bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Plasma, Imaging, Cerebrospinal Fluid Biomarkers and Naturalistic Driving Behaviors, Cognitive Tests Among Cognitively Normal Persons
Authors: Roe Catherine M , Bayat Sayeh , Murphy Samantha , Doherty Jason , Walker Alexis , Pina Yasmin , Babulal Ganesh M
Published: December 2022

Background

Previous work indicates that imaging and cerebrospinal fluid (CSF) amyloid and tau biomarkers are associated with driving behaviors, and that driving behaviors can be used to identify preclinical Alzheimer’s disease (AD). Along with traditional biomarkers, we examined the extent to which newer plasma and CSF biomarker are related to driving and cognitive metrics among cognitively normal older drivers.

Method

Mean driving and cognitive metrics were computed for all available time points in cognitively normal (Clinical Dementia Rating ® = 0) participants (N=167, mean age=73.3±4.9). Participants had a data logger installed in their personal vehicles and drove at their discretion for at least 6 months (mean follow‐up 2.2y±0.9y, range=0.6y‐4.7y) between 6/2/2015 and 2/29/2020 (pre‐COVID data) and took part in cognitive testing yearly. Participants took part in biomarker testing including, imaging (positron emission tomography [PET] amyloid, PET tau, normalized hippocampal volume [nHV]), CSF (Aβ42, Aβ40, tau, ptau181, neurofilament light chain [NfL]), and/or plasma (Aβ42, Aβ40, Aβ42/Aβ40, NfL) within 2 years of data logger installation. Fisher’s Z transformation was used to examine the correlations between the biomarker variables and the driving and cognitive measures.

Results

(Figure attached) Individual biomarkers were differentially related to different driving behaviors (e.g., number of trips was associated with PET amyloid [p<0.035], plasma Aβ42 [p<0.012] and Aβ40 [p<0.004], but not the other imaging, CSF, and plasma biomarkers [p>0.275]); and to different cognitive scores (e.g., Montreal Cognitive Assessment [MoCA] total scores were associated with amyloid imaging [p<.026], nHV [p<0.033], and plasma Aβ42/Aβ40 [p<0.035] but to no other biomarkers [p>0.080]). Some biomarkers were associated with driving behaviors but not cognitive scores (e.g., CSF Aβ40, tau, NfL; plasma Aβ42 and Aβ40 considered separately) whereas others were related to cognitive scores but not to any of the individual driving metrics (e.g., CSF Aβ42/Aβ40 ratio).

Conclusions

Different biomarkers are associated with different aspects of driving and cognitive functioning. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD impact various sensorimotor and cognitive processes.
White Matter Fractional Anisotropy in a Nonhuman Primate Model of Early Alzheimer’s Disease‐like Neuropathology: Relationships with Social Status and Physiologic Measures of Stress Responses
Authors: Frye Brett M. , Craft Suzanne , Register Thomas C. , Kim Jeongchul , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Sai Kiran K. Solingapuram , Shively Carol A.
Published: December 2022

Background

Psychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.

Method

Using diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).

Result

Repeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p<0.05). Dominants also had higher FA, on average, in the body of CC (p=0.07) and cerebrum (p=0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p>0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s<0.05), but not correlated with serum cortisol.

Conclusion

Psychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.
Comparison of degu (Octodon degus), Naked Mole Rat, Mouse and Human genomes identified common hallmarks of aging and Alzheimer's Disease
Authors: Cogram Patricia , Urra Claudio , Travisany Dante , Yañez Cristian , Hurley Michael J
Published: December 2022

Background

To provide new insight into the mechanisms of Alzheimer’s disease (AD) pathogenesis and aid the discovery of new therapies in humans it is important to expand and complement research using mouse models by developing, characterizing, and validating suitable new or unconventional mammalian, non‐murine models of AD. Our goal was to create genome assemblies at the chromosome level associated with AD‐like pathogenesis using two long‐lived animal models. The degu (Octodon degus) which naturally exhibits AD neuropathology and the naked mole rat (H. glaber) best known for its resistance to cancer and aging. To understand evolutionary paths to longevity and associated diseases like AD we characterized their genome features and identified common substitutions in long‐lived rodents that support enhanced tolerance to DNA damage.

Method

Synteny maps among M. musculus, H. glaber, H. sapiens and O. degus were created using SyMAP 5.0.6. To evaluate disease‐related mutations in humans a pairwise comparison of protein sequences was performed using the HGMD.

Result

We identified several synteny blocks that were part of the putative rodent ancestor genome. 78% genome was covered in H. glaber and 75% coverage in O. degus. In addition, 58 of the 426 synteny blocks were longer than 10 Mbp in M. musculus and 62 in O. degus. The identification of substitutions in orthologs at disease‐causing sites revealed that DNA damage and repair genes are under selection in long‐lived species. Our comparative genomic analyses identified that the top disease categories enriched in degu and naked mole rat were associated with lipid metabolism, DNA repair, stress and IGF‐1.

