bluuebunny/crossref_metadata_2025 huggingface dataset:
Apheleia‐001: A novel prescreening study designed to enrich and accelerate Alzheimer’s disease clinical trials by efficiently identifying trial‐eligible participants determined to have a high probability of study inclusion, including amyloid positivity
Authors: Smith Katy , Bork Jason , Jolkovski Allison , Schillinger Rona , Batchuluun Dawn , Ng Amanda , Brown Christina M. , Kraus Lori , Matilla Inmaculada , Bernard Emmanuel G. , Hollingshead Sarah , Florian Hana , Yu Lynch Shau , Lee Christa , Bannon Anthony W. , McGeeney Danielle , Schwartzbard Julie
Published: December 2023

Background

The clinical development ecosystem cannot support the current demand for participants needed in Alzheimer’s disease clinical trials which is further disrupted by: 1) high screen fail rates (≥80‐90%); 2) lengthy screening visits constraining site resources; 3) unnecessary participant burden. The field demands a unique approach to optimize site resource utilization, participant/caregiver time, and overall development costs. Apheleia‐001 will identify patients with a high probability of meeting study‐specific eligibility criteria for a therapeutic Alzheimer’s disease clinical trial.

Method

Apheleia‐001 prescreens potential participants using paper and digital cognitive tests, demographic and medical information, and blood biomarkers. Apheleia‐001 procedures are completed in <2 hours and they minimize both site and participant burden. Participants eligible through Apheleia‐001 are referred to an early phase therapeutic AD trial.

Apheleia‐001 will enroll ∼1600 participants across 28 clinical trial sites in both North America and Europe with an expected 24‐month enrollment period.

Result

Apheleia‐001 is currently open for enrollment and data is being collected. As of 18Jan2023, Apheleia‐001 has completed 300+ prescreens and has identified over 60 trial eligible participants. Of the 300+ prescreened, 35% have identified as an underrepresented minority (URM). It is projected that the Apheleia pre‐screener will ultimately reduce the screen failure rate of a specific sponsor clinical trial by up to 50%.

Conclusion

Apheleia‐001 is projected to accelerate clinical trial enrollment and reduce the cost of an early phase therapeutic AD clinical trial. With this approach, initial screen fails will be done more efficiently (e.g., reduced speed and cost) compared to traditional clinical trial approaches. In addition, Apheleia‐001 optimizes sites for randomizations, therefore improving site resource utilization and finances. If scaled, Apheleia‐001 could significantly impact recruitment timelines across multiple studies, reducing the cost and burden of clinical trial recruitment and execution for sponsors, sites, and participants.
Advanced Diffusion MRI of White Matter in Aging and AD
Authors: Benitez Andreana
Published: December 2023

Changes in brain white matter occur in normal aging and prior to the onset of cognitive impairment. We have shown that advanced diffusion MRI and biophysical modeling yield sensitive and specific metrics that distinguish age‐related (e.g. myelin remodeling) from amyloid‐related pathological processes (e.g. myelin repair) in the preclinical stage. In this presentation we provide an update on our ongoing observational longitudinal study to determine the extent to which these metrics can serve as predictive biomarkers of incident cognitive impairment. Cognitively unimpaired older adults completed brain MRI (including Diffusional Kurtosis Imaging) and standard clinical procedures (NACC UDS v3) at baseline and ∼2 years later, with 91.2% retention and 13.1% incident MCI (CDR = 0.5) at follow‐up. We found that in participants with preclinical AD, late‐myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. In the next 5 years of funding, we will expand our cohort in size and representativeness, incorporate complementary MRI biomarkers of myelin/gliosis (i.e. myelin water imaging [ViSTa] and 1H‐MRS of myo‐inositol and NAA) to test our inferences, and further develop diffusion MRI‐based biophysical modeling techniques (i.e. Fiber Ball Imaging‐based white matter modeling). Expected outcomes from this work include clinically feasible MRI biomarkers with which to empirically test a proposed conceptual model of white matter‐related changes in aging and AD, thereby providing translational support for trials of myelin/glia‐focused therapies which are grossly underexplored for asymptomatic AD. Our goal is to have an impact on the evolving conceptualization of how aging leads to AD and, critically, to illuminate novel mechanisms by which AD can be prevented or treated.
Saccadic latency differences in preclinical Alzheimer’s disease
Authors: Adams Sara W , Tavakoli Amir‐Vala , Molloy Cathleen , Wu Daw‐An , Hung Shao‐Min (Sean) , Minazad Yafa , Kloner Robert A , Shimojo Shinsuke , Arakaki Xianghong
Published: December 2023

Background

Previous studies indicate that individuals with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) have higher latencies on anti‐saccade tasks than healthy controls. We investigated whether this difference in latency appears even earlier, in cognitively healthy (CH) individuals at high risk of cognitive decline to MCI or AD and whether subliminal priming or task switching further impacted this latency difference.

