bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Regional Flortaucipir Profiles in Preclinical Alzheimer’s Disease: Evaluation using A4 phase 3 trial with Solanezumab
Authors: Kotari Vikas , Holdridge Karen Chilcott , Yaari Roy , Schultz Aaron P , Johnson Keith A , Aisen Paul S. S. , Sperling Reisa A , Sims John R. , Shcherbinin Sergey
Published: January 2025

Background

The A4 Study (NCT02008357) was a multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial, assessing the safety and efficacy of solanezumab in preclinical Alzheimer’s Disease (AD). We previously reported on the baseline regional flortaucipir (FTP) profiles in this study1. Here, we present the longitudinal tau profiles.

Methods

FTP scans were acquired at baseline and weeks 84,168, and 240. All FTP scans were analyzed using an established image processing pipeline to evaluate global[2] and regional tau patterns in template space. Global tau level was measured using an AD‐signature weighted volume‐of‐interest (VOI) (tauSUVR)2. Regional tau uptake and accumulation were measured in 3 prespecified composite regions representing tau pathology in preclinical AD, ordered by hypothetical pathologic spreading: 1) “early” (amygdala, entorhinal cortex, parahippocampal gyrus), 2) “middle” (fusiform, inferior, and middle temporal, and inferior parietal gyri), and 3) “late” (lateral occipital, posterior cingulate, superior parietal, and supramarginal gyri). We evaluated associations between baseline amyloid burden, age, sex, APOE ε4 carriage and longitudinal tau change within placebo group.

Results

At baseline, a lower tau signal was observed generally in regions identified later in pathologic sequences. Longitudinal change was region‐ and visit‐specific. In both treatment groups, the early and middle regions showed the largest change from baseline at Week 84; the middle region showed the largest change at Weeks 168 and 240; the global assessment changes were smaller than the early and middle regions at each time point (Figure 1; Tables 1&2) and a majority of participants remained global “tau negative”3(tauSUVR<1.11 Figure 2) throughout the trial. Higher baseline global amyloid level was most strongly associated with increased tau PET signal in the prespecified middle composite region at all timepoints (Figure 3).

Conclusion

A multi‐regional composite VOI staging scheme was developed using baseline tau profiles and prespecified for analysis of longitudinal tau PET images. Results confirmed that cognitively unimpaired, amyloid positive participants demonstrate larger tau accumulation in the early and middle than late and neocortical regions. The early composite performed better at detecting tau accumulation initially and middle composite at later timepoints. This multi‐regional staging scheme appears to be useful to characterize tau progression in this preclinical AD cohort.
Preliminary Evidence for the Combined Efficacy of Focused Ultrasound Blood‐Brain Barrier Opening and Delivery of a Novel Anti‐Amyloid Re Complex for Memory Improvement in a 3xTg‐Alzheimer’s Disease Mouse Model
Authors: Noel Rebecca L , Gorman Samantha L , Batts Alec L , Tsakris Deny L , Jimenez Daniella L , Pelecanou Maria , Sagnou Marina L , Konofagou Elisa
Published: January 2025

Background

Focused Ultrasound‐induced Blood‐Brain Barrier Opening (FUS‐BBBO) has demonstrated preventative and therapeutic efficacy for improving cognitive and pathological decline in Alzheimer’s Disease (AD). Previous work has demonstrated highly specific binding of a novel Re complex (Re‐1) complex to amyloid‐β (Aβ) in vitro, subsequently inhibiting fibril formation and reducing Aβ‐induced cytotoxicity in neuronal cell cultures. The aim of this preliminary study is to evaluate the efficacy of early intervention combining FUS‐BBBO and Re‐1 for anxiety amelioration and memory improvement in a triple transgenic (3xTg)‐AD mouse model.

Method

Four‐month‐old, male, triple transgenic (3xTg)‐AD mice, were divided into four groups for the present study: FUS+Re‐1, FUS, Re‐1, and anesthesia sham. This study consists of ten, bi‐weekly treatments spanning five months. Following treatment, the animals underwent five days of behavioral testing for anxiety (Open Field Test, OFT), spatial memory (Active Place Avoidance, APA), and reversal learning (Active Place Avoidance Reversal) to evaluate the progression of their AD‐associated cognitive deficits.

Result

Here we report that the combination of FUS‐BBBO and Re‐1 delivery improves anxiety, long‐term spatial memory, and short‐term reversal learning, compared to FUS or Re‐1 alone, and compared to the anesthesia sham group. The amount of time elapsed in the center of the brightly lit OFT arena is inversely related to each animal’s level of anxiety; thus, the FUS+Re‐1 cohort and the FUS cohorts exhibited the lowest levels of anxiety across the four groups (Figure 1A). Next, the number of shocks delivered to each animal over the course of an Active APA learning trial is inversely related to that animal’s spatial memory capacity. Comparison of animal performance in the final trial of the first day of training, with the first trial of the subsequent day demonstrates that the FUS+Re‐1cohort had the best long‐term memory of the four cohorts (Figure 1B). The FUS+Re‐1 group also demonstrated the most consistent reversal learning improvement when comparing the first and third (final) trial on each of the two APA reversal trial days (Figure 1C‐D).

