bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medium‐chain fatty acids in combination with a multidomain lifestyle intervention in Alzheimer’s disease prevention: Protocol design to study implementation
Authors: Hillebrandt Heidi L , Dias Cintia B , Chatterjee Pratishtha , Asih Prita Riana , Barin Edward S , Shah Tejal M , Fuller Stephanie Jane , Rainey‐Smith Stephanie , Bharadwaj Prashant , Pedrini Steve , Thota Rohith N , Castro Carolina B , Ramezani Matin , Sohrabi Hamid R , Martins Ralph N 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) neuropathology begins 20 to 30 years before clinical diagnosis. Thus, there is an opportunity to implement strategies to prevent the progression of AD. Insulin resistance in the brain causes a disruption in glucose utilisation. Medium‐chain fatty acids (MCFA) are readily available substrates for the synthesis of ketone bodies (KB), which are an alternative brain fuel not controlled by insulin. A constant supply of KB may close the energy gap in the AD‐prone brain, and in doing so prevent or delay symptom onset, or protect the brain from further degeneration. There is increasing evidence that multidomain lifestyle interventions with dietary components significantly impact cognitive decline. Yet, these interventions have not considered the effects MCFA supplementation, to ensure sufficient energy for the brain.MethodThis is a phase II placebo‐controlled, randomised double‐blind 24‐month intervention trial of MCFA supplementation within the AUstralian‐multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention (AU‐ARROW) study, to investigate the additive effect of MCFA supplementation in older adults at increased risk of AD. A total of 124 participants will be recruited aged 60‐79 years, with subjective cognitive decline. Participants will be randomised 1:1 into either the intervention or placebo groups and will consume 3 daily doses at 15mL per dose of either MCFA or placebo supplement whilst continuing the AU‐ARROW protocol, which includes dietary education, physical activity, brain training, and health education.ResultThe primary outcomes involve statistical assessment of cognition, blood ketone body levels, and brain glucose utilisation. At baseline, and every 6 months, participants will have fasting blood samples collected. At baseline, 12, and 24 months, participants will undergo cognitive assessments. At baseline and 24 months, participants will undergo fluorodeoxyglucose positron emission tomography scans to determine brain glucose utilisation.ConclusionThe final protocol is expected to maximise data collection and analyses. Combined with AU‐ARROW, it will allow for a) the implementation of MCFA supplementation guidelines in a plan to reduce cognitive decline and risk of AD, b) the determination of effects of MCFA consumption on neuroimaging and blood‐based biomarkers, and c) the comparison of between subject differences.
Allostatic load and the influence of economic adversity and neighborhood disadvantage on cognitive function in a multiethnic cohort
Authors: Longoria Anthony Joseph , Brinson Zabecca S. , Carlew Anne R , Cullum Munro , De Lemos James A , Goette William , Lacritz Laura , Rossetti Heidi 
Published: December 2022

AbstractBackgroundPrevious research has demonstrated a link between objective socio‐economic indicators and cognitive test performance. Although some studies include subjective indicators, such as perceived neighborhood environment, little is known about which specific factors are most strongly associated with cognitive performance and whether these measures are useful beyond traditional SES proxies. Further, in addition to being disproportionately at risk of experiencing neighborhood disadvantage and lower SES, racial/ethnic minorities are more likely to be diagnosed with dementia and receive less timely care compared with White individuals. This study aims to investigate how perceived neighborhood environment and neighborhood disadvantage are related to cognitive performance within a large diverse sample.MethodA probability‐based sample of participants (N = 3858; Female = 59%; Black = 51%; Hispanic = 14%) from the Dallas Heart Study Phase 2 (DHS‐2; Mean: Age = 50, Education = 13) were administered the Montreal Cognitive Assessment (MoCA), in addition to measures of perceptions of neighborhood physical environment and violence, and perceived SES. Multiple regression was used to determine associations of these variables with MoCA scores relative to traditional SES measures (i.e., income, education), controlling for demographic and relevant health factors. Post‐hoc analyses stratified by racial/ethnic group were conducted to determine whether indicators differentially influenced test scores.ResultAfter controlling for socio‐demographic and health factors, reporting lower quality neighborhood resources and difficulty paying for “very basics like food and heating” and “medical care” were associated with lower MoCA scores in the overall sample. Post‐hoc analyses revealed significant relationships between MoCA scores and quality of neighborhood resources, “food and heating,” and “medical care” only in Black participants, while “violence” was significantly associated with lower MoCA scores in Hispanics. There were no significant relationships found in Whites. Overall, subjective measures of SES and neighborhood environment contributed modest variance in the overall model, specifically for Black and Hispanic participants (R
2 = 3% to 5%).ConclusionExperiencing neighborhood and economic adversity was associated with lower scores on a cognitive screening measure and accounted for more variance than income or education in Black individuals and income in Hispanic individuals, while no relationship was seen in White participants. Future research is needed to determine whether these allostatic stressors influence cognitive impairment or dementia later in life.
