bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer’s disease spectrum profiled by CSF and imaging biomarkers: Tau PET best predicts cognitive decline
Authors: Bucci Marco , Chiotis Konstantinos , Nordberg Agneta K
Published: December 2021

Background

The concept of pathophysiologically profiling individuals based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N) is attracting interest in the Alzheimer’s disease research field. All three processes can be monitored by either cerebrospinal fluid (CSF) sampling or imaging (PET/MRI). We aimed to test the comparability of the CSF and imaging biomarkers in each AT(N) category and their ability to predict longitudinal cognitive decline.

Method

A subset of data from 254 patients who had had PET investigations with amyloid‐β and tau tracers, and CSF sampling at the same time point, and a structural MRI within one year was selected from the Alzheimer’s Disease Neuroimaging Initiative trial data. The participants were grouped by clinical diagnosis at that time: cognitively normal (n=88), subjective memory concern (n=82), early (n=35) or late (n=31) mild cognitive impairment, and Alzheimer’s disease (n=18). Agreement between the modalities for A, T and N was assessed with Cohen’s Kappa statistic. Linear mixed‐effects models were used to predict subsequent decline in the episodic memory composite score.

Result

Biomarkers for A in PET and CSF showed moderate agreement (Kappa=0.42‐64). Biomarkers for T in PET and CSF showed fair agreement (Kappa<0.40), except in the Alzheimer’s disease group where agreement was moderate (Kappa=0.64). The N biomarkers (CSF vs atrophy in MRI) showed evidence of discordance across all groups (Kappa<0.26). Baseline tau PET positivity predicted longitudinal decline in episodic memory irrespective of the p‐Tau181 (CSF) status (estimate=‐0.02, p≤0.05), but the same was not seen for isolated p‐Tau181 (CSF) positivity (estimate=0.00, p=0.58). Baseline tau and amyloid‐β PET positivity biomarkers predicted decline in episodic memory (estimate=‐0.02, p≤0.0001), but isolated amyloid‐β PET positivity did not (estimate=‐0.01, p=0.09). Isolated tau PET positivity was not observed in the absence of amyloid‐β PET positivity, with the exception of one participant with PET values close to the cutoff point.

Conclusion

While results for amyloid‐β are relatively similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration are not interchangeable. Tau PET positivity was superior to phosphorylated tau and amyloid‐β PET in predicting cognitive decline in the Alzheimer’s disease continuum.
Developing a digital assistive tool for dementia patients and their caregivers: A qualitative study on needs, potential functions, practical requirements, user acceptance, and ethical considerations
Authors: Wichmann Lenka J , Reiff Nele , Zintl Sophie , Berking Matthias
Published: December 2021

Background

Digital smartphone assistants for the care and support of people with dementia (PwD) have great potential due to the wide availability of smartphones and a growing number of users aged above 65. Research has mainly focused on the development of applications for only one user group (patients, caregivers, or relatives respectively), and with only one or a few functions included (Yousaf et al., 2020). A more integrative, multi‐user, and multifunctional application would be beneficial because it could be adapted to the users’ needs more flexibly. This qualitative interview study was the first step in a co‐creative process with a user‐centered approach aimed at developing a multifunctional digital assistant.

Method

Qualitative content analysis (Mayring, 2010) combining deductive and inductive techniques was applied to identify burdens, needs, functions, ethical considerations, and acceptance aspects. 14 semi‐structured interviews were conducted with three participant groups (relatives of PwD; caregivers and nursing staff; psychologists). Interviews were conducted via video conferences due to Covid‐19 restrictions. After the completion of all interviews, participants received several questionnaires on acceptance aspects (Technology Usage Inventory [TUI], acceptance rating of specific functions), and technological affinity (TA‐EG questionnaire) via letter. Interviews were transcribed verbatim with the software MAXQDA. Coding was done by two independent researchers. A coding frame was generated using the interview guide as a theoretical basis and the collected data for building inductive categories. The coding frame was pilot‐tested before the final analysis and intercoder reliability was sufficient (k=.81).

Result

Preliminary results showed that dealing with symptoms of dementia in everyday life was burdening. Emotional needs in patients and needs for additional care resources in relatives and caregivers were the most important unanswered needs. 53 functions were suggested in the areas: digital care, support, training, monitoring, navigation, leisure activities, and social contacts. Participants had ethical requirements (i.e. data protection, privacy, and autonomy) that if met, would enhance acceptance. Results on questionnaires showed positive attitudes towards, curiosity about, and no insecurity with regards to technology. The overall acceptability of suggested functions was high.

Conclusion

Participants showed a large interest in the digital assistant. The importance of data protection was underlined.
Multiscale motor activity regulation and cognitive performance in middle‐aged adults: A cross‐sectional study using baseline data of UK Biobank Cohort
Authors: Li Peng , Ulsa Ma Cherrysse , Zheng Xi , Yang Hui‐Wen , Gao Lei , Hu Kun
Published: December 2021

Background

Motor activity fluctuations in healthy young humans display robust temporal correlations across a wide range of time scales. The multiscale correlations are altered in elderly adults, and their changes are associated with cognitive decline and risk for Alzheimer’s disease. We sought to examine whether the multiscale regulation is associated with cognitive performance in middle age using a population‐based cohort.