Conclusion

This promising preliminary study offers evidence in support of early intervention with amyloid‐targeting Re‐1 and FUS‐BBBO for cognitive improvement in AD.
Revealing Patterns of Cognitive Function Trajectories in the Last Five Years of Life of Medicare Beneficiary
Authors: Lin Haiqun , Xia Weiyi , Zafar Anum , Montaner Olga F Jarrín
Published: January 2025

Background

Clinicians have observed various patterns of decline in cognitive function at the end of life. In a period of dynamic evolution in dementia care technology and delivery, tracking trends in cognitive function during last years of life provides a perspective on the need of patients and their caregivers and on demands on healthcare system. This work aims to characterize the functional decline in cognition during the last five years of life.

Method

The analytic cohort included a 10% random sample consisting of 195,240 Medicare beneficiaries who died in 2019, aged fifty or older and continuously enrolled in Medicare during their last five years of life. The group‐based trajectory modeling approach for ordered categorical outcomes was adopted to characterize beneficiaries’ changes in cognitive function over the last five years: no impairment, memory loss, mild cognitive impairment, and dementia. Cognitive function status in each quarter of the last five years of life was assembled from linked administrative, claims, and assessment data.

Result

Ten trajectory groups of cognitive function were identified and had a better value of Bayesian Information Criterion than either the 9‐class or the 11‐class solution. The 10 trajectory groups were categorized into four clusters: cognitively intact, mild cognitive impairment (MCI), steady decline to dementia, and early‐decline dementia. The intact cluster contains one trajectory group of 25% of beneficiaries who maintained their cognitive function throughout the last five years. The MCI cluster contains four trajectory groups with 37% in total of the beneficiaries who experienced slow decline in cognitive function and died with only MCI. The steady decline cluster contains four trajectory groups with 27% in total of the beneficiaries experienced steady decline in cognitive function and died with dementia. The early‐decline dementia cluster also contains only one trajectory group of 11% of the beneficiaries whose cognitive decline started more than five years before death. Sociodemographic and clinical factors associated with each cluster were assessed.

Conclusion

This study identified distinct patterns of cognitive trajectories that varied in the timing and rate of cognitive decline during the last five years of life.
A Bias‐Corrected Three‐Step Approach to Study the Association Between Aging Trajectories and Sociodemographic and Clinical Factors
Authors: Xia Weiyi , Zafar Anum , Montaner Olga F Jarrín , Lin Haiqun
Published: January 2025

Background

This work focuses on methodological aspects in assessing the association between group‐based aging trajectories and sociodemographic and clinical factors. The group‐based trajectories are derived from the latent class analysis of longitudinal variables of clinical interest. Each individual would be assigned a class membership with the highest posterior probability (modal assignment) and each class represents a particular pattern in the trajectory of the longitudinal variables. The Bolck–Croon–Hagenaars (BCH) method for bias adjustment in assessing the association of the latent class membership and external variables has increasingly become popular during the last twenty years.

Method

The BCH method is the three‐step approach that adjusts for the misclassification error in the latent class assignment. In the first step, we fit a group‐based trajectory model. In the second step, we calculate the posterior probability of class membership of each individual which is assigned to the class with either modal assignment or proportional assignment to each of the classes. The BCH class assignment weights are estimated in this step as well. In the third step, association parameters between latent class and external variables are estimated using weights from the step two. We generate simulation data to evaluate the performance of the three‐step approach without BCH adjustment and the bias‐corrected BCH approach. Subsequently, the association analyses between aging trajectory and external variables of interest among Medicare beneficiaries were conducted.

Result

The group‐based trajectory algorithm works well with truncated normal and ordered categorical longitudinal measurements among Medicare beneficiaries. We compute the inverse of the matrix and reweighting the data to obtain the desired joint probabilities of the latent class variables and external variables. The simulation result reveals the smallest bias when utilizing BCH‐proportional estimator and largest bias with the naive three‐step estimator. The BCH‐adjusted estimator outperforms the naive three‐step method in correcting bias.

Conclusion

Our results show the feasibility of applying BCH in the group‐trajectory analysis for both continuous and categorical longitudinal indicators for latent classes. The bias‐corrected three‐step approach with BCH can effectively reduce the bias from the latent class misclassification error.
Fatal Iatrogenic Cerebral Amyloid‐Related Encephalitis in a woman treated with lecanemab for Alzheimer’s disease
Authors: Solopova Elena
Published: January 2025

Background

We report the case of a 79‐year‐old woman with Alzheimer’s disease who enrolled in a clinical study of lecanemab. After the third, biweekly infusion she suffered a seizure followed by aphasia and progressive encephalopathy. Magnetic resonance imaging revealed multifocal cerebral edema and an increased burden of cerebral microhemorrhages compared to pre‐trial imaging. She was treated with an antiepileptic regimen and high‐dose intravenous corticosteroids but continued to worsen and died after five days.

Methods

Post‐mortem paraformaldehyde‐fixed coronal brain slices were embedded in degassed agarose solution and scanned with human clinical MRI scanners at 3 and 7 Tesla field strength. Free‐floating sections were immunostained using validated primary and corresponding secondary antibodies and imaged using a confocal laser‐scanning microscope. For three‐dimensional lightsheet microscopy, tissue blocks were embedded in CLARITY acrylamide hydrogel, optically cleared and stained with fluorescent probes and antibodies.

Results

Post‐mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β‐amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms.