Method

We studied CH participants whose cerebrospinal fluid (CSF) amyloid / tau ratio was normal (≥2.7132, low risk) or pathological (<2.7132, high risk) (PMID: 24260210). The testing paradigm included three blocks: (1) all saccades, (2) all anti‐saccades, and (3) patterned task switching with two saccades followed by two anti‐saccades. Trials began with a green (saccade) or red (anti‐saccade) cue appearing at a central fixation point. Then, a masked subliminal cue appeared on the right or left, followed by a target congruent or incongruent with the subliminal prime location. Trials ended 1000 ms after the participant first looked directly at the target for saccade trials or away from the target for anti‐saccade trials.

Result

Preliminary results (n = 19, 3 high risk) using a 3‐way mixed ANOVA (d.f. = 3484) indicate that high risk participants perform slower across all conditions (F = 26.36, p <<< 0.001). This effect is especially pronounced when task switching (F = 3.41, p < 0.05), with high risk participants performing 70.9 ms slower in the task switching block (Bonferroni‐corrected p = 6.62×10−6, 95% CI = [29.8, 112]). During the block with all anti‐saccades, however, the difference in performance is not significant (Bonferroni‐corrected p = 0.78), unlike the effects previously observed in individuals with MCI or AD. Additionally, subliminal cues do not show a significant overall effect on behavioral data (F = 2.32, p = 0.13).

Conclusion

Pilot results indicate that latency differences when task switching between saccade and anti‐saccade tasks exist in CH people at high risk of cognitive decline. Because eye tracking tasks are much less invasive and expensive than spinal taps, they could provide a potential screening tool for those at risk of cognitive decline.
Deep Learning‐based Integration of neuroimaging and genetic data for classification of Alzheimer’s Disease
Authors: Jo Taeho , Nho Kwangsik , Risacher Shannon L , Saykin Andrew J.
Published: December 2023

Background

The progression of Alzheimer’s disease(AD) is intricately linked to the accumulation of abnormal tau protein. Identifying single nucleotide polymorphisms(SNPs) associated with AD is crucial as it provides a deeper understanding of the underlying mechanisms of AD pathogenesis. Our goal is to develop a novel deep learning‐based approach that integrates neuroimage and genetic data to identify key features of tau protein accumulation in AD and identify potential genetic markers associated with the disease.

Method

To identify the morphological endophenotypes of tau deposition in tau‐PET images, we applied a deep learning framework utilizing convolutional neural networks(CNNs) and Layer‐wise Relevance Propagation(LRP) to data from a total of 300 ADNI participants(N = 300; 66 CN, 66 AD, 97 EMCI, and 71 LMCI) with tau PET scans(Fig.1A). This approach was used to classify AD in cognitively normal elderly individuals(CN) and to identify AD‐related morphological phenotypes of tau deposition. To identify informative SNPs associated with AD, we employed the Sliding Window Association Test(SWAT) method to GWAS data from ADNI (N = 981; 650 CN, 331 AD)(Fig.1B). We used stacking ensemble to integrate results from both analyses for AD classification.

Result

The proposed framework on tau PET identified the AD‐related morphological phenotype of tau deposition in tau‐PET images and yielded a classification accuracy of 90.8% as determined by 5‐fold cross‐validation. The LRP results were consistent with those from the traditional voxel‐wise analysis in SPM12, showing significant focal AD‐associated regional tau deposition in the bilateral temporal lobes, including the entorhinal cortex. The SWAT method effectively identified known APOE regions as the most critical genetic loci for AD and revealed the association of previously unreported SNPs with an AUC of 0.82.

Conclusion

This study developed a deep learning framework that uses CNNs and LRP to identify the morphological phenotypes of tau deposition in tau‐PET images for classifying AD. Additionally, the study examined the use of the SWAT method for identifying SNPs associated with AD. Combining these two deep learning frameworks resulted in a better classification model. The proposed method offers a promising approach for understanding the genetic factors that contribute to the development and progression of AD.
Good plumbing for a healthy brain: new insights into the relationship between cerebral blood flow and tissue microstructural integrity
Authors: Bouhrara Mustapha
Published: December 2023

Alzheimer’s disease (AD) has historically been regarded as a gray matter disease, with cortical atrophy on the macroscopic scale and development of amyloid‐β plaques and neurofibrillary tau tangles on the microscopic scale. However, this paradigm has been challenged mainly due to the continuous failure of anti‐amyloid interventions to stop cognitive decline. Researchers are now wondering whether these proteins aggregations are simply byproducts of other primary drivers of neurodegeneration. Based on these observations, a new paradigm put the myelination at the center of the pathophysiology of AD suggesting that alterations in myelin may lead to progressive disconnections of neural networks that could underlie age‐related cognitive decline and AD. Recent advances in quantitative MRI methodology have enabled probing tissue microstructure with exquisite sensitivity, particularly using diffusion tensor imaging and relaxation times, and has revealed nonlinear age‐related trajectories of cerebral tissues during aging. However, although sensitive to myelin, these MRI metrics are not specific precluding specific interpretation of the underlying mechanisms involved in these microstructural changes. To address this challenge, we have developed an advanced method, called BMC‐mcDESPOT, to measure myelin water fraction (MWF), a specific surrogate of myelin content, and provided the first in‐vivo evidence of myelin breakdown in mild cognitive impairment and dementias. Further, this method has opened the way to provide novel insights into the impact of vascular, genetic, and metabolic risk factors on myelination, as well as on the role of myelin in cognition and physical functioning. In this talk, we will present an overview of some of our recent improvements to further accelerate MWF imaging. We will also present results relating reversible risk factors, including cerebral blood flow, obesity and hypertension, to myelin integrity. Finally, we will discuss new results of the implication of cerebral myelination in longitudinal changes in cognition, including memory, executive function, attention, verbal fluency and processing speed, as well as in changes in gait speeds. Understanding the role of myelination in cognitive and physical functioning has the potential to provide a window into the underlying biology of age‐related brain diseases, and to nominate new MR imaging biomarkers for longitudinal assessment and targets for intervention.
Salivary tau as a probable diagnostic method for Alzheimer’s disease
Authors: Santos Gustavo A A , Vale Francisco Assis Carvalho , Fazan Valeria Paula Sassoli , Pardi Paulo Celso
Published: December 2023