Method

We analyzed motor activity recordings that were collected from 97,284 non‐demented participants [aged 39‐70 (mean±SD: 56.1±7.8) years old; female: 54,776 (56.3%)] in the UK Biobank. The detrended fluctuation analysis was performed to quantify temporal correlations at time scales ≤90 min (α1) and ≥2 h (α2; up to 10 h) according to previous studies. Participants also completed four neurocognitive tests, and poorer cognitive performance was characterized by longer reaction time (RT; for information processing speed), more errors made in the pairs matching test (for visual episodic memory), lower fluid intelligence (FI) score (for reasoning), or making incorrect first choice during the prospective memory (PM) test. Linear regression models (or logistic regression for PM) were used to examine the associations of each cognitive outcome with α1 and, separately α2, adjusted for ethnicity, college, social‐economic status, mental and behavioral disorders, diseases of the nervous system, and number of treatments/medications. The 95% confidence intervals (CI) were derived non‐parametrically based on 1,000 bootstrapped samples with replacement.

Result

Both α1 and α2 showed normal distributions: α1=0.99±0.05 (SD) and α2=0.91±0.11. There was a positive association between α1 and FI with 1‐SD decrease of α1 corresponding to a decrease of 0.03 in FI (95% CI 0.01—0.05) that was about the effect of being 2 years older. α2 was negatively associated with RT and positively associated with FI; for 1‐SD decrease in α2, participants took ln(1 ms) longer during RT, and FI decreased by 0.04 (95% CI 0.02—0.06), both equivalent to being ∼2.5‐3 years older.

Conclusion

Multiscale motor activity regulation is linked to cognitive performance of specific domains in the middle‐aged population. Further studies are required to establish the relevance of these domain‐specific associations to incident dementia in later life and to understand their underlying neurobiology.
Extraneous neuroimaging factors do not contribute to sex differences in flortaucipir signal: Analysis of skull binding and partial volume effects
Authors: Scott Matthew R. , Edwards Natalie C , Properzi Michael J , Jacobs Heidi I.L. , Price Julie C , Manning Lyssa K , Mayblyum Danielle V. , Rubinstein Zoe B. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Schultz Aaron P. , Buckley Rachel F.
Published: December 2021

Background

Clinically normal females exhibit greater [18]F‐flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off‐target skull binding to sex differences in FTP‐PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP‐PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer’s disease and associated tauopathies.

Method

343 clinically normal (female=58%; mean[SD]=73.8[8.5] years) (female=38%; mean[SD]=76.9[7.3] years) participants from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative underwent cross‐sectional FTP‐PET (standardized uptake value ratios [SUVrs]). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer‐defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group‐level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post‐smoothing.

Result

Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex‐related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1).

Conclusion

Our findings suggest that sex differences in FTP‐PET are not solely attributed to skull ‘clouding’ or PVE, but rather support hypotheses of female‐related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP‐PET do not significantly contribute to sex differences in cortical tau signal.
Associations of central auditory processing with brain volumes in the aging and cognitive health evaluation in elders and the atherosclerosis risk in communities neurocognitive study
Authors: Jiang Kening , Albert Marilyn S , Coresh Josef , Couper David , Gottesman Rebecca F , Hayden Kathleen M , Jack Clifford R , Knopman David S , Mosley Thomas H , Pankow James , Pike James R , Reed Nicholas S , Sharrett Richey , Lin Frank R , Deal Jennifer A
Published: December 2021

Background

Prior evidence has suggested associations between hearing loss and smaller brain volumes particularly in the temporal lobe where the primary auditory cortex is located, probably due to changes in cortical organization associated with reduced auditory stimulation. Evidence regarding associations of central auditory processing with brain volumes is relatively limited. The study aims to investigate cross‐sectional associations of central auditory processing with brain volumes in older adults.

Method

We studied 587 cognitively normal (Mini‐Mental State Exam ≥23 if high school degree or less and ≥25 if above high school degree) older adults (mean age: 77±4 years, 56% female, 17% black), including 426 with hearing loss from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) baseline (2018‐19), which is an ancillary randomized controlled trial of the Atherosclerosis Risk in Communities (ARIC) Study and 161 with normal hearing, comparable age and cognitive status from the ARIC Visit 6/7 (2016‐17/2018‐19). Brain volumes were measured by magnetic resonance imaging (MRI) scans and were transformed to z‐scores. Central auditory processing was measured by the Quick Speech‐in‐Noise (QuickSIN) test. Total scores range from 0 to 30 with lower scores indicating worse speech‐in‐noise performance. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes associated with differences in QuickSIN score. Models adjusted for age, sex, race, education, cohort, body mass index, smoking, hypertension, diabetes, stroke, intracranial volume, and pure‐tone average.