Translational potential of JAX humanized‐APOE mice: sex differences in bioenergetic function in brain
Authors: Cortes‐Flores Helena , Altemus Jesse , Wiegand Jean‐Paul L. , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundThe preclinical phase of late onset Alzheimer’s disease (LOAD), known as the preclinical phase, can start 10 to 20 years prior to onset of clinical symptoms. Hypometabolism and impaired mitochondrial bioenergetics can emerge during prodromal phase as early indicators of AD risk. APOEe4, the greatest genetic risk factor for LOAD, is well documented to induce lipid metabolic dysregulation. We therefore sought to determine the impact of APOEe4. The following study analyzed body composition and mitochondrial functions to elucidate how the presence of APOEe4 in a mouse model contributes to bioenergetic changes, and whether they affect females and males equally.Method18mo old transgenic mouse models (JAX #029018 and #027894) carrying humanized APOE alleles (hAPOE3/3, hAPOE3/4 or hAPOE4/4) were assessed for fat and lean mass content via EchoMRI. A week later, fasting blood glucose levels were assessed prior to sacrifice, and brain tissues were collected to determine mitochondria function by Complex I and IV activity.ResultBody composition analyses indicated that hAPOEe4 males had significantly lower fat percentage than male APOEe3 mice. Females, irrespective of APOE genotype, exhibited significantly lower lean weight relative to males. No sex or APOE genotype difference was detected in fasting blood glucose plasma levels nor in mitochondrial Complex I activity. In contrast, mitochondrial Complex IV activity was significantly lower in females relative to males. Lastly, Complex IV activity was lower in mice exhibiting dominance aggressive behavior, specifically barbering, irrespective of sex or genotype.ConclusionAPOE mice resembling a human population of approximately 60 years of age displayed a sex difference in body composition parameters, where total and lean weight was higher in males than females. Sex differences also emerged in bioenergetic function, with females exhibiting lower mitochondria Complex IV activity relative to males. Sex differences are consistent with human data, whereas no genotype differences were observed and thus may influence the translational potential of the humanized APOE mouse model in LOAD research. However, the translational potential might be greater when linked with phenotypic characteristics.This work was supported by NIA grants R01AG057931, and RF1AG059093
Voxel to voxel validation of brainstem MRI novel sequences to postmortem tissue reconstruction
Authors: LaMore Tia , Chen Yuheng , Otaduy Maria , Li Song Hua , Lee Wing Hung , Heinsen Helmut , Shi Yonggang , Grinberg Lea Tenenholz 
Published: December 2022

AbstractBackgroundNeuroimaging of brainstem structures has gained importance in ADRD as these regions degenerate early in AD. In recent years there has been an explosion of novel neuroimaging sequences to image the brainstem. However, most of these methods lack validation against the ground truth, i.e tissue visualization, making these methods less attractive for clinical use. Among the new proposed methods, high‐definition connectome promises to revolutionize BS imaging as it overcomes several limitations of standard structural MRI, including a high level of imaging deformation. In this project we have developed a pipeline to validate BS connectome sequences using a voxel to voxel comparison between 3D histological volumes and connectome signal. To this date we applied this pipeline to 6 human brains.MethodWe used 6 AD cases collected by the Neuroradiology Lab at the University of Sao Paulo. Patients underwent postmortem MRI prior to autopsy.We used a pipeline developed in‐house that allows for precise alignment of histology‐based cytoarchitectural 3D reconstructions of the brainstem to its T2 weighted 7T‐MRI counterpart. Upon