algorithm, with 1 being a “perfect” match (Figure 2). In the current cohort, each participant had at least one match that scored 0.708 or higher.

Conclusion

Our study established interest in a technology assisted peer‐to‐peer caregiver matching program that is a potential low‐cost, high‐impact resource. The study resulted in a set of matching characteristics and an algorithm prototype within a user influenced website and will be further tested in Phase 2. Research supported from NIA of the NIH.
Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging
Authors: Scharre Douglas W. , Nagaraja Haikady , Icenhour Jennifer , Rawson Kristina , Truelove Jessica , Knopp Michael V.
Published: February 2022

Background

Lewy body dementia (LBD) and Alzheimer’s disease (AD) are the two most common neurodegenerative causes of dementia. Autopsy studies report many cases with these clinical diagnoses having mixed pathology with alpha‐synuclein, tau and amyloid proteinopathies. There is limited research in trying to distinguish these potential mixed pathology conditions prior to death. We used functional neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate clinically diagnosed subjects with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present.

Method

Eighteensubjects (all Caucasian, male/female ratio 15:3) so far were recruited from Ohio State University Memory Disorder and Movement Disorder Clinics in this currently enrolling study. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing including Mini‐Mental State Examination (MMSE) and Self‐Administered Gerocognitive Examination (SAGE) were performed. Neuroimaging evaluations performed by neuroradiology faculty were blinded to clinical diagnosis.

Result

Nine subjects with clinical diagnosis of Lewy body disease (5 DLB and 4 PD) and nine subjects with clinical diagnosis AD were compared. The Lewy body subjects were 71.3 ± 7.4 years old, MMSE 22.3 ± 5.4, and SAGE 9.7 ± 4.8. AD subjects were 67.1 ± 9.6 years old, MMSE 18.6 ± 5.2, and SAGE 9.0 ± 5.2. One subject (11%) of the clinical AD cases showed mixed LBD and AD features, one subject (11%) of the clinical AD cases was negative for amyloid with normal DaTscan uptake, two subjects (40%) of the clinical DLB cases showed mixed LBD and AD features, one subject (20%) of the clinical DLB cases was positive for amyloid with normal DaTscan uptake, and all four subjects with clinical PD showed neuroimaging findings consistent with PD.

Conclusion

Based on functional neuroimaging, 21% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 14% were misdiagnosed. Although the sample size is small, functional neuroimaging studies revealed possibly incomplete or incorrect diagnoses in about one third of subjects clinically diagnosed by subspecialists using standard clinical diagnostic criteria. Larger studies are required to confirm these findings.
Blood pressure is associated with advanced brain aging patterns on MRI in midlife: The CARDIA Study
Authors: Dintica Christina S. , Habes Mohamad , Erus Guray , Vittinghoff Eric , Davatzikos Christos , Nasrallah Ilya M , Launer Lenore J. , Sidney Stephen , Yaffe Kristine
Published: February 2022

Background

High blood pressure has been associated with cognitive outcomes such as dementia. Most studies have focused on blood pressure in mid or late life, thus this association in early adulthood is undefined. We aimed to investigate the relationship between sub‐clinical blood pressure in early adulthood and brain aging in midlife.

Method

From the prospective study of Coronary Artery Risk Development in Young Adults, 662 Black and White participants were identified with follow‐up of 30 years (age 18–30 years at baseline) and brain MRI at Year 30. Cumulative exposure of systolic and diastolic blood pressure (BP) from baseline through Year 30 were estimated by areas under the curve and analyzed as time‐weighted averages. We used a previously‐validated high dimensional machine learning pattern analysis method to derive brain aging indices that quantify individual differences in spatial patterns of age‐related atrophy: the SPARE‐BA index (Spatial Pattern of Atrophy for Recognition of Brain Aging). Cognitive function was assessed at year 30 with the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), Stroop Test, and Verbal Fluency. We used linear regression models to estimate the associations between cumulative BP and predicted brain age and cognitive function at year 30.