Result

Every 5‐point decrease in QuickSIN score (worse performance) was associated with smaller volumes of the temporal lobe (‐0.07SD, 95% CI: ‐0.13, ‐0.01). QuickSIN score was also associated with subregions of the temporal lobe related to auditory processing, memory and emotion, including amygdala (‐0.13SD, 95% CI: ‐0.21, ‐0.04), middle (‐0.08SD, 95% CI: ‐0.15, ‐0.00) and superior temporal gyri (‐0.08SD, 95% CI: ‐0.15, ‐0.01).

Conclusion

Poorer central auditory processing was associated with smaller temporal lobe volumes, including but not limited to subregions important for auditory processing. The ongoing collection of ACHIEVE data with longitudinal MRI data will facilitate understanding of association between hearing loss and brain atrophy as well as the potential promising effects of hearing treatment in mitigating brain aging.
Multimodal preventive trial for Alzheimer’s disease (MIND‐ADMINI): Pilot trial progress and results
Authors: Kivipelto Miia , Sindi Shireen , Thunborg Charlotta , Rosenberg Anna , Coley Nicola , Andrieu Sandrine , Broersen Laus M , Hartmann Tobias , Solomon Alina , Soininen Hilkka
Published: December 2021

Background

Interventions simultaneously targeting multiple risk factors are most likely to prevent neurocognitive disorders. This was demonstrated in the 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). However, the feasibility and effects of multimodal interventions in individuals at an early symptomatic disease stage (prodromal AD) are unclear. The objective of the MIND‐AD trial was to evaluate the feasibility of an adapted FINGER‐based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD.

Methods

MIND‐ADMINI is a multinational proof‐of‐concept 6‐month randomized controlled trial (RCT, ClinicalTrials.gov NCT03249688), with four trial sites (Sweden, Finland, Germany, France). The target population is individuals with prodromal AD using the International Working Group‐1 criteria and vascular and/or lifestyle‐related risk factors. The parallel‐group RCT includes three arms: 1) multimodal lifestyle/vascular intervention (diet, exercise, cognitive training and social stimulation, vascular/metabolic risk management); 2) multimodal lifestyle/vascular intervention+medical food (Fortasyn Connect); 3) regular health advice/care (control group). Primary outcomes: feasibility and adherence. Secondary outcomes: adherence to the individual intervention domains and healthy lifestyle changes,

Results

Screening began September 2017 and was completed May 2019 in all four countries. Altogether, 93 participants were randomized, and the 6‐month intervention was completed December 2019. Electronic data entry and processing was completed December 2020 (delays due to Covid‐19). The mean (SD) age of the entire sample was 72.9 years, education level was 12.8 years, and MMSE score 27.6 points. Vascular and lifestyle‐related risk factors were expected based on the inclusion criteria. Impaired fasting glucose (≥ 6,1 mmol/L) was seen in 29%, and 40% were overweight, with BMI ≥25 and, 12% had BMI ≥30. The intervention proceeded as planned and the preliminary results and participant experiences are positive, supporting the feasibility. Detailed results will be presented, and lessons learned will be discussed.

Conclusions

For the first time, MIND‐AD tests the feasibility of and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. The positive intervention experiences are important for this patient group currently lacking effective treatments. The trial also offers a model for pharmacological/non‐pharmacological combination therapies and informs larger efficacy prevention trials.
Prevalence of dementia among elderly in Latin America and the Caribbean: A systematic review and meta‐analysis
Authors: Ribeiro Fabiana , Santos Ana Carolina Teixeira , Leist Anja
Published: December 2021

Background

Over the last decades, life expectancy in Latin America and the Caribbean showed a rapid increase, which led to a significant increase in the number of people with dementia. Moreover, 9% of the population in this part of the world are aged 65 or older, and by 2050 this percentage is projected to at least double. For this reason, it is essential to estimate the prevalence of dementia in LAC countries with the aim to determine suitable actions to enhance the quality of life of those affected.

Methods

Database searches for articles were conducted September 2020 throughout Pubmed, Web of knowledge, Scopus, Lilacs, and SciELO. The inclusion criteria comprised population‐ or community‐based studies, published in English, Spanish, or Portuguese, reporting data on the prevalence of dementia collected in LAC countries. The complete data search retrieved 1719 non‐duplicates.

Results

A total of 58 studies met the high‐quality inclusion criteria, published 1991‐2020, including participants in the following countries: Brazil, Mexico, Argentina, Colombia, Peru, Cuba, Dominican Republic, Venezuela, Ecuador, Trinidad and Tobago, and Jamaica. The most common form of dementia studied was Alzheimer’s disease with prevalence ranging from 5.9% to 23.4%. Estimates differed by age, gender, and education, with oldest, women, and lower‐educated adults living in rural areas presenting higher dementia prevalence.

Conclusion

This is the first study giving a comprehensive overview of dementia prevalence in LAC countries, which is relevant to estimate care needs and economic costs related to dementia treatment and care.
Profiling the metabolome of patients with dementia in the UK Biobank
Authors: Liu Jun , Amin Najaf , Arnold Matthias , Nho Kwangsik , Saykin Andrew J. , Newby Danielle , Winchester Laura M. , Nevado‐Holgado Alejo J. , Kastenmüller Gabi , Kaddurah‐Daouk Rima F. , Van Duijn Cornelia M.
Published: December 2021

Background

There is increasing interest in early metabolic changes in dementia, which may reflect the effects of genetic determinants of dementia, medical history and co‐morbidity, environmental risk factors, and aging. We studied the relation of blood‐based metabolites to the risk of dementia.