procurement, the brains were fixed in formalin, embedded in celloidin, and cut in horizontal sections of 300um. Selected BS structures were delineated on these slides stained for Nissl(gallocyanin)(Fig.1). Delineated images underwent manual quality checks, a series of alignment and registration processes to recover original coordinates. The stained sections and corresponding ROI masks were registered to the blockface to correct for any deformation of tissue during the staining process. Freeview commands applied to reconstruct the brainstems and masks. We registered the resulting 3D reconstruction to the matching MRI coordinates(Fig. 2), enabling voxel‐to‐voxel comparisons.Result6 cases went through the pipeline with ROIs reconstructed on block reconstructions(Fig. 3). Currently, dice coefficient analysis between MRI signal and the manually outlined ROIs on histology are being finalized.ConclusionOur pipeline enables voxel‐to‐voxel correlation analysis between histology and MRI scans for validation of brainstem neuroimaging. Current finalization of a total 9 cases is ongoing. Validation of such correlation maps will inform interpretations of connectome results in living patients with the potential to act as an eventual diagnostic tool for ADRD.
Clinically relevant monitoring of long‐term night‐time behaviour and physiology from the homes of people living with dementia.
Authors: Kolanko Magdalena A , Soreq Eyal , Lai Helen , Barnaghi Payam , Dijk Derk‐Jan , Sharp David J 
Published: December 2022

AbstractBackgroundDisturbances of sleep and night‐time behaviours are amongst the most disabling symptoms of dementia. They often increase carers’ burden and the risk of institutionalization. The causes are complex and are difficult to investigate because of a lack of acceptable methods for monitoring behaviours in the home. Here we show that a passive under‐mattress can be used to track changes in night‐time behaviour and physiology, and that a range of digital biomarkers produced are informative in understanding the effects of medication changes, disease progression and intercurrent illness in patients living with dementia (PLWD).MethodWe used contactless Withings Sleep Mattress (WSM) to monitor bed‐occupancy in 4 PLWD (age 74‐93, 3males) enrolled into the CR&T MINDER cohort study. Each participant was tracked over 1000 nights between 2019 and 2021. Minute‐to‐minute timeseries were extracted from WSM to calculate bed occupancy metrics and nocturnal physiology measures (heart and breathing rates (HR/BR)). Raw measures were standardized within subjects by comparing each time point to the mean of the time points that preceded it. We then investigated the relationship between these metrics and clinical events such as infections and medication.ResultThe 4 case studies illustrate the potential of this technology for passive health monitoring in PLWD. High levels of intraindividual variability in behavioural and physiological metrics were observed. Progressive changes in bed occupancy were observed in two patients with frontotemporal dementia and Alzheimer’s disease (Cases 1&2). Intercurrent illness and medications changes influenced the measures. For example, Patient 1 showed progressive night‐time wandering with increasing time spent out of bed, which improved following the initiation of risperidone. Case 2 showed recurrent episodes of heart failure accompanied by increased nocturnal HR. Cases 3 and 4 showed urinary tract infections, which were accompanied by transient changes in bed occupancy measures.ConclusionPassive monitoring of night‐time behaviour and physiology is a simple and cost‐effective way to monitor the effects of medication change and medical events in PLWD. Digital biomarkers derived from these simple measures hold great promise as measures of dementia progression, to enhance dementia care by identifying at risk individuals and as novel clinical outcome measures in clinical trials.