Background

Biomarkers can be detected in blood levels and, more recently, the feasibility of identifying TAU protein in salivary samples was verified.

Method

This is a case‐control study carried out in patients diagnosed with probable AD and cognitively healthy and non‐AD patients who had research centers in the cities of Ribeirão Preto, Jaboticabal, Louveira and São Paulo, Brazil. For the quantification of t‐Tau by the ELISA method in the saliva of research participants, we used the Kit MBS022635 Human Tau Protein ELISA. And for the quantification of phosphorylated TAU (pTAU), the Kit E‐EL‐H5314 Human pMAPT pTAU (microtubule‐associated phosphorylated tau protein) ELISA Kit was used

Result

Total TAU protein concentrations showed no evidence for differences in concentrations in the three groups of patients, with and without Alzheimer’s disease. However, the phosphorylated TAU protein brings a very interesting finding, as it showed variations between young and elderly patients with and without the disease.

Conclusion

Total TAU protein does not seem to be a likely biomarker to aid in the diagnosis of the disease. However, our results show that phosphorylated TAU was elevated in the elderly and, in the elderly with AD, it was even higher.
Discovery of disease‐associated, tau, and inflammatory microglial subpopulations and molecular drivers in Alzheimer’s disease using network‐based deep learning integration of human brain single‐cell RNA‐sequencing data
Authors: Cheng Feixiong , Xu Jielin , Pieper Andrew A. , Cummings Jeffrey L. , Leverenz James B
Published: December 2023

Background

Microglia have been implicated in the pathophysiology of Alzheimer’s disease (AD) for over 100 years, and substantial progress has been made in characterizing microglial heterogeneities and biology, including disease‐associated microglia (or DAM, amyloid‐pathology related, neuro‐protective), tau microglia (tau‐pathology related), and inflammatory microglia (neuro‐toxic). However, the crucial next step knowing how to apply these findings to develop new treatments for AD, through uncovering the functional roles and molecular drivers of each microglial subtype, has not yet been accomplished.

Method

In this study, we conducted single‐cell RNA‐sequencing data integration analyses of ∼0.8 million cells/nuclei by leveraging frozen brain samples from AD subjects across different brain regions from The Alzheimer’s Cell Atlas (https://taca.lerner.ccf.org/) using a deep learning analytic approach. We annotated three microglial subtypes (including DAM, tau, and inflammatory microglia) using well‐established marker genes and then used a human protein‐protein interactome network‐based approach to identify potential molecular drivers of different microglial subtypes across the spectrum of AD. We also applied transition gene network analysis to characterize microglial subtype transition from non‐disease associated to disease‐associated stages at transcriptomic levels.

Result

Via trajectory analysis we pinpointed the existence of three microglial subtypes across AD progression. We also identified that tau microglia were significantly associated with synaptic processes. Compared to DAM, upregulated genes within inflammatory microglia were more significantly enriched within key immune pathways (e.g., NF‐kappa B and toll‐like receptor signaling pathways). In addition, transition gene networks of inflammatory microglia and DAM were found to contain potential AD pathobiology regulators (e.g., SYK, LYN, IRF8, and CSF1R) and genetic risk genes (including INPP5D, PICALM, and MEF2A). We further conducted network‐based drug repurposing prediction by simultaneously activating DAM while inhibiting inflammatory microglia, which indicated that several predicted repurposable drugs (i.e., fluticasone and mometasone) are significantly associated with reduced risk of AD in large patient databases.

Conclusion

This study identifies potential underlying mechanisms of microglial subtypes involved in human AD brains, leading to potential drug targets for future development of microglia‐targeted therapies for AD.
Effect of intra‐nasal insulin therapy on food intake among African American adults: the FIINAAL study
Authors: Goodson Mia M , Gwizdala Kathryn L. , Newton Robert L , Beyl Robbie , Firmin Simon , Rao Arushi , Salceanu Vanessa , Carmichael Owen T. , Martin Corby K
Published: December 2023

Background

Intranasal insulin is a promising treatment for cognitive decline in Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). However, intranasal insulin has been shown to promote weight loss, leading to concerns about decreased appetite, decreased food intake, and unintentional weight loss as negative side effects among metabolic and ingestive behavior effects of intranasal insulin sprays among AD and MCI patients. But, side effects related to food intake and appetite are not well studied, particularly among African American adults who are under‐represented in AD research.