Conclusion

We conclude that the patient likely died as a result of severe cerebral amyloid‐related meningoencephalitis.
A Novel Approach to Identify Sundowning with Cyclomatic Complexity Movement Analysis and Noninvasive Ambient Sensors
Authors: Johnson Brian B , Jamadagni Radhakrishna S , Kresnasandi Ida Bagus , Bolstad Britni A
Published: January 2025

Background

Sundowning is the development or progression of neuropsychiatric symptoms (NPS) often occurring in the afternoon or early evening. Noninvasive ambient sensors (NAS) monitor individuals without the need to wear a device or use a camera. The data from NAS sensors can identify movement patterns in the context of cyclomatic complexity to indicate when an individual may be sundowning. This approach could improve the quality of life (QOL) for individuals with Alzheimer’s disease (AD) and their caregivers.

Method

NAS sensors placed in an individual’s home could identify wandering due to sundowning when new patterns of movement emerge. Quantification of movement with cyclomatic complexity uses machine learning (ML) to identify and notify caregivers when new sequences of room transitions emerge. Cyclomatic complexity is represented as M = E − N + 2P where E is the amount of walking paths, N is the number of rooms, P is the total number of connected rooms (Khan & Jacobs). A new pattern of movement categorized as wandering is one signal a caregiver could consider within the constellation of symptoms.

Result

The method of approaching quantification of movement in an ML framework was pioneered by Dr. Taha Khan and Dr. Peter G. Jacobs in the study “Prediction of Mild Cognitive Impairment Using Movement Complexity”. Labeling sequences of human movement within an ML framework could lead to novel insights for understanding human behavior. Individuals that prefer to age‐in‐place could benefit from early detection of neuropsychiatric symptoms and prevention of sentinel events with proactive clinical decision‐making.

Conclusion

The transition from CIN to MCI is a significant change for an individual. Current assessments are dependent on the clinical interpretation by the caregiver. Instead of waiting until a sentinel event occurs, predictive algorithms could be used for early intervention. Data could enhance the decision making‐support for further assessment or admission to a long‐term care facility. As the aging population continues to grow, affordable technological solutions will be critical for monitoring health factors in real‐time. By providing this early warning, caregivers can adjust their routines and interventions to better support the patient.
Supporting Aging through Green Exercise (SAGE): Comparing the cognitive effects of outdoor versus indoor aerobic exercise in older adults with mild cognitive impairment—A 12‐week proof‐of‐concept randomized controlled trial
Authors: Noseworthy Matt W , Wei Nathan , Grant Sofia , Zou Jammy , Puterman Eli , Handy Todd C , Liu‐Ambrose Teresa
Published: January 2025

Background

Evidence from randomized controlled trials (RCTs) shows that aerobic exercise (AE) can benefit cognitive function among older adults with mild cognitive impairment (MCI). Growing research suggests that outdoor, natural (i.e., “green”) environments, compared with indoor or built environments, may augment the health benefits of exercise. However, the potential cognitive benefits of green exercise are unclear. We compared the effects of AE performed in an outdoor, green environment (O‐Ex) versus indoor AE (I‐Ex) on executive functions among older adults with MCI.

Methods

A two‐arm parallel, single‐blinded, 12‐week proof‐of‐concept RCT. 72 community‐dwelling adults aged 65‐80 years with MCI were randomized (1:1) to either O‐Ex (n = 36) or I‐Ex (n = 36). Each arm involved two group‐based training sessions per week. Each session involved 10 min warm‐up, 40 min moderate‐intensity AE (progressing from 45%–75% of heart rate reserve), and 10 min cool‐down. We monitored exercise intensity using heart rate monitors and Borg’s 20‐point Rating of Perceived Exertion. AE consisted of outdoor walking in an urban forest (O‐Ex) or indoor treadmill walking or stationary cycling (I‐Ex). We measured working memory using the National Institutes of Health Toolbox (NIHTB) List Sorting Test and the Verbal Digits Forward and Backward Test. We measured set shifting and response inhibition using the NIHTB Dimensional Change Card Sort Test and Flanker Test, respectively. We performed a complete case analysis using a one‐way analysis of covariance to compare groupwise changes in executive functions (NIHTB corrected T‐score), with baseline outcome score and baseline Montreal Cognitive Assessment (MoCA) score as covariates. Overall alpha was ≤0.05.

Results

Mean baseline MoCA score was 22.36 (SD = 2.55). Mean age was 74.08 years (SD = 3.92). There were 26 males and 46 females. The attrition rate was 12.5% (O‐Ex = 5; I‐Ex = 4). At 12 weeks, after adjusting for baseline outcome and baseline MoCA scores, O‐Ex had significantly better scores than I‐Ex for set shifting (estimated mean difference: 7.46; 95% CI: [2.69, 12.23]; p = 0.003) and response inhibition (estimated mean difference: 3.81; 95% CI: [0.61, 7.01]; p = 0.021), but not for working memory.