Result

Cumulative systolic and diastolic BP were positively associated with higher predicted brain age (β: 0.10, 95% CI: 0.04‐0.17, β: 0.10, 95% CI: 0.02‐0.19, respectively), adjusted for chronological age at year 30, sex, education, and race. Participants with cumulative systolic or diastolic BP over the recommended guidelines (systolic BP>120, diastolic BP>80), had on average 3‐years older predicted brain age (95% CI: 1.00‐4.67; 95% CI: 1.45‐5.13, respectively), compared to those with normal levels. Moreover, higher predicted brain age was associated with poorer performance on the RAVLT (p= 0.009), DSST (p<0.001), Stroop Test (p<0.001) and Verbal Fluency (0.009).

Conclusion

Elevated blood pressure from early to middle adulthood, especially above recommended guidelines, is associated with worse cognition in midlife and advanced brain aging. Elevated sub‐clinical blood pressure could be an important target for early intervention in order to prevent cognitive impairment.
Effects of diet and social status on white matter integrity in female cynomolgus monkeys
Authors: Kim Jeongchul , Barcus Richard A. , Frye Brett M. , Lockhart Samuel N. , Craft Suzanne , Register Tom , Andrews Rachel N. , Appt Susan E. , Vitolins Mara Z. , Uberseder Beth , Chen Haiying , Corbitt Sarah E. , Solingapuram Sai Kiran K. , Shively Carol A. , Whitlow Christopher T.
Published: February 2022

Background

Mounting evidence suggests that diet may influence risk for cognitive impairment and neurodegenerative disease, including Alzheimer’s disease. Nonhuman primates are important models of cognitive aging and Alzheimer’s disease‐like neuropathology given their complex central nervous systems and susceptibility to diet‐induced diseases. Diffusion magnetic resonance imaging (MRI) studies in humans report age‐related increases in mean diffusivity (MD) and decreases in fractional anisotropy (FA). Whether nonhuman primate models of Alzheimer’s disease‐like neuropathology show similar changes in diffusivity, and whether diet affects these changers is unknown. As such, the purpose of this study was to determine the longitudinal effects of diet (Mediterranean vs Western) and social subordination stress on diffusion MRI measures of white matter structural integrity in a nonhuman primate model of aging.

Method

In this IACUC approved study, thirty‐seven middle‐aged cynomolgus monkeys (Macaca fascicularis) were evaluated longitudinally with diffusion MRI measures (FA, MD, axial diffusivity [AxD], and radial diffusivity [RD]). Monkeys were scanned at baseline and after 31 months of diet consumption (∼ equivalent to a 9‐year follow up in humans). Diffusion MRIs were preprocessed (corrected for eddy current and geometric distortion) and co‐registered to high resolution T1w MRI to derive diffusion measures. For statistical analyses, cerebral white matter and 9 bilateral regions of interest (ROIs) were selected from NeuroMaps nonhuman primate atlas. Statistical analyses were performed with repeated measures analysis of variance.

Result

We observed social status differences in frontal (p=0.021) and occipital (p=0.029) white mater ROIs, with greater longitudinal increase or smaller longitudinal decrease in FA among subordinates compared to dominants. Diet and social status interacted to impact AxD in the genu of the corpus callosum (p=0.028). Finally, subordinates in the Mediterranean group demonstrated greater longitudinal diffusivity increases compared to 1) dominants in the Mediterranean group, 2) dominants in the Western group, and 3) subordinates in the Western group (Figure below).

Conclusion

While the biological mechanisms underlying these findings require future investigation, our observations suggest that diet and social subordination stress illicit changes in structural white matter integrity that could modify vulnerability to Alzheimer’s disease‐like neuropathology in middle‐aged nonhuman primates.
Livestreaming, interactive, group movement classes to address social isolation and well‐being in people living with memory loss and their caregivers
Authors: Nicosia Francesca M , Lee Jennifer Ann , Chesney Margaret A , Mehling Wolf , Sudore Rebecca L , Barnes Deborah
Published: February 2022

Background

Non‐pharmacologic programs can improve function and quality of life in people with memory loss (PWML), but in‐person programs are not available in many communities. We previously developed the interactive, livestreaming, group‐based, Moving TogetherTM program for PWML and their caregivers (CGs). This study assesses feasibility, satisfaction, and qualitative outcomes in four groups that participated during the COVID‐19 pandemic.