Method

39 middle‐aged, cognitively normal, community‐dwelling African American adults (Table 1) were enrolled in the Food Intake and Intranasal Insulin in African American Adults (FIINAAL) study assessing effects of intranasal insulin on acute food intake and appetite ratings. This double‐blind, placebo‐controlled, randomized crossover study compared a single intranasal dose of 10 IUs of Novologã insulin, delivered with the Kurveã device, to an intranasal placebo. Participants ate a eucaloric, macronutrient‐balanced lead‐in diet for three days prior to each dose. The dose was administered in the morning following an overnight fast. An ad libitum test lunch followed the dose and participants rated their appetite immediately before and after each dose, and after the meal. Mixed effects linear model t‐tests were used to compare differences in food intake and appetite ratings between insulin and placebo conditions.

Result

There were no significant differences in test lunch energy (calories) or macronutrient intake between insulin and placebo conditions. However, fullness ratings increased significantly more after receiving a dose of insulin than after a dose of placebo (Figure 1). In addition, desire to consume sweet and fatty foods decreased significantly more after insulin than after placebo (Figure 2).

Conclusion

In middle aged African American adults, acute intranasal insulin administration was associated with a reduced desire to eat palatable foods and with increased feelings of fullness, but not with reduced food intake at a test meal. Because reduced appetite appears to be an acute side effect of intranasal insulin administration, future work should study whether chronic intranasal insulin administration results in reduced appetite and, consequently, reduced food intake and body weight over time.
Change in life space is associated with cognitive decline and increased risk of incident Alzheimer’s and Parkinson’s disease in older men
Authors: Bock Meredith A , Hoang Tina D , Patel Sheena , Yaffe Kristine
Published: December 2023

Background

Life space measures the range of geospatial movement through one’s environment during daily functioning. Prior studies on the association of life space and cognitive change are mostly cross‐sectional and have mixed results. To clarify this association, we prospectively evaluated change in life space with cognitive decline and incident Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Method

We studied 1,684 men enrolled in a prospective study of aging. We excluded individuals with probable dementia or PD at baseline (Study Year 7). Life space was evaluated with the self‐reported University of Alabama at Birmingham Life Space Assessment at Year 7 and Year 14. The composite life space score ranges from 0 (most restricted) to 120 (least restricted). Incident AD or PD was defined as a self‐reported physician diagnosis or medication use at Year 14. We conducted logistic regression analyses examining change in life space with the odds of our outcomes unadjusted and adjusted for age, clinic site, race, education, living arrangement, vascular risk factors, and depression. We also conducted mixed linear effects models to evaluate the association between change in life space and change in 3MS and Trails B score.

Result

Of 1,684 men (mean age 77.1 +/‐ 18.7 SD) in our analytic cohort, 80 (4.8%) developed incident AD and 23 (1.4%) developed PD over 7 years. The mean (SD) life space score at baseline was 92.9 (18.7) and change over 7 years was ‐9.9 (22.3). In the fully adjusted model, each 1 SD decrement in life space was associated with increased odds of AD (OR 1.6, 95% CI 1.3, 2.0) and PD (OR 1.6, 95% CI 1.1, 2.5). For each 1 SD decline in life space, men worsened by 20.6 seconds in their Trails B score and 1.15 points in their 3MS score over 7 years (p<0.001 for both).

Conclusion

In this novel longitudinal analysis, decline in life space is associated with cognitive decline and incident AD and PD. Future studies should examine whether decline in life space is a sensitive and practical way to identify older individuals at risk for cognitive dysfunction and neurodegenerative disease.
Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American ancestries
Authors: Hou Yuan , Zhang Pengyue , Fan Fan , Bekris Lynn M. , Haines Jonathan L. , Pieper Andrew A. , Hammock Bruce D. , Leverenz James B , Cummings Jeffrey L. , Cheng Feixiong
Published: December 2023

Background

Translation of massive genetic and genomic data into Alzheimer’s target and drug discovery has not materialized. One challenge in this process is ethnicity‐based differences in the field of Alzheimer’s disease (AD). For example, African Americans (AAs) and European Americans (EAs) differ in AD prevalence, risk factors, and symptomatic presentation, and AAs have historically been less frequently enrolled in AD clinical trials.

Method

We conducted ancestry genetic‐specific target and drug discovery by gathering large genetic data from a diverse population with real‐world patient data to boost the likelihood of identifying disease‐modifying drug targets and treatments for AD. We analyzed genetic data from 275,540 AD cases and 1.55 million controls across 7 AD genome‐wide association studies (GWAS) datasets for both EA and AA ancestries, using Mendelian randomization. We utilized the genetic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets from three large human brain biobanks: a) Mount Sinai Brain Bank (MSBB), b) Mayo clinic (Mayo), and c) Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP) (ROS/MAP).