Conclusions

Aerobic exercise performed outdoors in nature, compared with indoor aerobic exercise, may provide greater cognitive benefits among older adults with MCI.
Baseline energy and nutrient intakes of AU‐ARROW participants using a Food Frequency Questionnaire‐ Preliminary findings
Authors: Fernando Malika G , Castro Carolina B , Gardener Samantha L , Fuller Stephanie Jane , Naismith Sharon L , Baker Laura D , Kivipelto Miia , Villemagne Victor L , Grieve Stuart , Yates Paul A , Armstrong Nicola , Anstey Kaarin J. , Sohrabi Hamid R. , Garg Manohar , Chen Juliana , Martins Ralph N
Published: January 2025

Background

Lifestyle modifications incorporating a healthy diet, physical activity, brain training and health monitoring have proven effective in preventing dementia and related cognitive decline (REF). The Australian‐Multidomain Lifestyle Intervention to reduce dementia risk (AU‐ARROW) is an ongoing 2‐yearintervention, which is the Australian contribution to the World‐Wide FINGERS network. Here we report on preliminary findings of baseline dietary energy and nutrient intakes of AU‐ARROW participants.

Methods

Data from 99 cognitively‐unimpaired adults enrolled in AU‐ARROW were included (60% female; mean age 67.8±5.3 years). Participants self‐administered the validated Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to analyse dietary energy and nutrient intake. Nutrient intakes were compared against the Australian National Health and Medical Research Council Recommended Dietary Intakes (RDIs).

Results

Participants’ average energy and protein intakes were 8980±1980 kJ/day and 96.8±22.6 g/day for males, and 8250±2660 kJ/day and 88.1±25.3 g/day for females. Total fat intake (males 101±25.8 g/day, females 98.9±37.0 g/day) comprised approximately 31% saturated fat, 45% monounsaturated fat and 18% polyunsaturated fat. RDIs were met by participants for most vitamins and minerals, with exceptions for sodium, zinc, calcium, vitamin A, thiamine, riboflavin, vitamin D and iodine. Males exhibited higher sodium intake (2410±588 mg/day) than the Recommended Upper Level of Intake (2300 mg/day), and lower zinc (10.9±2.7 mg/day) and vitamin A (797±310 mg/day) intake than the RDI (Zinc 14 mg/day, vitamin A 900 mg/day). Females exhibited lower thiamine (0.8±0.6 mg/day) and riboflavin (1.0±0.7 mg/day) intake than the RDI (1.1 mg/day for both). Both genders exhibited lower calcium intake (males 856±264 mg/day, females 860±345 mg/day), and iodine (males 123±40.1 µg/day, females 125±54.9 µg/day) than the RDI (calcium: males 1000 mg/day, females 1300 mg/day, iodine: 150 µg/day for both).

Conclusion

Habitual macro‐nutrient intakes of AU‐ARROW participants largely meet the RDI for Australians, except for higher saturated fat and lower calcium and iodine intakes. The Australian Health Survey:2011‐2012 has also reported similar concerns on Australians’ usual nutrient intakes. Attention to a healthy diet is crucial for optimal saturated fat, vitamin, and mineral levels. These baseline data identify deficiencies in the Australian diet which hopefully will be corrected following dietary‐intervention of the AU‐ARROW participants.
Association of Retinal Layer Thickness with Brain Volume and Cortical Thickness in older adults
Authors: Han Ji Won , Kim Hyeong Min , Kwon Min Jeong , Park Jieun , Kim Jun Sung , Woo Se Joon , Kim Ki Woong
Published: January 2025

Background

To elucidate the biological mechanisms underpinning the association between macular Retinal Nerve Fiber Layer (RNFL) thickness and cognitive function in older adults, this study investigates its correlation with brain volume and cortical thickness.

Method

From a community‐dwelling prospective cohort, we included 166 non‐demented participants aged over 65 years (mean age 75.2 ± 5.3; 61.4% women) who had 3D T1 MRI images and no ocular pathologies that could affect retinal layer thickness. Using spectral‐domain optical coherence tomography, we assessed the thickness of the macular RNFL. We analyzed the relationship between RNFL thickness and regional brain volumes using voxel‐based morphometry, adjusting for age, sex, and total intracranial volume (uncorrected p < 0.001, cluster size threshold = 100 voxels). The relationship between RNFL thickness and cortical thickness by FreeSurfer was assessed using Pearson's correlation analysis, with adjustments for age and sex.

Result

Increased gray matter volumes correlating with outer RNFL thickness were present in the right inferior parietal (t=3.81), the left superior frontal (t=3.71), and left inferior temporal (t=3.95) cortices. The total RNFL thickness was associated with the volume of the right inferior parietal cortex (t=3.62). Significant associations were found between RNFL thickness and the cortical thickness of multiple brain regions. In particular, the cortical thickness in the left posterior cingulate and both supramarginal regions was significantly correlated with total, inner, and outer RNFL thickness. Upon adjusting for multiple comparisons, these associations did not retain statistical significance.

Conclusion

RNFL thickness was associated with various brain regions involved in sensory information processing and integration, as well as cognitive functions. We also observed correlations with brain regions implicated in the early stages of Alzheimer's disease pathology.
Cortical cholinergic pathway integrity is reduced in Parkinson’s disease dementia
Authors: Slater Nicola M , Myall Daniel J , Horne Kyla‐Louise , Anderson Tim J , Heron Campbell Le , Melzer Tracy R , Dalrymple‐Alford John C
Published: January 2025

Background

Normal cognitive function is supported by the neuromodulatory mechanisms of the cholinergic system. In Parkinson’s disease (PD), histological and molecular imaging evidence suggests disruption to cholinergic circuitry is associated with progression to Parkinson’s disease dementia (PDD). The primary source of cortical cholinergic input is the Ch4 region of the basal forebrain. Reduction in cholinergic projection axon integrity may precede Ch4 neuronal decline, so we examined differences in the integrity of medial and lateral Ch4‐to‐cortex pathways from three subregions of Ch4.