Conclusion

Our comparative genome analysis revealed changes in genes and pathways associated with adaptations to acquired longevity. Substitutions at AD causing sites may contribute to long‐term survival pathways affected by natural selection in long‐lived models. When compared to short‐lived mouse models, pathways associated with lipid metabolism, oxidative stress and DNA repair were identified. This data is particularly valuable for providing a within family (Rodentia) comparison for mouse AD model genomics to develop a comprehensive analysis to determine conserved genetic alterations between the unconventional animal models and to bridge our existing databases of mouse models and humans.
Multidisciplinary medication therapy management and participant responses to recommendations: Results from the INCREASE trial
Authors: Smith Noah I , Huffmyer Mark , Eckmann Lynne , George Rosmy , Abner Erin L , Jicha Gregory A , Moga Daniela C
Published: December 2022

Background

Medication use, especially in the context of polypharmacy and inappropriate medications, may be a modifiable risk factor for cognitive impairment and dementia. Medication therapy management (MTM) interventions, which seek to optimize patient‐specific medication regimens, may restore cognitive function and delay onset of cognitive decline. Here, we describe an MTM protocol, delivering patient‐centered recommendations through joint decision‐making among the study participant, pharmacy specialist, and non‐pharmacist clinician (e.g., study physician) directed at delaying the symptomatic onset and progression of AD.

Method

Community dwelling adults age 65 and older, without dementia, using at least one potentially inappropriate medication (PIM) were enrolled in a clinical trial to evaluate the effect of the MTM on improving medication appropriateness and cognition (INCREASE; NCT08245639). In a three‐step process, study pharmacists first identified potential mediation‐related problems (MRPs) and made initial recommendations for prescribed and over‐the‐counter medications, vitamins, and supplements. Second, study team clinicians and pharmacists reviewed all initial recommendations together with the participants, allowing for revisions to make a final recommendation. Third, participant responses to final recommendations were recorded. Here, we evaluated participant responses in relation to medication class and type of final recommendation.

Result

Among the 90 randomized participants, a mean 6.7±3.6 MRPs per participant were reported. A total of 259 initial MTM recommendations were made for the treatment group participants, with 40% percent undergoing revision in the second step (Table 1). Participants reported willingness to adopt 46% of final recommendations and need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications (Table 1).

Conclusion

As integration of healthcare disciplines and specialized services become an increasingly important part of collaborative healthcare practices, this study demonstrated that initial MTM recommendations often change through group discussion, and multidisciplinary decision‐making that incorporated the preferences of patients themselves often led to positive participant responses. Further studies are needed to assess whether participants adhere to MTM recommendations long‐term, and to evaluate the health and economic impact of MTM on chronic disease prevention and maintenance, such as with AD and related dementias.
Associations among plasma ptau181, tau PET, and amyloid PET in a community‐based study during midlife
Authors: Lao Patrick J. , Simoes Sabrina , Banjoko Michael B. , Benavides Andrea , Lippert Rafael , Berroa Joncarlos , Igwe Kay C , Schupf Nicole , Mayeux Richard , Manly Jennifer J , Brickman Adam M.
Published: December 2022

Background

The amyloid‐tau‐neurodegeneration (AT(N)) research framework uses a biomarker definition of Alzheimer’s disease (AD); neuroimaging has been the in vivo gold standard, but plasma‐based measures are becoming more widely available yet need to be characterized earlier in the life course and AD continuum, as well as in representative samples. Our objective was to understand how plasma measures of ptau181 correspond with PET‐derived measures of amyloid and tau in middle age.

Methods

In the ongoing Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease, participants (n=61; 61±6, 52‐79 years old, 67% women, 14±4 years of education, 10% Non‐Latinx White/25% Non‐Latinx Black/65% Latinx) underwent measures of amyloid (weighted average Florbetaben SUVR in Thaal phase regions) and tau (average MK‐6240 SUVR in Braak stage I; SIMOA‐based plasma ptau181). Amyloid‐positivity was determined at >1.25 SUVR and tau‐positivity was determined at >2 SD above the mean SUVR in an independent sample of cognitively unimpaired individuals. General linear models tested associations among plasma ptau181, tau PET, and amyloid PET.

Results

Fifteen percent were amyloid‐positive while five percent were tau‐positive. Ptau181 was not associated with PET‐based tau burden (R=‐0.18, p=0.17). Amyloid burden increased with age (R=0.37, p=0.003). PET‐based tau burden increased with amyloid (R=0.29, p=0.02), but not with age (R=0.16, p=0.22). Conversely, ptau181 increased with amyloid (R=0.26, p=0.04) and with age (R=0.25, p=0.05).