Method

The analyses are conducted in 121,389 participants of the UK Biobank (UKB) and include over 1172 incident dementia patients who developed dementia during the follow‐up. The metabolome was characterized using Nuclear Magnetic Resonance of the Nightingale Health platform. The platform covers 249 metabolic measures, including small molecules, fatty acids and detailed lipoprotein lipids. We integrated metabolic data measured before dementia onset with genetic data to determine whether the metabolites associations reflect causal pathways or rather consequences of the disease process. After log transformation of metabolites, scaling, and quality control, data were analysed using Cox‐regression. We adjusted for age, sex, BMI, technical variables ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication and APOE genotypes.

Result

We identified 36 novel metabolites that are significantly associated with incident dementia (FDR<0.05), with positive associations of ketone bodies to the future risk of dementia and negative associations of fatty acids, various amino acids, and cholesterol subfractions. The metabolic pattern is remarkably similar for incident patients with Alzheimer disease and vascular dementia and overlaps substantially with the metabolic profile identified for incident Parkinson’s disease. We found evidence that a number of metabolites may mediate the association between the APOE e2 and APOE e4 variants and dementia.

Conclusion

Our findings suggest that changes in the metabolism that occur before the onset of disease are associated to the future risk of dementia.
Resting‐state functional connectivity of basal forebrain is associated with training gains in normal aging
Authors: Faraza Sofia , Dyrba Martin , Wolf Dominik , Fischer Florian U , Fellgiebel Andreas , Teipel Stefan J
Published: December 2021

Background

Cognitive training can improve cognitive performance in healthy older adults. The effectiveness of a training is considered as a maintenance of training skills outside of a training context. Research data indicate an association between cognitive decline and changes of brain function in normal aging. A better understanding of the brain mechanisms that can enhance or preserve cognitive training skills could help identifying healthy older adults who will benefit from cognitive interventions. The cholinergic basal forebrain is involved in several aspects of cognition including attention. In our study, we aimed to assess the association of functional connectivity of the basal forebrain with maintained training skills.

Method

A sample of 60 healthy older adults (mean age: 68 years) underwent a 4‐week multi‐modal cognitive training and neuropsychological assessments before and after the training. A second follow‐up assessment was applied 12 weeks after the training. Baseline resting‐state functional magnetic resonance imaging was used to derive the global functional connectivity of the anterior‐medial and posterior‐lateral compartments of the basal forebrain. We focused on attention capacities using the Test battery for Attention Performance (TAP), which assesses a variety of attentional aspects, including alertness. Maintenance of training gains was defined as higher improvement in the alertness tasks after 12 weeks than a no‐training control group.

Result

A high functional connectivity of anterior basal forebrain was a significantly associated with maintenance of training gains in the phasic arousal tasks, i.e. the reaction time in response to a critical stimulus preceded by a cue stimulus presented as a warning tone. There was no significant association for the posterior basal forebrain.

Conclusion

Functional activation patterns of basal forebrain contribute to maintenance of training gains of alertness tasks.
Effects of healthy aging on internal brainstem structure
Authors: Mueller Susanne G
Published: December 2021

Background

The brainstem is a complex structure and is often affected in the earliest stages of a neurodegenerative diseases. However, internal brainstem structures are not delineated on standard MR sequences complicating the differentiation between healthy aging and an incipient neurodegenerative process in‐vivo. The overall goal of this project was to characterize age‐related atrophy of different brainstem structures using a modification of a previously published multi‐contrast brainstem segmentation approach (1) using standard MR sequences.

Method

The T1 and T2‐weighted images from 677 subjects (age range: 36‐100) of the Lifespan Human Connectome Project Aging were selected. Each subject’s T1w and T2w were co‐registered, re‐scaled and a T1/T2ratio image calculated. After extracting the brainstem/thalamus, a k‐mean cluster analysis was used to identify 4 different brainstem tissue clusters based on the intensities from the 3 images. DARTEL was used to generate a population template from the brainstem tissue‐maps of 100 randomly selected subjects covering the whole age range. Each subjects tissue‐maps were warped onto this template and the Jacobian determinants calculated (Figure 1). The subjects were then divided into 6 groups (4th, 5th, 6th, 7th, 8th, 9th decade). SPM with threshold‐free cluster enhancement (p<0.005, FWE) was used for group comparisons. 58 gray and white matter brainstem regions‐of‐interest were used to extract voxels surpassing this statistical threshold to further characterize the age‐related volume loss.

Result

See Figure 2 for abbreviations and detailed findings. Mesencephalic centers such as NR, CS, CI and PTPT showed age‐related volume loss starting at the age of 50. SN, VTA, and pontine centers such as NRPO, PB, NRPT, NRPC and medullary regions such as OI, NTS, VML, NRMOC and other major white matter tracts became atrophied starting at 60 and after 70 all 58 brainstem centers except for the DR and SC were atrophied.