Method

Structural and diffusion‐weighted MRI and neuropsychological assessment was acquired from a convenience sample of 108 PD patients, 60 with normal cognition, 37 with mild cognitive impairment, 12 PDD, and 41 control participants. Streamlines connecting the anterior‐lateral, anterior‐intermediate, and posterior Ch4 subregions to the cortex were grouped according to medial and lateral cortical cholinergic pathway definitions by Selden et al. [1]. Integrity was assessed using diffusion tensor, NODDI, and fixel‐based models.

Results

Accounting for age and sex, Bayesian mixed‐effects models indicated moderate to strong evidence of increased free water in PDD in all pathways, especially in connections with anterior‐intermediate and posterior Ch4 subregions (Cohen’s d (Control–PDD) = 0.47). Across connections with all subregions there was moderate to strong evidence of increased mean diffusivity (Cohen’s d (Control–PDD) = 0.76) and reduced fibre density (Cohen’s d (Control–PDD) = 1.24) in PDD. In PD‐MCI, moderate evidence of increased mean diffusivity was observed (Cohen’s d (Control–PD‐MCI)= 0.64), but no evidence for alterations in other metrics.

Conclusion

Our results reveal evidence of reduced integrity in the major cortical cholinergic pathways in PD‐MCI, and more extensive evidence of reduced integrity in PDD. While these findings support an association of cholinergic circuity disruption in PD‐related cognitive impairment, they contrast with a commonly held view that losses in cholinergic projection integrity may explain, and potentially precede, cognitive impairment in PD. Ch4 projection pathway integrity may be more pertinent to future cognitive decline than current cognitive status. Longitudinal investigation will examine how Ch4 projection pathway integrity relates to the progression of cognitive decline in PD.

Reference:

[1] Selden, et al. Brain 121, 2249–2257 (1998).
Social connection profiles of older adults as both heritable and modifiable influences on brain health: data from the Older Australian Twins Study
Authors: Samtani Suraj , Casey Anne‐Nicole , Thalamuthu Anbupalam , Lam Ben C.P. , Catts Vibeke S. , Brodaty Henry , Sachdev Perminder S.
Published: January 2025

Background

Social connections are associated with brain health, but the extent to which social connections are heritable remains unclear. Using longitudinal twin data, we explored the heritable and environmental contributions to social connections. We hypothesised that social connections patterns would be moderately heritable and would be associated with better cognitive and mental health over time.

Method

We analysed data from 333 monozygotic and 266 dizygotic twins aged 65+, collected at baseline, 2‐ and 4‐year follow‐up in the Older Australian Twins Study. Outcome variables were depressive and anxious symptoms, MMSE and neuropsychological subtest scores, and social activity items. We ran exploratory structural equation modelling, univariate heritability models, genetic correlations and linear mixed‐effects, and Inference about causation from examination of familial confounding (ICE FALCON) modelling. Fully adjusted models controlled for age, sex, education, hypertension, diabetes, smoking, alcohol use, history of depression, BMI, exercise, and additionally for APOE4 status and hearing loss (for cognition) and pain and neuroticism (for mental health).

Result

We identified three social connection factors with weak to no heritability: interacting with friends and community (h2 = 0.09,95%CI: 0.00,0.44), family interactions and childcare (h2 = 0.13,95%CI: 0.00,0.43); and involvement in religious groups and caregiving (h2 = 0.00,95%CI: 0.00,0.19). Genetic correlations indicated overlap in genetic influences for friend interactions with global cognition (r = 0.21), depressive (r = ‐0.96), and anxious symptoms (r = ‐0.47). Shared environmental correlations between friend interactions and global cognition (r = 0.24), depressive (r = ‐0.53), and anxious symptoms (r = ‐0.54) indicated some overlap in environmental influences. Friend interactions were associated with fewer depressive symptoms cross‐sectionally (B = ‐0.14, adjusted p = 0.004) and longitudinally (B = ‐0.09, adjusted p‐value = 0.010); social connections were not associated with cognition. ICE FALCON analyses did not reveal causal relationships between social factors and cognitive/mental health.

Conclusion

Certain social connection profiles were weakly heritable (friend and family interactions) and were associated with brain health (friend interactions). There was moderate overlap in the genetic and shared environmental influences affecting social connections and cognitive and mental health. Interacting with friends was associated with fewer depressive symptoms; social connections were not associated with cognitive change over 4 years. Health care for older adults should include paying attention to social connections to support brain and mental health.
Differences in cerebrospinal fluid and cerebral blood flow measurements by age, sex, and APOE4 status in older adults
Authors: Dong Yilei , Sakhare Ashwin , Stradford Joy , Monreal Teresa , Isenberg A. Lisette , Pa Judy
Published: January 2025

Background

The glymphatic system is important for clearing waste and transporting nutrients throughout the brain, but it’s still unknown how cerebrospinal fluid (CSF) and cerebral blood flow (CBF) contribute to Alzheimer’s Disease (AD). Phase‐contrast MRI (PC‐MRI) has been shown to reliably measure CSF and CBF at the cerebral aqueduct (CA) and second and third cervical vertebrae (C2‐C3) non‐invasively. The purpose of this study is to demonstrate CSF and CBF flow dynamics variations by age, sex, and APOE4 status in older adults.