Conclusions

A temporal discrepancy between plasma and PET‐based tau, particularly in a sample of mostly amyloid‐ and tau‐negative middle‐aged adults, may explain the lack of association between ptau181 and tau PET. However, both plasma and PET‐based tau were associated with elevated amyloid burden, which is thought to be necessary for the spreading of pathological tau in AD. Prior studies suggest that associations between plasma ptau181 and tau PET are stronger and shift from early Braak stage regions to late Braak stage regions further along the AD continuum. Therefore, it is important to understand the utility of plasma ptau181 in the context of age and disease stage.
Announcing the Vietnamese Insights into Aging Program (VIP)‐ The First Cohort Study of Cognitive Aging in Vietnamese Americans
Authors: Meyer Oanh L. , Farias Sarah Tomaszewski , Whitmer Rachel A. , Kanaya Alka , Hinton Ladson , Harvey Danielle J. , Tiet Quyen Q , Vuong Quyen , Park Van Ta
Published: December 2022

Background

Asian Americans are the fastest growing racial population in the U.S; yet very little is known about their cognitive aging and Alzheimer’s disease and related dementias (ADRD) risk. Vietnamese Americans are the largest Southeast Asian group and are at high risk for health disparities. Unlike other large Asian subgroups, due to their sociopolitical history and experiences as refugees, Vietnamese Americans have faced a significant amount of adversity and trauma. As Vietnamese Americans age and their susceptibility to ADRD increases, their context may provide unique understanding in terms of within‐group heterogeneity and reveal key factors in ADRD and cognitive aging. The Vietnamese Insights into Aging Program (VIP) is the first longitudinal study of older Vietnamese Americans and addresses the dearth of ADRD research in this high‐disparity population. The goal is to obtain estimates of cognitive impairment and dementia in the community and identify ADRD risk (e.g., early life trauma) and protective (e.g., social support) factors in this understudied population.

Method

We will enroll 540 Vietnamese (age ≥65 years) across two sites in Northern California. Participants will be seen annually over 3 years to assess cognitive change over time. The following data will be collected: 1) a full neuropsychological battery; 2) an extensive interview about early life history and trauma as well as psychological and sociocultural factors, and 3) cardiovascular risk factors (hypertension, diabetes, smoking, etc.). Assessments will be conducted in Vietnamese and take place at a community partner site. In collaboration with local community partners, extensive community outreach and education were conducted prior to study recruitment.

Result

VIP has developed a protocol for the bilingual Vietnamese assessments which has been further refined by scientists, staff, and VIP’s community advisory board, many of whom are bicultural and bilingual Vietnamese American. VIP currently has a waitlist of over 250 participants as of January 2022. We aim to complete Time 1 assessments of all 540 participants by Spring 2023.

Conclusion

Innovative research with older Vietnamese Americans provides a unique opportunity to refine research methodology and more fully delineate the factors that contribute to ADRD disparities in underserved populations.
Characterizing Caregiver Outcomes in a Culturally Diverse Sample
Authors: Meyer Oanh L. , Alto Raquel , Harvey Danielle J. , Tran Duyen , Luu San , Nguyen Rachel , Hinton Ladson
Published: December 2022

Background

Caring for a family member with cognitive impairment is accompanied by challenges that place caregivers at risk for significant health problems. Yet the study of racially/ethnically diverse caregivers across the spectrum of Alzheimer’s disease and related dementias (from mild cognitive impairment: MCI to dementia) is understudied. In this study, we characterize caregiver stress and burden and examine their role on caregiver self‐rated health and depressive symptoms.

Methods

We enrolled 158 adults (non‐Hispanic White (NHW): 66%; Latino: 16%; Black: 9%; Asian: 8%) caring for a family member with MCI (35%) or dementia (65%). Approximately 37% were recruited from an Alzheimer’s Disease Research Center (ADRC) and 63% from the community. Caregivers completed demographic and psychosocial questionnaires online or by paper in English or Spanish. Linear regression models were used to assess associations between perceived stress and burden and caregiver outcomes (depressive symptoms and self‐rated health), controlling for caregiver demographics.

Results

Black caregivers reported less burden (mean = 23.7) than NHW caregivers (mean = 35.4), p = .007. There was no difference in perceived stress by race/ethnicity (p = .2). Burden was higher (p = .001) for caregivers of individuals with dementia (mean = 35.9) than those with MCI (mean = 27.6), as was perceived stress (dementia caregivers: mean = 16.0; MCI caregivers: mean = 13.6), p = .03.