Method

We assessed feasibility based on number of participants and attendance. We administered an online survey at the end of the 12‐week program to assess satisfaction. The survey included a 6‐item Class Experience scale (e.g., feeling accepted, energized) and the 4‐item PROMIS Social Isolation scale, both using 4‐point Likert response scales. Open‐ended questions asked about changes noticed in themselves and others during the program. We used a previously established coding scheme informed by a biopsychosocial framework to code free‐text survey responses and refined codes as we identified new concepts.

Results

We offered four 12‐week class series (1 hour, 2 days/week) from April to July 2020 that included 8 to 14 participants each (total N=39: 24 PWML, 15 CGs). Average attendance was 78% (range: 58% to 98%). Surveys were sent to 31 participants who completed the program, of whom 25 (16 PWML, 9 CGs) responded. Nearly all respondents reported that they often, mostly or always felt acceptance and well‐being during classes (6‐items, 88% to 100%), and most reported that they rarely or never felt social isolation (4 items, 50% to 100%). Qualitative analyses of free‐text responses identified self‐reported improvements in both PWML and CGs in several areas: 1) emotional well‐being, including better mood, lower stress, and increased relaxation; 2) social connection, such as friendship and camaraderie; 3) physical function, including more energy, increased activity, improved movement, and increased mind‐body awareness; and 4) cognitive function such as better focus.

Conclusion

This study demonstrates that the interactive, livestreaming, group‐based, Moving TogetherTM program is feasible and associated with high satisfaction among both PWML and their CGs. Technology offers tremendous potential to increase accessibility to evidence‐based, non‐pharmacologic programs that people with memory loss (PWML) and caregivers (CGs) can participate in from the safety of their homes.
The effect of APOE4 on plasma and cerebrospinal fluid polyunsaturated fatty acids following DHA supplementation
Authors: Yassine Hussein N. , He Xulei , Lee Mitchell , Gomez‐Loarte Sol , Evans Jim E. , Oberlin Sarah , Abdullah Laila
Published: February 2022

Background

Past studies indicate that APOE4 promotes a metabolic shift toward greater fatty acid usage. We have shown that APOE4 is associated with lower increase in cerebrospinal fluid (CSF) polyunsaturated fatty acids (PUFAs) following supplementation with triglyceride (TG) based DHA. The purpose of this study is to define the effect of APOE4 on plasma and CSF lipids using a comprehensive lipidomic analysis.

Method

Plasma and CSF samples were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA treatment (n=13) vs placebo (n=13) in non‐demented older participants (CDR ≤ 0.5, age> 55 years old) and stratified by APOE4. Participants were provided 2,040 mg DHA daily in the form of TG‐DHA for six months.

Result

Following supplementation, levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increase in CSF (p<0.0001). Using principal component analysis, changes in plasma TG (56:8), TG (58:10), ePE (40:8), TG (56:9), PC (40:6) and PC (38:6) had the strongest correlations with changes in CSF PC (38:6, p<0.001). Figure 1 shows Pearson correlation coefficients of all plasma and CSF lipids. Among all lipid species, changes in PUFA enriched TGs were significantly correlated between CSF and plasma. APOE4 had a significant effect on CSF TG (52:6) changes, with the mean increase in E4 carriers significantly (0.039 units) less than in E4 non‐carriers (p=0.0072) after adjusting for baseline levels and treatment group.

Conclusion

Our findings demonstrate the first time the existence of PUFAs within a TG pool in CSF that correlates with the corresponding plasma TG pool, suggesting an exchange of TG particles at the CSF‐blood barrier. The effect of APOE4 on the metabolism of PUFAs is strongest on TG enriched PUFAs and supports their greater oxidation in APOE4. These findings help explain why APOE4 carriers are vulnerable to dietary omega‐3 deficiency, and less responsive to short term omega‐3 supplementation.
Examining the structural correlates of amyloid‐beta in people with DLB
Authors: Gajamange Sanuji , Yassi Nawaf , Chin Kai Sin , Desmond Patricia M. , Villemagne Victor L. , Rowe Christopher C. , Watson Rosie
Published: February 2022

Background

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized pathologically by the deposition of alpha synuclein. Many patients with DLB also have brain compatible with Alzheimer’s disease (namely Amyloid‐β and tau), which can lead to challenges with clinical diagnosis and management. In this study we aim to understand the influence of Aβ on brain atrophy in DLB patients.