Method

Seventy‐nine healthy older adults (66.9±7.1 years old, 47 women) were recruited for this study from two larger clinical trials. All subjects received an MRI scan at baseline. CSF and CBF measurements were obtained using a 2D cine PC‐MRI pulse sequencing with retrospective cardiac gating. Measurements for CSF and CBF flow were taken at the CA, subarachnoid space (SS), and arteries between the C2‐C3. Correlation coefficients were calculated for age and CSF and CBF flow measurements, while mean and standard deviations of CSF and CBF flow measurements were calculated for sex and APOE4 status.

Result

Age: For the CA, stroke volume (r=.23, p=.04) and total CBF (r=‐.26, p=.02) were significantly associated with age. For arteries, there was a non‐significant trend‐level association between age and arterial pulsatility index (r=.21, p=.06), arterial resistive index (r=.21, p=.06), and total stroke volume (r=‐.20, p=.08).

Sex: Though non‐significant, there was a trend towards significance for women to have a greater SS fill peak than men (p=.07). In general, women had higher absolute values for CSF and CBF measurements, but they were largely not significant.

APOE4 Status: There was no significant difference between APOE4 carriers and non‐carriers for any CSF and/or CBF measurements.

Conclusion

This study shows that across age, sex, and APOE4 status, there are variations in CSF and CBF measurements for participants that may contribute to glymphatic clearance and AD.
The moderating effect of diet on the relationship between depression and Alzheimer’s disease‐related blood‐based biomarker
Authors: Shamsi Hilal Salim Al , Gardener Samantha L , Smith Stephanie Rainey , Sohrabi Hamid R. , Fernando Warnakulasuriya Mary Ann Dipika Binosha , Martins Ralph N
Published: January 2025

Background

Interplay between diet, depression, and Alzheimer's disease (AD) shows promise as an important area of study for early intervention and therapy. Associations between both depression and diet and heightened AD risk underscore the need to examine the moderating effect of dietary patterns on the relationship between depression, and AD‐related blood‐based biomarkers.

Method

Data from cognitively unimpaired older adults (n=89; age ≥60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were included. Participants completed a food frequency questionnaire, self‐report measures of depression, and had AD‐related blood‐based biomarker levels for phosphorylated tau (ptau181) 181, Aβ40, Aβ42, Neurofilament Light Chain (NfL), and Glial Fibrillary Acidic Protein (GFAP). Scores for two dietary patterns, 1) Mediterranean diet (MeDi), and 2) western diet were generated for each individual. Moderation and simple slope analyses were used to examine the interactions between dietary patterns, depression, and biomarker levels.

Result

Depression was positively associated with NfL levels in males with lower than mean MeDi score adherence (β=3.759, SE=1.248, p=0.005). Depression was also positively associated with NfL levels in Apolipoprotein E (APOE) ε4 allele non‐carriers with lower than mean and mean MeDi score adherence (β=7.384, SE=1.972, p<0.001; β=3.797, SE=1.004, p<0.001, respectively).

Moreover, depression was positively associated with Aβ40 levels in APOE ε4 allele non‐carriers with lower than mean and mean MeDi score adherence (β=16.837, SE=5.242, p=0.002; β=7.502, SE=2.669, p=0.005, respectively).

No moderating effects of MeDi on the relationship between depression and levels of ptau181, Aβ42, and GFAP were observed. Furthermore, western diet had no moderating effect on the relationship between depression, and AD‐related blood‐based biomarkers.

Conclusion

This study highlights MeDi adherence as a potential moderator of the relationship between mood and AD‐related blood‐based biomarker levels. These findings also emphasize the importance of gender‐ and genotype‐specific approaches to depression‐cognition‐diet research and highlight the need for further investigation.
DETECT‐AD ‐ Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease: Results of amyloid screening methodologies in a simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Mattek Nora , Mar Amanda B , Marcoe Jennifer , Hanna Elise J , Pierce Aimee , Shang Yanan , Wright Kirsten M , Wyatt Jonathan A , Schwartz Daniel , Gothard Sarah , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T , Duff Kevin , Silbert Lisa C
Published: January 2025

Background

With the advent of anti‐amyloid therapies, identifying those with underlying amyloid burdens and detecting subsequent clinical effects of this AD pathology is critical. The DETECT‐AD study (ClinicalTrials.gov, NCT05385913) is a simulated secondary prevention anti‐amyloid clinical trial testing digital biomarkers as more sensitive and meaningful primary outcome measures. Clinically prodromal AD patients with estimable rates of AD progression based on Aβ PET status are enrolled as Aβ “positive” (higher amyloid burden) patients who predictably progress (as if receiving placebo) and Aβ “negative” patients progressing more slowly (representing the treatment group). Typical of current trials, participants are screened at entry to determine those with critical CNS amyloid burdens. Given the effort and cost of establishing AD phenotypes, efficient means for this screening are needed. Here we report to date the results of examining the screening process using blood‐based amyloid determinations for identifying florbetapir PET imaging‐based, amyloid status leading to enrollment of prodromal AD trial participants.