Higher caregiver burden (p<.001) and perceived stress (p<.001) were positively associated with depressive symptoms. Caregiver burden was not associated with self‐rated health (p = .1); but higher perceived stress was associated with poorer self‐rated health (p<.001).

Conclusions

Caregivers of persons with cognitive impairment suffer a substantial burden emotionally and physically. Our results indicate that dementia caregivers may have greater challenges in caring for their family member compared to those caring for someone in the early or milder stages of illness. The racial/ethnic difference may be due to the fact that NHW caregivers actually experience more burden in caregiving; an alternative explanation is that burden may not be felt or manifested in the same way in Black caregivers. Lastly, perceived stress is an important determinant of caregiver health and mental health outcomes. More research is needed to understand the variety of factors associated with caregiver outcomes and how they may differ across racial/ethnic groups.
Pathological consequences of microglial derived exosome (MDEs) cargo in vivo
Authors: Winston Charisse N. , Rissman Robert A. , Mante Michael N , Florio Jazmin N , Guzman Estefani N , Salehi Sahar N
Published: December 2022

Background

Exosome cargo proteins may serve as useful biomarkers for AD however very few studies have characterized the pathological consequences of exosome cargo in vivo. We determined that neuronally‐derived exosomes isolated from autopsy‐confirmed demented AD patients induced AD‐like neuropathology in the WT mouse CNS. Here, we extended our previous studies to investigate the neuropathological and behavioral consequences of plasma cargo proteins derived from microglia cells in vivo.

Method

Plasma exosomes derived from autopsy‐confirmed, cognitively normal controls and demented AD patients were extracted, precipitated, and enriched against a microglial source (TMEM119, MDE) using magnetic immunocapture. MDEs were characterized by Nanosight and exosome marker profiling. MDEs were injected unilaterally into the brains of normal mouse CNS. Brains from MDE injected mice were probed for AD‐related proteins to confirm cargo transfer to recipient cells at 3 and 6 months post injection (mpi). Deficits in spatial learning and memory, gait stability and anxiety were assessed at 6 mpi.

Result

Plasma MDEs demonstrate similar size distributions and shape to previously reported exosome preparations. MDEs were positive for exosome marker Flotilin‐1; microglial markers CD68 and IBA1 and negative for astrocyte marker, GLAST. At 3mpi, pathological forms of tau, as measured by PHF1 and MC1, and amyloid beta (Ab) as measured by 6E10, were observed the cortex and hippocampus of MDE injected mouse. At 6 mpi, we will determine the neuropathological behavioral consequence of MDE cargo in vivo.

Conclusion

MDEs can transfer AD‐related proteins to normal mouse CNS. The behavioral consequence of MDE cargo in vivo is currently being investigated.
Using a smart audio device, Tochie to deliver family messages in long‐term care
Authors: Hung Lillian , Yang Sophie , Lin Margaret , Chen Irene
Published: December 2022

Background

Long‐term care (LTC) residents are more likely to experience loneliness, social isolation and have dementia (Garner et al., 2018; Hou & Ngo, 2021). The effects of isolation have been exacerbated by the COVID‐19 pandemic. While assistive technology has been a popular topic in gerontological health research, there have been limited findings on the experience of technology adoption in complex care environments such as LTC, and on family member and staff perspectives. “Tochie” is a smart audio device that allows family and significant others to remotely record and schedule messages, such as daily reminders or comforting audio recordings, to send to their loved ones in care settings. Our research explores the experiences of residents, families, and staff using the Tochie device in LTC.

Method

We applied qualitative descriptive design with interview and focus group methods. 10 residents, 9 family members, and 6 care staff from two long‐term care homes in British Columbia, Canada, participated in the study. Each resident was given a device to use with their family member for a four‐week intervention period. The research team checked in with family members and staff weekly via telephone and email to provide support and gather feedback. Pre‐ and post‐intervention focus groups and interviews were held via Zoom and phone correspondence to learn about participants’ experiences using Tochie. Thematic analysis was performed to identify themes.

Result

Four common themes were identified to describe the experience of using Tochie in LTC: (a) Tochie as a means to facilitate emotional connection (b) Using Tochie in creative, personalized ways (c) Challenges and contextual considerations in LTC (d) Ideas for future developments

Conclusion

The COVID‐19 pandemic has provided us an opportunity to redefine and reconstruct what it means to “keep in touch” with loved ones in care settings. In our study, residents, families and staff highlighted the ways in which Tochie has enabled this connection and provided feedback on their challenges and device recommendations. This study explores the valuable perspectives of residents, their loved ones, and care staff in the use of assistive audio devices to inform product development and adoption into LTC.
Midlife engagement in cognitive activities and cognitive function in middle aged individuals at high risk for AD
Authors: Ravona‐Springer Ramit , Heymann Anthony , Moshier Erin , Yore Iska , Shamir Tamar , Soleimani Laili , Beeri Michal Schnaider
Published: December 2022

Background

We examined the cross‐sectional relationship of engagement in cognitive activities with cognitive function in cognitively normal middle‐aged (40‐65y) individuals enriched for high risk for Alzheimer’s disease (AD) due to a parental family history (FH+), and matched controls (FH‐), participants of the Israel Registry for Alzheimer’s Prevention (IRAP) study.