Method

19 participants with probable DLB underwent 3T MRI T1‐weighted (voxel size=0.8x0.8x0.8mm3, TR=2400ms, TE=2.31ms) and β‐amyloid (Aβ) PET (radiotracer 18F‐NAV4694) imaging. Participants were grouped into Aβ negative (n=10; age=71.6±5.8 years) and Aβ positive (n=9; age=75.1±4.3 years) with a threshold of 50 centiloid units to identify neuropathological change (Amadoru et al. 2020). Brain volume measures (regional subcortical grey matter and global white and grey matter) were segmented from T1‐weighted images with FreeSurfer (Fischl et al. 2002, Fischl 2012). Given previous literature suggesting prominence of thalamic structural changes in DLB, we also specifically analysed changes in the thalamus by segmenting the thalamus into 25 nuclei, which were then grouped into six regions (anterior, lateral, ventral, intralaminar, medial and posterior) (Watson et al. 2017, Iglesias et al. 2018). All brain volumes were expressed as fractions of intracranial volume to account for differences in head size. Group comparison analyses were not controlled for age and sex as both these covariates did not statistically differ between groups.

Result

Brain volume differed significantly between Aβ‐ and Aβ+ DLB patients in the left thalamus (Aβ‐:4.39±0.37x103, Aβ+:4.07±0.19x103, p=0.03) and right thalamus (Aβ‐:4.17±0.34x103, Aβ+:3.84±0.22 x103, p=0.03). Specifically, the ventral (LEFT; Aβ‐:1.78±0.15, Aβ+:1.63±0.14, p=0.03. RIGHT; Aβ‐:1.83±0.15, Aβ+:1.65±0.12, p=0.01) and posterior (LEFT; Aβ‐:1.30±0.12, Aβ+:1.17±0.10, p=0.04. RIGHT; Aβ‐:1.42±0.14, Aβ+:1.21±0.12, p=0.003) regions were significantly reduced in Aβ+ compared to Aβ‐ DLB patients.

Conclusion

We demonstrated significant thalamic atrophy in Aβ+ patients compared to Aβ‐ DLB patients. We did not observe significant differences in grey matter and hippocampal volume between patient groups. This study showed that AD‐related processes in DLB patients are associated with thalamic atrophy, specifically in the ventral and posterior regions. Future studies would benefit a larger DLB cohort to further understand the association between AD‐related pathology and the regional thalamic correlates of clinical function.
Cortical microstructural associations with CSF amyloid and tau
Authors: Nir Talia M. , Reina Julio E. Villalon , Haddad Elizabeth , Zheng Hong , Thomopoulos Sophia I. , Maiti Piyush , Zhu Alyssa H. , Thompson Paul M. , Jahanshad Neda
Published: February 2022

Background

Multi‐shell diffusion MRI (dMRI) biophysical models can estimate intracellular (ICVF), extracellular (ECVF) and free water (ISOVF) volume fractions (VFs) in brain tissue, and may offer insight into Alzheimer's disease pathological processes. These microstructural measures can be calculated in the cortex using a gray matter specific model that may be sensitive to amyloid and tau burden. Here, we evaluated relationships between regional cortical microstructural VFs and CSF amyloid and tau biomarkers.

Method

Multi‐shell dMRI and CSF biomarker data were available for 50 ADNI‐3 participants (age: 72.4±6.4 yrs; 20 male; 36 cognitively normal, 12 MCI, 2 dementia). Cortical ICVF, ECVF and ISOVF were estimated with the multi‐tissue spherical mean technique (MT‐SMT). Mean cortical measures were extracted from 4 lobes and the cingulate cortex, parcellated with FreeSurfer. Random‐effects linear regressions tested associations between regional dMRI measures and CSF pTau or Aβ42/Aβ40 burden, adjusting for age, sex, education, and grouping by scanning site. FDR (q=0.05) was used to correct for multiple comparisons across 5 regions, 3 diffusion measures, and 2 tests.

Result

Higher Aβ42/Aβ40 was associated with lower ISOVF throughout the cortex (Figure 1), and higher ECVF and ICVF in the cingulate, frontal and temporal lobes. Higher ICVF was also found in the parietal cortex. Higher pTau was associated with higher ISOVF in the occipital and parietal lobes, and lower ECVF in the frontal and parietal lobes (Figure 2). No pTau ICVF associations were detected.