Conclusion

Age‐related brainstem atrophy starts in the mesencephalon and progresses to the pons and medulla and also affects white matter tracts. The pattern of age‐related atrophy reflects the timing of typical age‐related brainstem dysfunctions, e.g., age‐related hearing loss. This method might be useful for the early detection of neurodegenerative diseases starting in the brainstem. Reference: Hum Brain Mapp.2020;41:2173‐2186.
TMS‐induced EEG perturbation as a marker of psychological resilience to deleterious mental health effects during the COVID‐19 pandemic
Authors: Perellón‐Alfonso Ruben , Redondo‐Camós María , Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Delgado‐Gallén Selma , España‐Irla Goretti , Sánchez Javier Solana , Tormos‐Muñoz Josep M. , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: December 2021

Background

Social, economic and psychological hardships associated with the COVID‐19 pandemic are expected to result in a global burden on mental health outcomes. However, while some individuals suffer from increasing distress and reduced quality of life, others will show no negative effects. A better understanding of brain mechanisms subtending resilience would be helpful in informing future recommendations to individuals and societies facing the present pandemic and future similar events. Here, we compared neurophysiological brain markers between individuals who exhibited resilience or vulnerability to pandemic associated psychological stress.

Method

23 participants from the longitudinal study cohort of the Barcelona Brain Health Initiative (Cattaneo et al., Front. Aging Neurosci. 2018;10:321) who underwent concurrent transcranial magnetic stimulation with electroencephalography (TMS‐EEG), were classified as either resilient (n=16) or non‐resilient (n=7), based on their scoring in the PHQ‐4 questionnaire (Kroenke et al., Psychosomatics 2009;50(6):613–21) along four timepoints; one before COVID‐19 outbreak and three spanning 2.5 months during the pandemic. Individuals maintaining a score below 3 across all timepoints were deemed resilient, while those scoring below 3 before pandemic but higher than 2 at any pandemic timepoint were considered non‐resilient. TMS‐EEG data was collected by delivering 120 single TMS pulses to the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). TMS evoked global mean field amplitude and local response at the stimulation site were computed.

Result

Figure 1 depicts time‐series for DLPFC and IPL responses for both groups of subjects. Overall, non‐resilient individuals exhibited a larger global response to TMS perturbation during DLPFC stimulation, as well as larger local current density estimates during IPL stimulation.

Conclusion

These preliminary results revealed that non‐resilient individuals were more susceptible to TMS perturbation, shown by global DLPFC and local IPL reactivity. Notably, these targets are nodes of the default mode and cognitive control networks affected by stress (van Oort et al., Neurosci. Biobehav. Rev. 2017;83:281–97), and the left frontal cortex has been proposed as a cognitive resilience hub (Franzmeier et al., J. Alzheimer’s Dis. 2017;59(4):1381–92.). Future studies should investigate and confirm the possibility that these nodes constitute a shared neurophysiological substrate for psychological and cognitive resilience.
Wisconsin ADRC research education component: Fostering AD researchers via a virtual network
Authors: Spensley Sheryl , Kohli Akshay , Puglielli Luigi , Shah Manish N , Kind Amy J , Bendlin Barbara B
Published: December 2021

Background

Worldwide, 47 million people have Alzheimer’s disease or related dementias (Alzheimer’s Association). The National Institute on Aging has introduced Alzheimer’s Disease Research Center Research Education Components (RECs) to “support research educational activities to complement the training of a workforce to meet the nation's research needs in AD and related dementias.” By recruiting and training promising researchers, the goal of RECs are to increase the pool of researchers studying ADRD, advance the mission of translating research advances into improved diagnosis and care, as well as treating and preventing ADRD.

Method

The Wisconsin Alzheimer’s Disease Research Center (ADRC) REC, funded in 2019, aims to deliver a rigorous training program to ensure research proficiency in AD research, infuse research concepts into predoctoral to junior faculty training programs, and measure the effectiveness of the REC. The REC sponsors didactic learning, facilitates networking for ADRD research trainees across campus, identifies ADRC REC Scholars who engage in mentored, 2‐year, research projects, and created a REC junior fellowship to reach students who are underrepresented in AD research. Using a previously created database, survey methods were used to assess trainee career promotions, demographics, and awards. During the COVID‐19 pandemic, the REC modified its strategies to use virtual methods to ensure continued availability of training opportunities. An E‐newsletter was introduced to communicate training and funding opportunities.

Results

Our REC Scholars (N=3) secured an R01, NIH R21/R33 and Beeson K76. Attendance at ADRD‐focused didactic events grew by nearly three‐fold using virtual methods. The E‐newsletter is shared with 550 individuals weekly and has a 35% open rate. The REC held a virtual introduction to ADRD research with UW Madison Precollege Enrichment Opportunity Program for Learning Excellence students via Zoom. Planned internships for the REC junior fellows were not completed due to the pandemic.