Method

Engagement in cognitive activities by type and intensity was evaluated via the Florida Cognitive Activities Scale (FCAS) (score range 0–100), resulting in three scores: 1) FCAS‐Total, 2) FCAS‐Higher Cognitive (HC), capturing activities more cognitively demanding (e.g. playing chess) and 3) FCAS‐Frequent Activity (FA), capturing frequent activities (e.g. watching TV). A comprehensive neuropsychological battery yielded scores for four cognitive domains; executive functions, language, working memory and episodic memory. Global cognition was the mean of the four cognitive domains. Regression analysis adjusting for age, sex and education examined the relationship of each one‐point increase in the FCAS scores on cognitive function for the total sample.

Result

The study included 473 participants (FH+ = 374; FH‐ = 99) (Table 1). Participants' mean age was 54.9 (SD = 6.7) years (64.4% women) with 16.5 (SD = 3.1) years of education. The groups did not differ in sociodemographic, cognitive or FCAS characteristics. The FCAS‐Total score was associated with better global cognition (slope = 0.0150; p = 0.001), executive functions (slope = 0.0147; p = 0.005), language (slope = 0.0095; p = 0.0052) and working memory (slope = 0.0117; p = 0.0142). Higher FCAS‐HC score was associated with better global cognition (slope = 0.0221; p = 0.010), executive functions (slope = 0.0315; p = 0.001), language (slope = 0.0214; p = 0.0008) and working memory (slope = 0.0244; p = 0.006). FCAS‐FA was not associated with function in any of the cognitive domains. There were no associations between total cognitive activity nor its sub‐types with episodic memory.

Conclusion

Higher engagement in cognitive activities, specifically those requiring higher cognitive effort, is associated with better cognitive function already in midlife. This relationship was not detected for episodic memory, which is the domain most typically affected in the first stages of AD. The longitudinal phase of the IRAP study will reveal the underlying mechanisms and whether reduced engagement in cognitive activity is a risk factor or a very early indicator of incipient cognitive decline high AD risk adults.
Baseline and Longitudinal Ioflupane SPECT Findings in DLB and MCI‐LB
Authors: Boeve Bradley F. , Miyagawa Toji , Przybelski Scott A. , Min Paul H , Jordan Lennon , Lesnick Tim , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , Ramanan Vijay K , Knopman David S. , Petersen Ronald C. , Graff‐Radford Neill R. , Day Gregory S , Fields Julie A. , Machulda Mary M. , Ferman Tanis J , Forsberg Leah K. , Diaz‐Galvan Patricia , Li Wentao , Christine Cliatt Brown J , Jack Clifford R. , Jain Manoj K. , Kantarci Kejal , Lowe Val J.
Published: December 2022

Background

Reduced striatal uptake on ioflupane SPECT is considered an indicative biomarker for Dementia with Lewy Bodies (DLB), and has been proposed as an indicative biomarker for Mild Cognitive Impairment with Lewy Bodies (MCI‐LB). Little data exists on the profile of uptake on key striatal regions of interest (ROIs) in DLB or MCI‐LB.

Method

Participants with DLB or MCI‐LB at baseline based on the presence of ≥2 core clinical DLB features, and ≥2 ioflupane SPECT scans performed approximately annually, were identified from the Mayo ADRC database. Minimum brain laterality z‐score values for the putamen (whole, anterior and posterior), caudate and striatum were determined using DaTQUANT 2 software. Baseline clinical and scan data was used for all analyses, and the annualized minimum putamen z‐change was determined on serial scans. The scan was considered abnormal if the minimum putamen z‐score was <‐0.98 based on clinicopathologic data.

Result

27 participants were included (21 DLB and 6 MCI‐LB, 96% male). Compared to MCI‐LB, DLB had a lower mean MoCA score and a trend toward a higher UPDRS score compared to MCI‐LB; there were no statistically significant differences in age, sex, onset age or duration of cognitive decline, or presence of other core DLB features. The majority (89%) had an abnormal scan at baseline. All ROI z‐scores showed the expected general trend of DLB<MCI‐LB, and the annualized z‐change was more negative in DLB, but none of the findings reached statistical significance.