Result

We identified 25 drug targets in EAs and 6 new drug targets in AAs among 1,176 investigated druggable targets. Notably, the inflammatory target of epoxide hydrolase 2 (EPHX2) emerged as a potent AD target in EAs, and treatment of transgenic TgF344‐AD rats with an EPHX2 inhibitor was therapeutic. Among 6 AA‐specific targets, we identified that TRPV3 is a potent drug target for AA individuals with AD, and further replicated our finding in AA‐specific eQTL data. We additionally identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment (MCI) patients after analysis of ∼80 million electronic health records. Using a propensity score‐matched design, we identified that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69 – 0.80) or amlodipine (HR = 0.91, 95% CI 0.88 – 0.94) were both significantly associated with reduced progression to AD in people with MCI.

Conclusion

Combining genetics and real‐world patient data has identified ancestry‐specific therapeutic targets and medicines for AD.
Simulation‐based effect size analysis in the absence of drug effects to inform the design of clinical trials in Alzheimer’s disease
Authors: Andrews Daniel , Arnold Douglas L , Bzdok Danilo , Ducharme Simon , Chertkow Howard , Collins D Louis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Randomized clinical trials of Alzheimer’s‐modifying drugs typically report a clinical effect as the final observation difference in means for a cognitive endpoint between treated and placebo groups. However, randomization of subjects naturally following different cognitive decline trajectories could produce a between‐group endpoint difference even when a drug has no disease‐modifying effect. Recent work used data from ADNI subjects matching trial inclusion criteria to simulate patient trajectories [Jutten et al. (2021). https://doi.org/10.1212/WNL.0000000000012022]. We build on such simulations by incorporating a trial’s specific design parameters, including multiple visits, visit time windowing, dropout rate, and measurement noise using jittering. We estimate treatment‐independent group differences in a cognitive endpoint’s rate of change in simulations of the Phase 3 aducanumab and lecanemab trials.

Method

563 ADNI subjects matched inclusion criteria for the identically designed Phase 3 aducanumab trials EMERGE and ENGAGE [clinicaltrials.gov/ct2/show/NCT02484547]. We fitted a continuous time linear mixed effect model tracking CDSRB change from baseline (CDRSBΔbl). ADNI subjects’ baseline data were resampled and jittered, generating data for 1,070 synthetic subjects total while preserving the real trials’ baseline Alzheimer’s stage distribution. Subjects were randomized 1:1 to “treated” and “placebo” groups, but without any treatment effect. We simulated 4 visits, ∼26 weeks apart, with 30% dropout. Our sample size and visit scheme matches the real trials’ Statistical Analysis Plans. We generated 10,000 simulated trials, each a unique randomization of subject trajectories. The “treated” vs. “placebo” CDRSBΔbl linear slope difference was extracted from each simulation. We repeated this procedure for the demographics and design of lecanemab’s Phase 3 trial Clarity AD [clinicaltrials.gov/ct2/show/NCT03887455].

Result

Histograms of simulated slope differences differ between the trial designs (see Figures). Averages are zero because there is no simulated treatment effect. Each successful trial’s real‐world difference (EMERGE high dose: –22%, Clarity AD: –27%) corresponds to a statistically significant reduction in cognitive decline rate for treated subjects vs. placebo.

Conclusion

Our results suggest low false positive probabilities for the successful trials. Cohort composition, sampling, and other trial characteristics might influence treatment‐independent group difference in cognitive decline rate. With our method, future trials could target treatment effects outside the target population’s false positive range.
Beyond the hippocampus: amygdala and memory functioning in older adults
Authors: Bookheimer Tess Helen , Ganapathi Aarthi S. , Iqbal Fatima , Mattinson Jenna M , Popa Emily S. , Glatt Ryan M. , Merrill David A. , Porter Verna R. , Bookheimer Susan Y. , Bramen Jennifer E. , Lampa Melanie G. , Kim Mihae , Bookheimer Austin , Panos Stella E. , Siddarth Prabha
Published: December 2023

Background

Medial temporal lobe atrophy has been linked to decline in neuropsychological measures of explicit memory function. While the hippocampus has long been identified as a critical structure in learning and memory processes, less is known about contributions of the amygdala to these functions. We sought to investigate the relationship between amygdala volume and memory functioning in a clinical sample of older adults.

Methods

A serial clinical sample of older adults that underwent neuropsychological assessment at an outpatient neurology clinic was selected for retrospective chart review. Patients were included in the study if they completed a comprehensive neuropsychological assessment within six months of a volumetric MRI scan. Each subject underwent scans conducted on a GE 3.0 Tesla scanner, and volumetric analyses were performed using imaging software which quantifies regional brain volumes. We used bilateral hippocampal and amygdala volumes in our analyses. Associations between these volumes and memory scores, derived from immediate and delayed recall conditions of a verbal story learning task and a nonverbal design reconstruction task [1], were examined using mixed‐effects general linear models, controlling for total intracranial volume, age, sex and education. Partial correlation coefficients, controlling for these covariates, were calculated to estimate the strength of the association between volumes and memory scores.

Results

A total of 68 (38F, 29M) participants were included in the analyses, with a mean (SD) age of 80.1 (6.0) and educational level of 15.9 (2.5) years. Controlling for age, sex, education, and total intracranial volume, greater amygdala volumes were associated with better verbal and nonverbal memory performance (p<.001), comparable to hippocampal volume. The interaction term of hemisphere and memory was not significant for any of the models, indicating no lateralized effects. Partial correlation coefficients ranged from 0.45 to 0.31.