Psychotropic medication use is higher in early‐ than late‐onset Alzheimer’s disease
Authors: Polsinelli Angelina J , Salazaar Krystal , Lane Kathleen A. , Gao Sujuan , Apostolova Liana G. 
Published: December 2022

AbstractBackgroundPsychotropic medication use in Alzheimer’s disease (AD) is important in symptom management as neuropsychiatric symptoms (NPS) often reduced quality of life for both patients and families. The extent to which these medications are prescribed at similar or discrepant rates between those with early symptom onset (EOAD) and late symptom onset (LOAD) is unknown but may have important implicants for clinical careMethodData were obtained from the National Alzheimer’s Coordinating Center database. Baseline data from those with primary Alzheimer’s disease (AD) diagnosis were used for this analysis. Baseline was defined as the first time the individual was diagnosed with impaired cognition. Participants who completed the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at baseline and had psychotropic medication use data available were included. Participants were excluded if they had additional neurological, systemic, psychiatric, or medical disease that could have significantly contributed to cognitive impairment. The AD group was divided into EOAD (n = 2796) or LOAD (n = 8446) using onset age < 65 or ≥65, respectively.Multiple logistic regression models (examining any medication use) and multiple poisson regression models (examining number of medications used) were run for each of the NPI‐Q categories to examine the association between age of symptom onset (i.e., EOAD, LOAD) and medication use, adjusting for sex, education and disease severity (CDR‐SB).ResultParticipant demographics are in Table 1. EOAD were more likely than LOAD participants to be taking at least one psychotropic medication for all NPS, except motor disturbance and nighttime behaviors (OR range: 1.16‐1.47; Table 2). Similarly, EOAD compared to LOAD participants were more likely to be taking a greater number of medications for each NPS, except motor disturbance (OR range: 1.10‐1.33; Table 3).ConclusionCompared to LOAD, EOAD is associated with increased psychotropic medication use at baseline – in terms of both presence and number of mediations prescribed – for almost all NPS. This fits well with previous findings showing greater NPS burden in EOAD. Future research will examine medication use longitudinally and explore potential group differences in efficacy.
Clinical validation of the Virtual Reality Functional Capacity Assessment Test – Short List (VRFCAT‐SLx) for assessment of iADL functioning in early symptomatic Dementia: Sensitivity to cognitive and functional change over time
Authors: Schoemaker Dorothee , Atkins Alexandra S , Abraham Chelsea , Flanagan Chloe , Evans Haley , Madsen Corrine , Sickel Nancy , Stevens Heather , Amaya Alexandra C , Plassman Brenda L , Loewenstein David , Welsh‐Bohmer Kathleen A. , Keefe Richard SE 
Published: December 2022

AbstractBackgroundAssessment of functional capacity is critical to the diagnosis and monitoring of Alzheimer’s disease and related dementias. The VRFCAT (Keefe et al., 2016) is a performance‐based assessment of iADL functioning that is completed on a tablet. Previous work on the VRFCAT has demonstrated correlations with clinical endpoints and sensitivity to cognitive impairment in individuals with subjective cognitive decline (SCD) and schizophrenia. To facilitate use longitudinally and in more impaired patient groups, the VRFCAT “short list” (VRFCAT‐SLx) was recently developed to reduce task complexity and length (see Atkins et al. AAIC submission). The aim of the present work was to characterize the VRFCAT‐SLx’s sensitivity to longitudinal clinical changes in subjects with early symptomatic MCI/AD dementiaMethodAt the time of submission, participants included 77 adults (32 male; mean baseline? age = 73.29, SD = 7.52) with clinical diagnoses of