Conclusion

These findings suggest in MCI‐LB and DLB that 1) an abnormal ioflupane SPECT scan is frequently present at diagnosis, 2) z‐scores become more negative over time, and 3) the annualized z‐change is similar. Similar findings in larger cohorts would support the use of ioflupane SPECT as a biomarker in both MCI‐LB and DLB clinical trials.
NOVEL VIRTUAL REALITY‐ BASED METHOD FOR OBJECTIVE MEASUREMENT OF EMOTIONAL REACTIVITY IN PATIENTS WITH ALZHEIMER'S DISEASE
Authors: Ravona‐Springer Ramit , Wilf Meytal , Koren Or , Rosenblum Uri , Galor Noam , Lapid Michal , Plotnik Meir
Published: December 2022

Background

Diminished emotional reactivity in cognitively normal (CN) older adults and in patients with Alzheimer's disease (AD) is associated with higher burden of neuropathology and predicts faster cognitive decline, stressing its potential to serve as a behavioral screening tool for individuals at high AD‐risk and for a more aggressive disease course. Its measurement is currently based on questionnaires which are prone to subjectivity biases. We present preliminary results of a study aimed to examine the feasibility of using autonomic nervous system (ANS) reactivity to emotional stimuli presented in a virtual reality (VR) environment, as an objective measurement tool of emotional reactivity. Specifically, we test the hypothesis that emotional reactivity, as expressed by galvanic skin response (GSR), will be reduced in patients with AD compared to CN individuals.

Method

Participants are patients with mild‐ moderate AD and cognitively normal age matched controls. Cognitive function is assessed via the Montreal Cognitive Assessment (MoCA) battery. Participants are exposed in the VR‐ environment to emotionally‐ laden stimuli (positive, neutral and aversive, 12 repetitions per stimulus type) while measuring GSR. Response weighted mean was calculated for each participant for each stimulus type. Non parametric group comparisons (AD vs. CN) were performed (U‐test) for each stimulus type separately (Bonferroni corrected).

Result

So far, 30 patients with AD and 21 CN individuals have been recruited. Participants' mean age is 75.6 years, 60.8 % females (Table 1). Patients with AD had lower scores on the MoCA (p<0.001), but did not differ from CN in demographic variables. VR‐based evaluation was well accepted by the participants with no adverse events. CN participants showed higher GSR reactivity as compared to AD patients for aversive stimuli (p<0.05) but not for neutral or positive stimuli (Figure 1).

Conclusion

GSR reactivity to emotional stimuli presented in the VR environment is a feasible method to study emotional reactivity in CN older adults and in participants with AD. GSR reactivity to aversive stimuli is reduced in AD participants compared to CN. These preliminary findings should be further established in larger populations while detecting the optimal type of stimulus required to differentiate between clinically distinguished cohorts.
Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading
Authors: Franzmeier Nicolai , Ewers Michael , Brendel Matthias , Biel Davina , Ossenkoppele Rik , Hager Paul , Steward Anna , Dewenter Anna , Rubinski Anna , Buerger Katharina , Janowitz Daniel , Binette Alexa Pichet , Smith Ruben , Strandberg Olof , Mattsson‐Carlgren Niklas , Dichgans Martin , Frontzkowski Lukas , Hansson Oskar
Published: December 2022

Background

In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD.

Method

We included two independent samples with longitudinal Flortaucipir tau‐PET covering the AD spectrum (ADNI: n(controls/AD‐preclinical/AD‐symptomatic)=93/60/89, BioFINDER, n(controls/AD‐preclinical/AD‐symptomatic)=16/16/25). In addition, we included resting‐state fMRI from human connectome project participants (n=1000), applying a 200‐ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A‐D). Applying the same atlas to tau‐PET we transformed SUVRs to tau positivities using a pre‐established gaussian‐mixture modeling approach (Fig.1E‐F). By mapping tau‐PET positivities to the fMRI‐derived global connectivity map (Fig.1G‐L), we assessed the degree to which subject specific tau‐PET patterns were shifted towards globally connected hubs or non‐hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation.

Result

In symptomatic AD patients, younger age was associated with a stronger shift of tau‐PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau‐PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau‐PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046).

Conclusion

Younger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.
Antipsychotic prescriptions and neuropsychiatric symptoms (NPS) in nursing home (NH)residents with dementia: a comparison of pre‐ and during COVID pandemic.
Authors: McDermid Joanne , Khan Zunera , Sweetnam Adrienne , Ballard Clive G
Published: December 2022

Background

The COVID‐19 pandemic has put tremendous pressures on nursing homes, but there is limited direct data evaluating the impact on residents or prescribing practices

Method

As part of our clinical trial programme in nursing homes we have baseline data from 971 residents across 69 nursing homes collected in 2016/17 prior to the pandemic, and from 747 participants across 149 nursing homes from the baseline assessment of our COIVD WHELD RCT collected in 2021/22. In both studies the frequency if antipsychotic prescriptions was recorded and the Neuropsychiatric Inventory Nursing Home version was completed.