Method

Participants were initially screened by telephone using inclusion/exclusion criteria questionnaires. If passing this phase, participants underwent in‐person cognitive and neurological examinations and clinical blood tests; if passing this phase, an MRI/amyloid PET scan was performed; if passing this last step, the digital technologies were deployed in‐homes. The first 47 participants used this protocol. The subsequent 140 participants underwent a blood amyloid test (plasma Aβ42:40) first, and then the remaining procedures if intermediate or high risk for CNS amyloid (Aβ42:40 < 0.170).

Result

A Consort Diagram shows the study results (Figure). As of 1/3/2024, 85/100 have been enrolled with mean(SD): follow‐up=59.4(21.3) weeks; age=78.2(6.5); 65% women; MoCA=25.0(2.5); PET SUVR=1.14(0.23), range: 0.806‐2.18. Without blood amyloid pre‐screening, 26% of participants were PET amyloid positive (SUVR≧1.11). With the blood amyloid screening, 52% were PET amyloid positive.

Conclusion

A simple telephone screen and blood amyloid test significantly improved the yield of amyloid PET positive participants in a simulated clinical trial, which can reduce costs, personnel effort, and participant burden and risk. Follow‐up will suggest how additional simple clinical, digital, and blood‐based biomarkers may further aid in identifying well‐defined target populations for clinical trials.
Safety of the CSF1R Inhibitor EI‐1071 in Human and Its Pharmacological Effects to Reduce Neuroinflammation and Improve Memory Function in a Mouse Model of Alzheimer’s Disease
Authors: Tamayanti Wahyu Dewi , Lin Jun Ru , Ariyanti Agnes Dwi , Chang Yenni , Cheng Haw Yuan , Huang Chia Wei , Ru Wu Cheng , Wang Chuan Yao , Hsieh Tsung Han , Lin Uni D , Pai Chi Yun , Tsai Jin‐Wu , Chen Hung‐Kai
Published: January 2025

Background

Microglial activation is one of the neuropathological hallmarks of Alzheimer’s disease (AD). Evidence suggest that chronic activation of microglia cause neuroinflammation and neuronal injuries, contributing to cognitive impairment. Therefore, modulation of microglial pathway like CSF‐1R represents an attractive therapeutic strategy. EI‐1071 (enrupatinib) is a brain‐penetrant CSF‐1R selective inhibitor that is in clinical development for AD treatment. Here we report the pharmacological effects of EI‐1071 on microglial modulation and neuronal functions in the 5xFAD model and the safety/tolerability demonstrated in a first‐in‐human trial.

Method

In animal studies, neurons in brains of 5xFAD mice were marked with EGFP via in utero electroporation. Mice with/without EI‐1071 treatment were assessed by behavioral studies including Novel Object Recognition (NOR) and Y‐maze followed by microscopic examination of Aβ plaques and GFP‐labelled neurons in brain slices. Changes in microglia and inflammatory biomarkers were analysed by immunofluorescent microscopy, RNA sequencing and/or quantitative PCR. A first‐in‐human phase 1 trial (NCT04238364) was conducted in healthy volunteers in compliance with the protocol approved by the regulatory authorities.

Result

Pharmacological inhibition of CSF‐1R by EI‐1071 induced significant changes in microglial homeostasis, neuroinflammation, and neuronal injuries. Those activated microglia surrounding amyloid plaques were greatly reduced accompanying with a declining tendency in amyloid plaques and neuronal death. Treatment of EI‐1071 did not eliminate all microglia. Homeostatic microglia were relatively well preserved as compared to the plaque‐associated microglia. Gene expression analysis revealed declines in microglial and proinflammatory genes and AD‐associated biomarkers including Iba1, Csf1r, Trem2 and Tyrobp. In addition, mice treated with EI‐1071 showed enhanced cognitive functions in NOR and Y maze tests.

The phase 1 study enrolled 58 healthy volunteers into the single ascending dose and multiple ascending dose phases to assess the safety and tolerability of EI‐1071. All treatment emergent adverse events in the multiple dosing phase were grade 1, and were unrelated to EI‐1071 dosing.

Conclusion

1. EI‐1071 is effective in reducing activated microglia, neuroinflammation and neuronal injuries, resulting in a significant improvement of memory function in the 5xFAD model.

2. EI‐1071 is well‐tolerated in a phase 1 clinical trial. The safety profile supports further investigation in patients with AD.
Prioritizing the Lived Experience: The Peer Reviewed Alzheimer’s Research Program
Authors: Fontaine Sarah N. , Brandt Katherine
Published: January 2025

The Congressionally Directed Medical Research Programs (CDMRP) originated in 1992 via a Congressional appropriation to foster novel approaches to biomedical research in response to the expressed needs of its stakeholders‐the American public, the military, and Congress. Currently there are 35 CDMRP programs each addressing a specific disease or condition.

The Peer Reviewed Alzheimer’s Research Program (PRARP) began in 2011 and has a vision to mitigate the impact of Alzheimer’s and related dementias associated with military and diverse risks. To do this, the PRARP funds person‐centered research to address critical needs and improve quality of life for people living with Alzheimer’s diseases and related dementias.