Conclusion

These findings contribute to a growing body of knowledge highlighting the amygdala as a target for further research in memory functioning through the adult lifespan, supporting a holistic understanding of limbic system operations in which multiple subcortical structures contribute synergistically to memory processes and decline in older adults.

References

[1] Wechsler, D. (2009). Wechsler Memory Scale fourth edition. San Antonio, TX: Pearson.
Heart Rate Variability during Slow Wave Sleep is Linked to Resting‐state Functional Connectivity in the Central Autonomic Network among Older Adults ‘at‐risk’ of Dementia
Authors: Kong Shawn Dexiao , Gordon Christopher J , Hoyos Camilla M , Wassing Rick , D’Rozario Angela L , Mowszowski Loren , Ireland Catriona , Palmer Jake R , Grunstein Ronald R , Shine James M , McKinnon Andrew C , Naismith Sharon L ,   Healthy Brain Ageing Research Clinic
Published: December 2023

Background

Reduced heart rate variability (HRV) can be an early sign of autonomic dysfunction in neurodegenerative diseases, and may be related to brain dysfunction in the central autonomic network (CAN). As yet, such autonomic dysfunction has not been examined during sleep – which is an ideal physiological state to study brain‐heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, we aimed to examine whether nocturnal HRV, especially slow wave sleep (SWS), is associated with CAN functional connectivity in older adults ‘at‐risk’ of dementia.

Method

Older adults (n = 78; age range = 50‐88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting‐state functional magnetic resonance imaging and an overnight polysomnography. From these, CAN functional connectivity strength and HRV data during sleep were derived, respectively. High‐frequency heart rate variability (HF‐HRV) was extracted to index parasympathetic activity during distinct periods of sleep, including SWS as well as secondary outcomes of non‐rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between CAN functional connectivity and HF‐HRV.

Result

Analyses revealed that increased HF‐HRV during SWS was associated with stronger functional connectivity (F = 3.98, p = 0.022) in two core brain regions within the CAN, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, p = 0.005) between broader CAN brain regions – the right amygdala with three sub‐nuclei of the thalamus. There were no significant associations between HF‐HRV and CAN functional connectivity during wake after sleep onset or rapid eye movement sleep.

Conclusion

These findings show that in older adults ‘at‐risk’ of dementia, parasympathetic regulation during SWS is uniquely linked to differential functional connectivity within both core and broader CAN brain regions. It is possible that dysfunctional brain‐heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if HRV drives neurodegeneration, or if brain degeneration within the CAN promotes aberrant HRV.
Potentially Inappropriate Medications and cognitive performance: cross‐sectional results from the ELSA–Brasil study
Authors: Santos Adriana Nancy Medeiros , Benseñor Isabela M. , Goulart Alessandra C. , Brunoni Andre R , Viana Maria Carmen , Lotufo Paulo A. , Suemoto Claudia Kimie
Published: December 2023

Background

Potentially inappropriate medications (PIM), especially those with potential effects on the central nervous system, can increase the risk of cognitive impairment. We investigated the association of the use of PIM with cognitive performance among older adults.

Method

In this cross‐sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil), 2,626 participants were included (mean age = 65.1±4.1 years old, 54% women, and 61% White). PIM was defined by the 2019 American Geriatrics Society Beers criteria. We calculated global cognition and memory, verbal fluency, and Trail Making Test B version (TMT‐B) z‐scores. Linear regression models adjusted for sociodemographic and clinical variables were used to investigate the association between PIM and cognition.

Result

27% of the sample used at least one PIM. PIM use was associated with worse performance in the TMT‐B (β = ‐0.17, 95% Cl = ‐0.29; ‐0.05, p = 0.007).

Conclusion

The use of PIM was associated with worse executive function among older adults.
Sex‐specific impact of brain estrogen deficiency on astrocyte reactivity, neurodegeneration, and memory loss in aromatase knockout mouse models
Authors: Halle Ariel , Rodriguez Guadalupe , Locci Andrea , Coon John , Kujawa Stacy , Dong Hongxin , Bulun Serdar E , Zhao Hong
Published: December 2023

Background

Nearly two‐thirds of Americans with Alzheimer’s disease (AD) are women, however, the molecular mechanisms underlying this sex difference in AD vulnerability remain unclear. Prior research has reported that women with AD have lower brain estrogen. Yet, how estrogen deficiency modulates this sex difference in AD is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, with high levels in the hippocampus. To explore the underlying mechanism of estrogen deficiency in sex‐specific AD vulnerability, we generated mouse models with brain‐specific aromatase knockout (bArKO) and whole‐body total aromatase knockout (tArKO).

Method

We performed a series of memory and behavior tests including spontaneous alternation, social interaction, and tail suspension tests on 6‐ and 19‐month‐old bArKO and tArKO mice with both sexes (n = 10/group). Hippocampus tissues from these mice (n = 3∼4) were collected for bulk RNA‐seq and qPCR. Brain tissues (n = 5) were fixed and stained for astrocytes and neurons by immunofluorescence. Serum and tissue estrogen were measured using liquid chromatography‐mass spectrometry.