Results

The average age of residents (84.5 v 85.1) and gender balance (71%F v 69% F) was similar in both cohorts. In the current study 64% of participating nursing homes had experienced a COVID‐19 outbreak. There were fewer people with severe dementia in the COVID WHELD Cohort (6.7% v 23%). Antipsychotic usage was 55% higher in the COVID WHELD cohort compared to the original WHELD cohort (28% v 18%), with 25% of nursing homes having prescription rates >40%, but the rates of neuropsychiatric symptoms were similar in the 2 studies. To ensure that the results were not confounded by the lower number of people with severe dementia in the COVID WHELD cohort, a further comparison was undertaken for people with moderate/moderately severe dementia, with very similar results. We undertook an additional analysis comparing nursing homes above and below prescription rates of 20% (the pre‐COVID level of prescribing). Nursing homes with increased antipsychotic prescribing had significantly higher levels of overall neuropsychiatric symptoms on the NPI (p = 0.02), and significantly higher levels of agitation (p = 0.02) compared to nursing homes with lower prescribing rates. There were also 31% more staff sick days in the higher prescribing nursing homes.

Conclusion

There is a substantial increase in antipsychotic prescriptions in 50% of nursing homes since the onset of the COVID‐19 pandemic, associated in those nursing homes with an increase in neuropsychiatric symptoms. This will need to be a major focus as we begin to move forward from the pandemic.
Increased pro‐inflammatory plasma markers are associated with a longitudinal decrease in left hippocampal volumes in MCI patients
Authors: Breese James , Nowell Joseph , Crook Harry , Edison Paul
Published: December 2022

Background

Apart from amyloid and tau, neuroinflammation plays a significant role in the Alzheimer’s disease (AD) pathogenesis. However, the role of blood bound pro‐inflammatory cytokines on neurodegeneration is still being debated. It is theorised that the activation of inflammation‐associated microglia in the CNS can oscillate through AD’s course, showing elevations in the early stages of AD progression [1]. This study aimed to establish the relationship between the presence of pro‐inflammatory markers and hippocampal volumes, in individuals with an AD diagnosis, late mild cognitive impairment (LMCI) and a cognitively normal control.

Method

281 participants were recruited from the AD Neuroimaging Initiative (ADNI; adni.loni.usc.edu) database. For each participant, left and right hippocampal volume values were calculated from the volumetric MRI at baseline and after 12 months follow up. 34 known pro‐inflammatory plasma biomarkers were measured at baseline and 12 months. Principal component analysis (PCA) was conducted on the pro‐inflammatory cytokine change. The change in each participant’s hippocampal volumes was correlated with the independent component‐1 of pro‐inflammatory cytokine change, in the AD, LMCI and control groups.

Result

We demonstrated a negative correlation between changes in left hippocampal volume and changes in the independent component‐1 for pro‐inflammatory cytokines in the LMCI group (r=‐0.245; p=0.011). No correlation was found in the change in left and right hippocampal volumes and the pro‐inflammatory markers in both the AD group, and in the cognitively normal control group.

Conclusion

These results indicate that pro‐inflammatory markers can have a deleterious effect on hippocampal volume in individuals with LMCI – and are strongly linked to atrophy in this region. This suggests that peripheral inflammation could be a driving force of neurodegeneration in the early stages of AD’s trajectory. The lack of correlation in the AD patients may imply that once neuronal damage is triggered, a vicious cycle of neurodegeneration occurs, which is independent of peripheral cytokines. These findings suggest that therapeutics which target the pro‐inflammatory response early in AD’s progression trajectory could prevent AD’s progression.
Associations between default‐mode functional connectivity and distress, cardiovascular and metabolic risks and cognition in middle aged and older adults
Authors: Rashid Barnaly , Glasser Matthew F. , Nichols Thomas , Van Essen David , Juttukonda Meher R , Schwab Nadine A , Yacoub Essa , Lovely Allison , Terpstra Melissa , Harms Michael P , Bookheimer Susan Y. , Ances Beau M , Salat David H , Arnold Steven E.
Published: December 2022

Background

“Stress” and cardiovascular and metabolic (CVM) conditions are frequently related and affect brain function and increase risk for neurocognitive disorders in aging. The mechanisms by which these occur are unclear. This study investigates how indices of psychological distress and CVM relate to functional connectivity (FC) of the default‐mode network (DMN) and cognition in generally healthy middle‐aged and older adults.