A CDMRP hallmark is the inclusion of people with lived experience at all levels. For the PRARP, this means inclusion as an equal voice and vote in setting the annual investment strategy and priority areas for a program, reviewing research applications, and making funding recommendations. They may be a person with a dementia diagnosis, family member, and/or care partner. This collaborative approach brings an important perspective and insight on the needs of the Alzheimer’s and dementia community and brings a sense of urgency to the entire process. The PRARP goes one step further and requires community collaboration in funded research projects. Any project proposing clinical research is required to have community collaboration throughout the design, execution, and dissemination of the research. This talk from the PRARP program manager and a PRARP lived experience peer‐reviewer will describe how people with lived experience are empowered to share their voice and are integrated throughout the PRARP’s processes and funded projects.
Participatory research involving people with neurodegenerative diseases and family caregivers: a systematic review
Authors: Daum Marcel , Ferra Fenia Gkolfo , Drewelow Eva , Walde Peggy , Gerullis Kai , Kilimann Ingo , Völlm Birgit , Teipel Stefan , Klein Olga A.
Published: January 2025

Background

Participatory research or patient and public involvement refer to the process of actively involving people with lived experience into the research process to improve its relevance, quality, and impact. In the PART project we aim to establish a sustainable structure to include underrepresented patient groups with neurodegenerative diseases into a patient advisory board for research. As one of our milestones, we conducted a systematic literature review with the aim of examining the impact of participatory research on people involved, such as those with cognitive impairment, caregivers, and researchers.

Objective

To explore the benefits, limitations and barriers of participatory research in the field of neurodegenerative diseases.

Method

We conducted a systematic literature review covering the databases PubMed, PsycINFO, CINAHL, Embase, Scopus, ClinicalTrials.gov, and Google Scholar, and added hand searches. The search strategy consisted of the terms “patients” AND “dementia” AND “participation” AND “impact” AND “research”. Based on the selection of relevant articles published between 2000 and 2022, we performed a quality assessment using the Mixed Methods Appraisal Tool (MMAT).

Result

The entire search yielded 1,994 articles, of which 1,169 remained after the removal of duplicates and were integrated into the screening process. Following a two‐step screening process and subsequent validation of a subset of 20% of the articles by a second reviewer, a set of 30 articles were selected for inclusion in the review. Current findings indicate that participatory research in the field of neurodegenerative diseases provides various advantages, such as empowering people with lived experience and enhancing researchers' understanding of those affected. Challenges included the extra time and effort required, as well as the difficulty of establishing a balanced relationship between researchers and co‐researchers.

Conclusion

The number and quality of scientific articles regarding participatory research in the field of neurodegenerative diseases has been growing over the past two decades. The terminology used in reporting was frequently ambiguous, the description of participatory methods was often insufficient, and the impacts were frequently disregarded. Further research is required to address these issues and to investigate the impact of peer research in dementia studies.
Assessing the impact of fasting condition and storage time on plasma Amyloid‐β 42 and 40, pTau181, Nf‐L and GFAP measurements
Authors: Blasco‐Forniés Helena , Torres‐Torronteras Javier , Ortiz‐Romero Paula , Escalante Armand González , Minguillón Carolina , Anastasi Federica , Jiménez‐Moyano Esther , Suárez‐Calvet Marc , del Campo Marta
Published: January 2025

Background

Blood biomarkers are essential in identifying Alzheimer's disease (AD) pathology. To ensure their clinical use, it is crucial to understand pre‐analytical factors such as fasting conditions and long‐term storage at ‐80°C. This study evaluates the effect of these factors on plasma biomarker concentrations for detecting AD pathology and neurodegeneration.

Methods

Plasma biomarkers were measured in participants from the ALFA cohort using N4PE (Amyloid‐β [Aβ]40, Aβ42, Nf‐L, GFAP) and the pTau181 v2.1 advantage kits on Simoa HD‐X analyzer (Quanterix). To study the impact of fasting conditions, plasma samples from the same 16 participants in fasting and non‐fasting conditions were analysed. Aβ positivity in these participants was determined using CSF Aβ42/40 ratio. To assess long‐term storage at ‐80°C, we measured plasma biomarkers in samples stored at ‐80°C for 10 years (n=2339) and one year (n=381) from different participants. We compared differences on biomarker levels across groups, adjusting for age, sex and APOE‐ε4 genotype.

Result

Plasma concentrations of Ab40 and Aβ42 were lower in samples obtained under fasting conditions than non‐fasting ones independently of their amyloid status. However, this effect was not observed in the plasma Aß42/40 ratio. No differences in the plasma concentration of GFAP, Nf‐L or pTau181 were detected between fasting and non‐fasting conditions. The performance of the different markers to discriminate amyloid positivity was similar across fasting conditions. We observed no differences on pTau181 levels between long‐ and short‐term storage at ‐80°C. However, we observed higher levels of Ab40, Ab42 and Ab42/40 (mean difference: 9.7%, 16.8% and 7.0%, respectively) and lower levels of GFAP (32.1%) and Nf‐L (13.9%) in samples stored for 10 years.

Conclusion

Plasma pTau181, a key predictor of amyloid pathology, remains unaffected by fasting and long‐term storage. However, fasting conditions influenced the measurements of Aβs, which was mitigated by considering the Aβ42/40 ratio. Notably, long‐term storage at ‐80°C may influence the concentration of Abs, GFAP, and Nf‐L, underpinning the need to consider storage time on plasma biomarker analyses. Future studies should include larger data sets for fasting conditions and evaluate additional factors that may influence the effect of storage time on biomarker levels.