Conclusion

Training during the COVID‐19 pandemic presented several opportunities for new initiatives. We observed that virtual tools increased the number of individuals engaged in training activities, although level of engagement and learning has not been assessed. Assessment of virtual training will be formally evaluated in collaboration with the UW Learning through Evaluation, Adaptation, and Dissemination Center.
Improved methods for recruiting Latino participants for Alzheimer’s disease research using the Brain Healthy Registry
Authors: Camacho Monica R , Weiner Mike W , González Hector M , Mayeda Elizabeth Rose , Alaniz Roxanne , Ashford Miriam T , Nosheny Rachel L
Published: December 2021

Background

Traditional strategies have been largely unsuccessful in recruiting Latinos and other underrepresented groups for Alzheimer’s disease and related dementias (ADRD) clinical research. Online registries are a promising approach to recruit hard to reach populations. This project, funded by the California Department of Public Health Alzheimer’s Disease Program, aimed to use internet advertising and culturally‐tailored messaging to enroll participants in the Brain Healthy Registry (BHR), an online registry for ADRD research.

Methods

Researchers collaborated with marketing professionals experienced in marketing to Latinos. A community advisory board, comprised of professionals from different industries who identify as Latino and/or have knowledge and experience within local Latino communities, was formed to guide recruitment strategies tailored to Latinos’ values and beliefs. Custom audience targeting displayed Facebook and Google ads to Latinos living in California zip codes with large Latino populations. Recruitment strategies, including “look‐alike” audience targeting, ad retargeting, simplification of the BHR enrollment process, and revamped email campaigns to individuals that did not complete enrollment, were employed.

Results

Internet advertising from September 2020 and mid‐January 2021 resulted in email addresses from 5,095 individuals, of which 2,560 (50%) joined BHR. Seventy four percent of new participants self‐reported Latino ethnicity. Prior to this, there were only 3,761 Latino participants (out of total sample size of > 70,0000) since BHR’s inception in 2014. A larger percentage of new participants also self‐reported being non‐White/Caucasian compared to previously enrolled participants (Table 1). The cost to enroll a participant recruited from these efforts ranged from approximately $35 – $80.

Conclusion

Internet advertising with culturally tailored recruitment messaging substantially increased representation of Latino participants in BHR during a short timeframe. Future efforts include a Spanish‐language BHR website, Spanish digital ads, and messaging to improve engagement and retention of Latino participants once they are enrolled.
The relationship between blood‐brain barrier permeability and cerebral blood flow in cognitive impairment
Authors: Barisano Giuseppe , Montagne Axel , Nation Daniel A. , Sagare Abhay P. , Joe Elizabeth B. , D'Orazio Lina , Buennagel David P. , Harrington Michael G. , Ringman John M. , Schneider Lon S. , Chui Helena C. , Pa Judy , Law Meng , Toga Arthur W. , Zlokovic Berislav V.
Published: December 2021

Background

The contribution of cerebral microvascular dysfunction to early cognitive impairment and dementia is increasingly recognized. Here we investigated cerebral blood flow (CBF) and blood–brain barrier (BBB) permeability in relation to early cognitive decline in APOE3‐homozygotes (ε3/ε3) and APOE4‐carriers (ε3/ε4; ε4/ε4).

Method

A total of 237 participants underwent neuropsychological evaluations, venipuncture, and magnetic resonance imaging (MRI). The global Clinical Dementia Rating (CDR) was used to classify participants in cognitively unimpaired (CU, CDR=0) and mild cognitive impairment (CDR=0.5). APOE genotyping was performed via polymerase chain reaction‐based retention fragment length polymorphism analysis on DNA extracted from buffy coat. BBB permeability and CBF were estimated from dynamic contrast‐enhanced and 3D pseudo‐continuous arterial spin labeling (pCASL) MRI data, respectively, using in‐house pipelines. After excluding APOE2‐carriers and participants with CDR>0.5, 143 participants (86 females [60.1%]) were included in the analysis. (Table 1)

Result

Standardized CBF levels in grey matter (GM), hippocampus (HC), and parahippocampal gyrus (PHG) were not significantly different in APOE3‐homozygotes and APOE4‐carriers, after controlling for age and sex. (Figure 1) Our results of BBB permeability in 52 CU participants (27 APOE3‐homozygotes and 25 APOE4‐carriers) confirm a significantly higher BBB permeability in the HC of APOE4‐carriers compared with APOE3‐homozygotes (p<0.001), as previously reported (Montagne et al., Nature, 2020), and show no relationship between BBB permeability and CBF. (Figure 2) In a subgroup of 46 participants (21 CU APOE3‐homozygotes, 18 CU APOE4‐carriers, and 7 APOE4‐carriers with CDR=0.5) who underwent a second MRI approximately 2 years after the first MRI, we observed a significant reduction (p=0.008) of CBF in APOE4‐carriers with mild cognitive impairment, but not in CU individuals.