Result

Aromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairments of spatial working memory and social interaction behavior were found in 19‐month‐old female bArKO and tArKO mice. Female tArKO mice also displayed depression‐like behavior at 6‐ and 19‐month‐old. The number of neurons in the CA1 region was significantly decreased in 19‐month‐old female (but not male) tArKO mice. Bulk RNA‐seq showed abnormal expression of genes associated with astrocyte reactivity (e.g., Gfap, Ctgf, Apoe, Lcn2, Sparc, Bdnf, Col1a1, Col1a2) only in aged female bArKO mice. Given growing evidence indicating a causal relationship between neurotoxic reactive astrocytes and neurodegeneration, this finding indicates brain estrogen deficiency triggering neurotoxic astrocyte reactivity in the hippocampus of aged female bArKO mice.

Conclusion

Our findings provide novel mechanisms that link estrogen deficiency to sex‐specific astrocyte reactivity in the hippocampus, and neurodegeneration and memory loss in aged female mice. Future studies will focus on defining impact of estrogen signaling deficiency on AD mouse models and identifying druggable targets to inform the development of new therapeutic strategies for the prevention and treatment of AD.
TREM2 AD risk variants impact pTau and microglia and astrocyte related biomarkers in cognitively unimpaired subjects
Authors: Hsiao‐Nakamoto Jennifer , Davis Sonnet , Suh Jung , Model Fabian , Lee Sven J , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Van Bokhoven Pieter , Teunissen Charlotte E. , Scearce‐Levie Kimberly , Huang Fen
Published: December 2023

Background

In the central nervous system, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is expressed primarily in microglia. TREM2 receptors are important for microglial functions including phagocytosis, lipid metabolism and inflammatory responses. TREM2 coding variants (e.g. R47H rs75932628 and R62H rs143332484) increase the risk of late onset Alzheimer’s Diseases (AD). However, the impact of TREM2 risk variants on microglial cell functions in humans remains to be elucidated.

Method

CSF and plasma samples were collected from AD patients (n = 120) and cognitively unimpaired control subjects (n = 53) with subjective complaints who do not meet biomarker‐based criteria for AD diagnosis. TREM2 AD risk variant carriers (n = 52) were screened from over 6000 samples of the Amsterdam dementia cohort using a combination of genotype array and exome sequencing. We performed extensive biomarker analysis of CSF and plasma samples with multidisciplinary approaches. We compared the effect of TREM2 mutations on AD disease and microglial and astrocytic biomarkers in AD patients and in cognitively unimpaired control subjects, respectively. A linear model was used with age and gender adjusted for the data analysis.

Result

We found higher levels of pTau181 and pTau231 in CSF and plasma in cognitively unimpaired TREM2 mutation carriers compared to non‐carriers, while no difference was observed between TREM2 genotype among the AD patients. Microglia and astrocyte biomarkers including sTREM2, FABP3, OLR1, YKL40 and GFAP were higher in the CSF from cognitively unimpaired TREM2 mutation carriers compared to non‐carriers, but no difference was detected between TREM2 genotype among the AD patients. We also found different levels of lipid metabolites in CSF and plasma samples from the TREM2 mutation carriers compared to non‐carriers in both AD patients and cognitively unimpaired control subjects.

Conclusion

TREM2 AD risk variants in cognitively unimpaired subjects increase pTau biomarkers and microglial and astrocytic related biomarkers. In AD patients, the biomarker differences between TREM2 genotype are diminished likely due to the extensive microglial responses to AD pathology. Moreover, our data indicates TREM2 AD risk variants may impact lipid‐metabolic processes in microglial cells. These data provide the biomarker insights on how TREM2 mutations may increase the risk of AD.
Allele‐specific histone acetylation in Alzheimer’s disease brain
Authors: Urbanaviciute Paulina , Nott Alexi , Marzi Sarah
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with cell type‐specific H3K27ac signatures, an epigenetic modification that marks active enhancers and promoters. Genomic regions marked by H3K27ac, particularly enhancers, are enriched for AD genetic risk. We aim to identify nearby genetic variants regulating histone acetylation to better understand the link between genetic risk and disease.

Method

For the first time we have performed allelic specific analysis of histone epigenetic modifications in AD. We used H3K27ac ChIP‐seq data from human post‐mortem entorhinal cortex samples from AD cases (n = 24) and controls (n = 23) (Marzi et al., 2018) to differentiate the histone acetylation signal originating from both alleles in an individual.

Results

We identified 844 significant loci with allele‐specific histone acetylation by testing individual samples, and 344 by testing across samples. Both sets featured an FDR‐significant acetylation imbalance in a region predicted to be regulating SETD1B, a histone lysine methyltransferase previously found to be elevated in AD patients (Cao et al., 2020). Using linear regression, we also identified 329 SNPs associated with histone acetylation levels. Cell type deconvolution of the overlap between the SNP‐associated H3K27ac regions and genomic regions differentially acetylated in AD highlighted multiple brain cell types. In addition, there was an enrichment for biological processes involving myelination, and cell type‐specific regions were enriched for oligodendrocytes.