Method

Structural, Resting‐state fMRI, and fieldmap scans were collected in a large sample of 930 healthy volunteers aged 36 to 90+ years old (mean ± SD: 61.6 ± 16 years; female= 55.6%) from the Human Connectome Project in Aging (HCP‐A) study. Data were preprocessed using the currently recommended HCP pipelines, including precise spatial preprocessing, multi‐modal cross‐subject alignment, and selective temporal denoising. FC values were computed using full correlation with FSLNets amongst the neocortical brain areas of the HCP’s multi‐modal parcellation and standard FreeSurfer subcortical structures and converted to z‐scores with the Fisher transform. A psychological distress index (PDI) was composed from standard measures of external and social stressors, personality and mental health factors. A CVM index (CVMI) was composed from common physiological and laboratory measures (e.g., blood pressure, lipids, C‐reactive protein), and cognitive functioning was summarized with a multi‐domain cognition composite index (CCI) with standard measures of general cognition, memory, processing speed, and executive functioning. Using linear regression models controlling for age, associations between DMN FC and PDI, CVMI and CCI were evaluated.

Result

Figure 1 highlights the associations (uncorrected, p<0.05) between DMN FC and (a) PDI, (b) CVMI and (c) CCI. The overlapping associations in Figure 1(d) suggest that there might be a shared mechanism through which PDI and CVMI impact DMN FC and cognition. Although associations based on PDI were relatively weak, it is possible that effects may be linked to specific elements or subgroups, and this will be explored in future work.

Conclusion

Our findings indicate that psychological distress and CVM health affect the integrity of DMN connectivity, and that these effects show regional overlaps with the associations between DMN connectivity and cognition.
Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals
Authors: Xie Long , Wisse Laura EM , Das Sandhitsu R. , Lyu Xueying , de Flores Robin , Yushkevich Paul A. , Wolk David A.
Published: December 2022

Background

Neurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD).However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.

Methods

420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.

Results

Tau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.

Conclusions

The results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.
First results of the AMYPAD Prognostic and Natural History Study: amyloid‐PET Centiloid predicts cognitive functioning in a pre‐dementia population
Authors: García David Vállez , Collij Lyduine E. , Mastenbroek Sophie E , Alves Isadora Lopes , Gispert Juan Domingo , Ritchie Craig W. , Boada Mercè , Marquié Marta , Grau‐Rivera Oriol , Fauria Karine , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Schöll Michael , Frisoni Giovanni B , Boecker Henning , Jessen Frank , Wolz Robin , Grootoonk Sylke , Stephens Andrew W , Buckley Chris J , Ford Lisa , Visser Pieter Jelle , Farrar Gill , Barkhof Frederik ,   AMYPAD consortium
Published: December 2022

Background

The AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐) quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid pathology.

Methods

As of 17th January 2022, a total of 1,460 participants had been included. Of those, clinical data of 1,015 were processed, with 688 (68%) having at least a quantified amyloid PET at baseline, with [18F]flutemetamol or [18F]florbetaben. The primary metric used to assess amyloid burden was the Centiloid (CL), measured from the ratio of the GAAIN cortical target and whole cerebellum. Scans were categorized as negative (CL≤12), gray‐zone (1250). The distribution of these groups was assessed using a Gaussian mixture model. Independent linear mixed‐effect models were used to explore the predictive value of CL, and its interaction with time, for several cognitive outcomes: mini‐mental state examination (MMSE), memory (immediate recall, IR), attention (digit‐span forward, DSF), language, visuospatial, and executive functions. In addition, years from baseline, parent cohort, age, sex, education, APOE‐ε4, and the Clinical Dementia Rating (CDR) score were used as independent variables.

Results

Demographics are shown in Table 1. At baseline, 88% of the subjects were classified as cognitively unimpaired (CDR=0). A majority of 384 (56%) was categorized as negative (1±7CL), 210 (30%) as grey‐zone (14±11CL), and 94 (14%) as positive (58±31CL) [Figure 1]. Baseline CL (‐0.007 [‐0.010; ‐0.004]) and its interaction with time (‐0.002 [‐0.003; ‐0.001]) were predictive of IR. Baseline CL, but not its interaction with time, predicted MMSE (‐0.007, 95%CI [‐0.010; ‐0.003]) and DSF (‐0.003 [‐0.005; ‐0.001]) [Figure 2]. No significant relationships were observed for executive, language, or visuospatial function.

Conclusions

Higher baseline CL were associated with lower global cognitive function and attention scores. Whereas, higher CL were associated with a steeper memory decline over time. Current results suggest that cerebral amyloid accumulation is predictive of future overall cognitive function, attention, and memory decline. Further analysis is assured, including more participants, longitudinal PET outcomes, and other biomarkers of the disease.