Conclusion

APOE4 is associated with higher BBB permeability in CU participants compared with APOE3‐homozygotes, but CBF is not different between the two genotypes. In the future, longitudinal data will be collected to confirm whether BBB breakdown precedes CBF alterations and to assess their relationship with cognitive decline, amyloid‐β and tau pathology.
MRI markers of accelerated brain aging and misappraisal of sleep depth
Authors: Baril Andree‐Ann , Mysliwiec Vincent , Beiser Alexa S. , Redline Susan , DeCarli Charles S. , Seshadri Sudha , Pase Matthew P. , Himali Jayandra J.
Published: December 2021

Background

Slow‐wave sleep (SWS) is the deepest sleep stage, and has been linked to many important physiological functions, including the cerebral metabolic clearance of toxins associated with Alzheimer’s disease. SWS loss might correlate with accelerated brain aging. However, older individuals and people with cognitive impairment have an impaired ability to appraise their sleep, suggesting that accelerated brain aging might affect how sleep depth is perceived. The purpose of this study was to evaluate whether misappraisal of sleep depth was associated with MRI markers of accelerated brain aging.

Method

We studied 242 participants (mean: 62.0±8.7 years) participants in the Framingham Heart Study Offspring Cohort that were evaluated with an overnight in‐home polysomnography and an MRI 3.4 years later on average. Self‐reported sleep depth (whether sleep was light or deep) on the night of the polysomnography was compared to objective SWS (percent of total sleep spent in SWS, separated by the median). Four groups were created: 36% of the sample had consistent appraisal of deep sleep; 12% of the sample had consistent appraisal of light sleep; 36% misappraised their light sleep as deep; and 16% misappraised their deep sleep as light. We evaluated total brain volume, cortical gray matter volume, and subcortical gray matter volume on MRI. A first set of models were adjusted for age, sex, time between MRI and neuropsychology; a second set of models were additionally adjusted for APOE4 allele status, body mass index, sleeping pills, depression, and stroke risk.

Result

Participants who misappraised light sleep, i.e., reported deep sleep but had lower SWS, had lower cortical gray matter volume (model 1: β±SE=‐0.62±0.26, p=0.018; model 2: ‐0.56±0.27, p=0.036) compared to those that reported deep sleep with higher SWS. We also observed a trend for lower subcortical gray matter volume in the same group (model 1:β±SE=‐0.09±0.05, p=0.084). No other between‐group differences were observed.

Conclusion

Participants with lower SWS that reported their sleep as deep displayed lower cortical volume. Accelerated brain aging might affect the ability to appropriately perceived sleep depth, which could be occurring in preclinical stages of dementia. Relying on self‐report sleep depth may introduce systematic misclassification.
An increase in fatty acid indices in cerebrospinal fluid of mild cognitive impairment precedes a decrease in Alzheimer’s
Authors: Fonteh Alfred N. , Cipolla Matthew , Arakaki Xianghong , Chui Helena C. , Harrington Michael G.
Published: December 2021

Background

Processing of membrane‐bound amyloid precursor protein (APP) may produce toxic amyloidogenic or less toxic non‐amyloidogenic amyloid (Aβ) peptides. We propose that brain membrane lipid composition and metabolism can dictate APP processing.

Method

Using neuropsychology measures, brain MRI, and consensus clinical conferencing, we classify three groups of elderly subjects: cognitively healthy (CH, n=70), mild cognitive impairment (MCI, n=40), and Alzheimer’s disease (AD, n=25). We fractionated CSF and determined the fatty acid composition of the unesterified fatty acid (UFA), the supernatant fluid (SF), and the nanoparticulate (NP) fraction using gas chromatography coupled with negative ion/chemical ionization mass spectrometry. We determined fatty acid indices for each fraction for chain length, unsaturation, peroxidation, and desaturase.

Result

Chain length, unsaturation, peroxidation, and desaturase indices were significantly different in the CSF fractions (p<0.0001). UFA carbon‐chain length, unsaturation, and peroxidation indices were higher in CH and MCI than in AD. In contrast, these indices did not significantly differ in the other CSF fractions. The UFA desaturase index was significantly higher in MCI (0.32±0.14) than in CH (0.26±0.2, adjusted p‐value (q) = 0.0220)) and AD (0.16±0.11, q <0.0001). In the SF and NP fractions, the desaturase index was lower in AD than MCI and CH. The changes in fatty acid indices were not associated with age, sex, BMI, and ApoE genotype.

Conclusion

Our studies show the compartmentalization of fatty acid metabolism in CSF fractions and changes in the AD spectrum. A higher carbon chain length, unsaturation, peroxidation, and desaturase index in MCI suggest higher lipid membrane turnover. A lower desaturase, peroxidase, and desaturase index in AD suggests enhanced lipolysis and oxidation of lipids. These data suggest that lipolysis and oxidation are features of AD pathophysiology, and monitoring fatty acid indices can help effectively monitor new therapies.
Amyloid time: Quantifying the onset of abnormal biomarkers and cognitive impairment along the Alzheimer’s disease continuum
Authors: Betthauser Tobey J. , Koscik Rebecca L. , Jonaitis Erin M. , Van Hulle Carol A. , Basche Kristin E. , Kohli Akshay , Suridjan Ivonne , Kollmorgen Gwendlyn , Chin Nathaniel A. , Mueller Kimberly D. , Clark Lindsay R. , Christian Bradley T. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Carlsson Cynthia M. , Zetterberg Henrik , Blennow Kaj , Johnson Sterling C.
Published: December 2021

Background

Quantifying the temporal progression of key pathophysiological events in Alzheimer’s disease is crucial for staging disease, dementia risk assessment, and informing clinical trials. This work extends a novel algorithm (sampled iterative local linear approximation; SILLA) developed for modeling PET trajectories to: 1) generate a unified CSF and PET amyloid accumulation timeline, and 2) characterize the temporal progression of biomarker and cognitive changes in AD.