Conclusion

Genetic variants are associated with levels of H3K27ac in genomic regions regulating disease‐related processes.
Characterizing the yes‐no reversal phenomenon in patients with primary progressive apraxia of speech
Authors: Meade Gabriela , Schwarz Christopher G. , Clark Heather M , Duffy Joseph R , Botha Hugo , Whitwell Jennifer L , Josephs Keith A , Utianski Rene L
Published: December 2023

Background

Patients with a yes‐no reversal verbally and non‐verbally respond “yes” when they mean “no” and vice versa. They are typically aware of the error and able to correct it given additional time. This symptom commonly, but not exclusively, occurs in patients with primary progressive apraxia of speech (PPAOS). PPAOS is a form of frontotemporal dementia associated with hypometabolism in the supplementary motor area (SMA; e.g., Utianski et al., 2018); as the disease progresses, a wider network of frontal and subcortical regions become implicated. Behaviorally, this symptom seems to reflect poor response inhibition, but the specific anatomical underpinning is not yet understood. Given the brain regions known to be involved in PPAOS, we hypothesized that yes‐no reversals emerge due to degeneration of regions near the SMA and/or frontostriatal regions.

Method

We conducted an exploratory retrospective study of 28 patients who presented with PPAOS and had an FDG‐PET scan; 14 (50%) endorsed yes‐no reversals (see Table 1 for group characteristics). Clinically, AOS severity was measured using clinician ratings (0 = absent, 4 = severe) and frontal dysfunction was captured by the Frontal Assessment Battery (FAB) and the Frontal Behavioral Inventory (FBI). We also measured median standardized uptake value ratios (SUVRs) in the SMA and pre‐SMA, as well as the head and body of the caudate with automated, in‐house software. The caudate ROI was selected based on visual comparison of the FDG‐PET scans between groups and the association between this region and inhibition during response interference (e.g., Schmidt et al., 2020).

Result

Neither AOS severity nor hypometabolism in the pre‐SMA/SMA regions differed significantly between groups. In contrast, patients with a yes‐no reversal demonstrated significantly lower scores on the FAB and greater hypometabolism in the caudate body relative to patients without (see Figure 1).

Conclusion

Results suggest that yes‐no reversals relate to frontostriatal dysfunction rather than AOS severity or SMA activity in these patients. Further research is needed to address why a disproportionate number of patients with PPAOS develop this symptom.
Social determinants of modifiable dementia risk in Māori and Non‐Māori: Results of the New Zealand Health, Work and Retirement study
Authors: Röhr Susanne , Gibson Rosemary , Alpass Fiona , Stephens Christine
Published: December 2023

Background

Dementia risk varies along the social gradient, which needs to be considered in risk reduction and prevention strategies. Revealing links of social determinants of health (SDOH) and modifiable health and lifestyle factors for dementia holds clues towards maximizing dementia risk reduction opportunities, especially for vulnerable populations. Therefore, the aim was to investigate associations of SDOH and a dementia risk score in Indigenous Māori and Non‐Māori (mainly European descent) in midlife and early late‐life.

Method

A subsample of the New Zealand Health, Work and Retirement study completed standardized face‐to‐face cognitive assessments (adapted ‘Kiwi’ Addenbrooke’s Cognitive Examination/ACE‐R) in 2010. We computed the Lifestyle for Brain Health (LIBRA) dementia risk score, comprising 8 risk factors (low/moderate alcohol consumption, heart disease, physical inactivity, chronic kidney disease, diabetes, smoking, hypertension, depression). Higher scores indicate higher dementia risk/poorer lifestyle (range = ‐1;+9.2). First, we assessed associations of LIBRA and cognition. Second, we performed adjusted regression analysis for area‐based (socioeconomic deprivation, health care access, neighborhood safety) and individual SDOH (education, employment status, net income, social loneliness) with LIBRA stratified for Māori and Non‐Māori.

Results

In 918 participants (age: M = 62.9 years, SD = 6.7, range = 48‐75; females = 52.8%; Māori = 26.2%), a higher LIBRA score (M = 1.8, SD = 1.6, observed range = ‐1; +7.4) was associated with lower cognitive functioning (b = ‐0.30, 95%CI = [‐0.48;‐0.11], p = .002) and cognitive impairment (OR = 1.41, 95%CI = [1.10;1.81], p = .007), adjusted for age, sex, education, ethnicity and area‐based socio‐economic deprivation. Higher area‐based socio‐economic deprivation was associated with higher LIBRA in Māori (b = .10, 95%CI = [0.02;0.18], p = .020), but not in Non‐Māori (b = 0.01, 95%CI = [‐.03;0.05], p = .677). Employment status and lower neighborhood safety were associated with higher LIBRA in Non‐Māori only. Health care access difficulties and social loneliness were associated with higher LIBRA in both populations, while education and net income were not.

Conclusion

SODH are differentially associated with dementia risk in midlife and early late‐life New Zealanders. Area‐based socioeconomic deprivation was linked to dementia risk in Indigenous Māori, but not in Non‐Māori. This points to systematic inequities in dementia risk, which require equity‐focused policy‐based public health approaches to risk reduction.