MCI/AD and CDR global scores of 0.5 or 1.0. Participants completed the VRFCAT‐SLx and other established measures (i.e., ADCS‐ADL‐MCI, MMSE, CDR, BAC cognitive tests) at Baseline and Follow‐up. At submission, 22 participants had completed both visits (mean follow‐up interval ± SD: 13 ± 4.8 months). We evaluated VRFCAT‐SLx performance as a predictor of cognitive and functional change over time, and examined relationships between longitudinal change on the VRFCAT‐SLx, MMSE, ADCS‐ADL‐MCI, and CDR‐SB.ResultBaseline VRFCAT‐SLx performance predicted decline on both the CDR Sum of Boxes (β = 0.44, p<0.05) and MMSE Total score (β = ‐0.48, p = 0.01), even when controlling for baseline performance, age, and length of follow‐up interval. Additionally, increases in the VRFCAT‐SLx Total Adjusted Time (i.e., worsening performance) at follow‐up was significantly correlated with observed decline on the MMSE (r = ‐0.55, p<0.01), CDR‐SB (r = 0.59, p<0.01), and ADCS‐ADL‐MCI (r = 0.44, p<0.05). These associations remained significant after adjusting for age and length of follow‐up interval.ConclusionLongitudinal results indicate that performance on the VRFCAT‐SLx reliably predicts and tracks cognitive and functional change in early symptomatic dementia. These findings support the validity of the VRFCAT‐SLx as a sensitive assessment of iADL functioning in MCI/AD dementia.
Recruitment and enrolment feasibility of the Luci risk reduction study in Québec
Authors: Lussier Isabelle 
Published: December 2022

AbstractBackgroundEvidence suggests that lifestyle interventions can reduce the incidence of cognitive decline in older adults. Multidomain lifestyle intervention thus generates major interest. Luci is a Web‐based multidomain coach‐assisted dementia risk reduction program. Although such a technology‐based delivery mode represents a scalability opportunity, reaching the target population may be a challenge. A main goal of the Luci pilot feasibility study was to evaluate recruitment and enrolment rates.MethodThis is an ongoing 24‐week, Luci vs waitlist randomized, single‐blind pilot feasibility study to enrol cognitively healthy individuals aged 50‐70 with ≥1 lifestyle risk factor (physical activity, diet, cognitive engagement). Exclusion criteria comprised severe health conditions (e.g., neurocognitive, psychiatric) and logistical reasons (e.g., no device or internet). We aimed to recruit 120 participants at a rate of ≥30 participants/month over 4 months, and to achieve a screening‐to‐enrolment ratio of ≥48%. Participants were recruited in weekly waves from a list of volunteers obtained through a media campaign on the Luci project, and a research centre database.ResultOf the 178 people invited to complete screening, 157 (88.2%) did so, and 124 (78.9%) met inclusion/exclusion criteria. The recruitment of the 120 participants was achieved over 1 week, and screening‐to‐enrolment ratio was 76.4%. Reasons for exclusion were not having any lifestyle risk factor (18.9%), exceeding study capacity (10.8%), logistical (24.3%) and health (45.9%) reasons. Included participants had a mean age of 60.7 (SD = 5.6) and 16.7 (SD = 3.4) years of education; 85% were female. Within enrolled individuals, 71.7% were living with someone, 37.5% were retired, and 66.7% had a household income greater than the Quebec median. 75.0% had ≥2 lifestyle risk factors.ConclusionOur recruitment and enrolment goals were met. Eligibility slightly exceeded our enrolment aim, a situation not unexpected. Almost all individuals who completed the screening had dementia risk factors suitable for Luci preventive interventions. However, some subgroups are not well represented in our sample, and in particular, men, individuals who are older (≥65 years), less educated, with a low‐income, and living alone. Results highlight the need to develop recruitment strategies to reach a more diverse population, and that specifically target individuals facing social inequities.