Method

941 participants from the Wisconsin Registry of Alzheimer’s Prevention, Wisconsin Alzheimer’s Disease Research Center, and Statins in Healthy, At‐Risk Adults: Impact on Amyloid and Regional Perfusion studies underwent [C‐11]PiB PET and/or lumbar puncture; and a subset underwent [F‐18]MK‐6240 PET and anatomical MRI using standardized protocols (Table 1). Amyloid burden was quantified from cortical PiB DVR and CSF Aβ42/40. Amyloid Time, quantified as years from CSF Aβ42/40 positivity, was estimated by simultaneously modeling Aβ42/40 and PiB DVR using an extension of the SILLA method in a subset of 248 participants with both measurements. CSF biomarkers measured using the exploratory Roche NeuroToolKit assays, imaging biomarkers, and cognitive impairment (global CDR, CDR SOB, and diagnosis) were plotted as a function of Amyloid Time. Time between key AD events was estimated using LOWESS curves and positivity thresholds for each AD biomarker and CDR scores.

Result

Figure 1 depicts biomarker thresholds. Amyloid Time suggested PET Aβ+, CSF T+, PET T+, CDR=0.5, and CDR=1 occurred 4.0, 12.0, 13.8, 17.7, and 22.0 years following Aβ42/40 positivity (Figure 2, Table 2). Heterogeneity was observed in tau levels relative to Amyloid Time for individual cases. Those with worsening CDR generally had high amyloid and at least one T+ biomarker.

Conclusion

Amyloid Time based on combined CSF and PET amyloid biomarkers and the SILLA algorithm provides a novel way to quantify the duration of amyloid exposure from the earliest pathophysiologic CSF changes to dementia onset in AD within individuals. This enables characterization of the time between key AD events, which could inform prognosis, identify intervention timing for novel therapies, and enable exploration of mechanisms related to resistance and/or resilience.
Sex and cerebral small vessel disease‐specific longitudinal trajectories of amyloid, tau, and neurodegeneration
Authors: Shaaban C. Elizabeth , Snitz Beth E , Tudorascu Dana L , Lopresti Brian J , Royse Sarah K , Yu Zheming , Aizenstein Howard J , Klunk William E , Cohen Ann D
Published: December 2021

Background

The AT(N) model of Alzheimer’s disease (AD) posits a temporal evolution of β‐amyloid (Aβ) accumulation followed by tau then neurodegeneration. We investigated whether longitudinal relationships of these pathologies varied by sex and cerebral small vessel disease burden (cSVD), hypothesizing stronger associations in women and those with high baseline cSVD.

Method

Participants included 37 non‐demented older adults (mean 74 y/o at inclusion; 59% female; 89% white; 29% APOE4+). Tau was measured once at time 0 using 18F‐AV‐1451 in an AD composite region of interest. Global amyloid and cerebral metabolism in lateral temporal lobe (neurodegeneration) were measured at repeated annual visits (8 years before tau‐PET to 2 years after), using 11C‐PiB and 18F‐fluorodeoxyglucose (FDG)‐PET. cSVD at study inclusion was characterized by high or low white matter hyperintensity (WMH) volume on MRI. We calculated individual slopes of Aβ and cerebral metabolism up to the tau‐PET visit (time ‐8 to 0) using linear mixed effects models. Using age‐adjusted linear regression models, we examined associations of Aβ slope, tau, and cerebral metabolism slope or metabolism at the final visit (time≥0). We tested effect modification by sex and WMH using interaction terms and stratified analyses when interaction p<0.10.

Result

Associations of Aβ slope with tau varied by sex (p‐interaction=0.007) but not WMH. Greater increase in Aβ slope was associated with greater tau in women (β=3.5, p=0.004), but not men (β= ‐1.2, p=0.34). Tau did not predict cerebral metabolism at the final FDG visit (β=0.10, p=0.67), but increasing Aβ slope predicted hypometabolism at the final FDG visit (β= ‐2.1, p=0.01). Neither of these relationships varied by sex or WMH. Associations of cerebral metabolism slope with tau varied by sex (p‐interaction=0.08), but not WMH. Decreasing cerebral metabolism slope was associated with greater tau in women (β= ‐16.3, p=0.05), but not men (β=4.7, p=0.59). Further adjustment for APOE4 (N=31) did not appreciably alter results.

Conclusion

In non‐demented older adults, we found that associations of Aβ and cerebral hypometabolism with later increased tau were stronger in women than men; cSVD did not modify these associations. Tau did not predict later cerebral metabolism, while Aβ did.