Conclusion

Lower ICVF and higher ISOVF with greater amyloid and tau may indicate neuronal loss or edema, while lower ECVF could reflect, for example, as neuronal swelling or an influx of activated microglia. Lower ECVF with greater amyloid and tau burden may also reflect accumulation of large hydrophobic amyloid plaques and neurofibrillary tangles in the extracellular space. These results are preliminary and, as many factors influence dMRI measures, should be interpreted with caution. Future work will incorporate multimodal imaging to map associations of diffusion measures with localized PET‐derived amyloid and tau measures.
Sex‐dependent age trajectories of subcortical brain volume: A UK Biobank study (N=39,544)
Authors: Ching Christopher , Muir Alexandra M , Santhalingam Vigneshwaran , Abaryan Zvart , Zhu Alyssa H , Thomopoulos Sophia I , Jahanshad Neda , Thompson Paul M
Published: February 2022

Background

Understanding the normative variation in brain structure across life may provide insights into healthy aging as well as neurological disorders such as Alzheimer’s disease (AD). Women are at greater risk of developing AD, but men tend to show faster rates of subcortical atrophy across adulthood. Sex‐dependent differences in male and female brain aging trajectories may change over the adult lifespan, and could play a role in differential risk for neurological illness. The current study maps normative trajectories (nomograms) of subcortical volume across adulthood and quantifies the interaction between age and sex in a large, healthy sample.

Method

T1‐weighted brain MRI from a sample of UK Biobank participants free from psychiatric/neurological illness (; N=39,544; 44.6‐82.8 years) were segmented using FreeSurfer 7.1 to derive average left and right thalamus, putamen, pallidum, hippocampus, amygdala, caudate, nucleus accumbens and ventricle volumes. Normative quantile regression models (nomograms) were created to visualize aging trajectories for each volume. Linear mixed models were fit in binned age groups to assess age‐by‐sex interactions across middle to late adulthood.

Result

Nomograms showed volumetric loss across adulthood, except for ventricular volume which was larger with increasing age (). Compared to females, males showed a steeper slope of volume change with increasing age in all regions across the full age range (Cohen’s d: ‐0.14 ‐ 0.12) (). Binned‐age analysis showed males to have steeper volume loss trajectories in middle adulthood, with fewer age‐by‐sex interactions detected later in life for most structures.

Conclusion

In a large sample of healthy adults, we found a structure‐specific interaction between age and sex, with males tending to show steeper age‐related volume loss trajectories compared to females until later decades of life, where trends appeared similar for men and women. This study provides normative subcortical aging trends and identifies potential sex‐dependent variations across life that may be used to understand healthy brain aging and risk for disorders such as AD.
Does [18F]FDG and [18F]AV1451 PET predict neurodegeneration?
Authors: Nowell Joseph , Young Megan , Raza Sanara , Livingston Nicholas R , Crook Harry , Edison Paul
Published: February 2022

Background

[18F]FDG PET is a well‐established and valuable biomarker in the assessment of neurodegenerative disorders, with high diagnostic utility, wide accessibility, and relatively low costs. Recent advances in PET imaging technology now allow for the in vivo exploration of tau deposition. However, it is still being debated which of [18F]FDG PET or [18F]AV1451 PET better predicts neurodegeneration. This study aimed to evaluate [18F]FDG PET and [18F]AV1451 PET imaging in predicting grey matter atrophy in patients with cognitive impairment.

Method

190 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.3 years, SD = 8.04) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, [18F]AV1451 and [18F]FDG PET scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within the medial temporal lobe. Whole brain grey matter volumes were obtained from processed data from ADNI. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.

Result

There was a significant negative association between [18F]AV1451 uptake in the medial temporal lobe and whole brain grey matter volume (r = ‐0.288, p = 0.001). A stronger positive relationship was identified between medial temporal lobe [18F]FDG uptake and whole brain grey matter volume (r = 0.444, p < 0.001).

Conclusion

This study demonstrated that regional FDG and tau tracer uptake in patients with cognitive impairment both display a significant relationship with total grey matter volume. Whilst both tracers show utility in predicting a patient’s level of neurodegeneration, glucose metabolism as indicated by [18F]FDG PET appears to have a closer relationship to grey matter atrophy than PET markers of tau deposition.