bluuebunny/crossref_metadata_2025 huggingface dataset:
Diffusion MRI subnetwork efficiency is associated with cognitive resilience to AD pathology in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Liu Zhen‐Qi , Strikwerda‐Brown Cherie , St‐Onge Frederic , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia ,   the PREVENT‐AD Research Group
Published: December 2022

Background

While higher levels of Aβ and tau pathology are typically associated with more pronounced cognitive decline in Alzheimer’s disease (AD), some older adults exhibit normal cognition even with a substantial burden of AD pathology. This phenomenon is known as ‘cognitive resilience’. The potential role of structural connectivity in cognitive resilience remains inconclusive. The present study tested whether higher global efficiency in structural brain networks moderate the relationship between AD pathology and cognitive performance in the preclinical phase of AD.

Method

We studied 118 cognitively normal older adults from the family history enriched Prevent‐AD cohort. Diffusion‐weighted MRI was used to measure the structural connectome, PET to measure global Aβ (18F‐NAV4694) and entorhinal tau (18F‐Flortaucipir) pathology, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to evaluate cognitive performance. We first used graph theory analyses to calculate global efficiency of networks known to be affected in early AD (i.e., limbic and default mode network (DMN)). Then multiple linear regressions were performed to examine relationships between Aβ / tau pathology, cognitive performance, and global efficiency of the two subnetworks. Interaction analyses were used to examine whether network efficiency attenuates the relationships between AD pathology and cognitive performance.

Result

As expected, higher levels of Aβ and tau pathology in the brain were associated with worse cognitive performance in individuals at risk of AD (Figure 1). Higher entorhinal tau pathology was also associated with lower global efficiency in the limbic network (Figure 2). Subsequent interaction analyses showed that global efficiency in the limbic moderated the relationships between AD pathology and cognitive performance. Specifically, higher global efficiency was associated with an attenuated effect of both amyloid and tau pathology on delayed memory performance (Figure 3).

Conclusion

Individuals with higher global efficiency in the limbic structural network exhibit better memory performance at a given level of AD pathology in preclinical stages of the disease. Structural network properties of the brain may play an important role in maintaining cognitive performance in the face of AD pathology, and could serve as a potential biomarker for cognitive resilience.
Inducible microRNA‐34a overexpression impairs cognition and promotes Alzheimer's pathology
Authors: Freitas Raul , McDonald Katherine , Wang Hanyun , Sarkar Saumyendra , Corbin Deborah , Bix Gregory J , Simpkins James W , Engler‐Chiurazzi Elizabeth
Published: December 2022

Background

Alzheimer’s disease (AD), a chronic neurodegenerative condition resulting from pathological brain aging, is the most common cause of geriatric dementia and is likely polygenic in origin. The discovery of microRNAs (miR), small, endogenous, non‐coding, and highly conserved RNAs that regulate post‐transcriptional expression of potentially hundreds of genes, has revealed new drivers and therapeutic targets of AD pathogenesis. Research from our group and others indicates that miR‐34a may be a promising candidate.

Method

We aimed to interrogate the dementia‐associated cognitive and neurobiological consequences of miR‐34a stimulation in vivo. We generated a global doxycycline (Doxy)‐inducible miR‐34a expression mouse model (miR34a+/‐ 2X (TetR‐TetO‐miR34a). Three‐month‐old male and female miR‐34a+/‐ mice were treated for ∼90 days with either normal drinking water or Doxy (2mg/ml) to induce miR‐34a expression (N= 7‐8 mice/group) and evaluated for cognitive and neurobiological factors disrupted in other transgenic AD mice. To ascertain brain‐ and cell type‐specific vulnerabilities of miR‐34a overexpression, we also generated a mutant mouse line in which miR‐34a overexpression is restricted to excitatory neurons using a CaMKIIα driver.

Result

Doxy‐treated miR‐34a+/‐ mice showed T/Y‐maze memory deficits, coinciding with upregulated miR‐34a expression in all brain regions assayed. They also showed evidence of known AD neuropathologies, including reduced NMDA2B glutamatergic receptor expression, altered amyloid precursor processing (alpha‐secretase), and increased phosphorylated tau. Experiments to determine consequences of brain‐specific miR‐34a overexpression are ongoing.

Conclusion

In conclusion, miR‐34a appears to contribute to an AD‐like phenotype. Future work will utilize this Tet‐inducible system to explore age‐related susceptibility to, and capacity for recovery from, the cognitive and neuropathological consequences of miR‐34a overexpression.
Concerted alterations of functional connectivity and WM integrity in relationship to early amyloid deposition
Authors: Lorenzini Luigi , Orso Beatrice , García David Vállez , Pontillo Giuseppe , Ingala Silvia , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Ritchie Craig W. , Gispert Juan Domingo , Visser Pieter Jelle , Mutsaerts Henri JMM , Tijms Betty M. , Wink Alle Meije , Barkhof Frederik
Published: December 2022

Background

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to amyloid deposition may increase our understanding of the neuropathological processes underlying AD.

Method

We included 648 non‐demented participants from the European Prevention for Alzheimer’s Dementia (EPAD) cohort vIMI baseline data release. The cut‐off for cerebrospinal fluid (CSF) amyloid‐β positivity (A+) was defined at <1000pg/mL (Elecsys assay). Functional connectivity was estimated with functional eigenvector centrality (EC) from the resting state functional MRI. White matter (WM) integrity was estimated with fractional anisotropy (FA), computed on diffusion MRI. Both measures were computed at the voxel level within the gray and white matter, respectively. First, we used linear regression models to investigate differences between A+ and A‐ participants within each modality separately, adjusting for age, sex, and site. In the whole group, we performed sparse canonical correlation analysis (sCCA) on functional and structural measures, identifying shared components between the two modalities. Individual sCCA scores were compared between amyloid groups using a generalized linear model (GLM). To evaluate this association in A+ individuals, the same sCCA analysis was performed normalizing the structural and functional matrices using the mean and SD from A‐ participants.

Results

Sample characteristics are provided in Table 1. Differences in voxelwise EC and FA between amyloid groups are shown in Figure 1. In the whole group, sCCA analysis showed that EC in the default mode, executive and cerebellar networks covary with FA in parietal, temporal and cerebellar areas (Figure 2). sCCA projections were differentially expressed according to amyloid status (Table 2). In A+ participants, stronger association of EC in the posterior DMN and cerebellum with FA in the splenium and brainstem were found (Figure 3).

Conclusion

Using a data‐driven multivariate analysis, we identified concerted patterns of functional and structural changes that occur with amyloid deposition in the predementia stage. These results highlight the importance of multimodal assessment for early diagnosis.
Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study
Authors: Territo Paul R , Quinney Sara K , Masters Andrea R , Haynes Katy A , Cope Zackery A , Little Gabriela , Williams Sean‐Paul , Meyer Jill A , Peters Jonathan , Figueiredo Lucas , Persohn Scott C , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Seyfried Nicholas T. , Onos Kristen D , Sasner Michael , Howell Gareth R , Carter Gregory W , Oblak Adrian L , Lamb Bruce T , Rizzo Stacey J Sukoff
Published: December 2022

Background

The Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.

Methods

Initial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.

Results

PK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.

Conclusions

chAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.
The Institute on Methods and Protocols for Advancement of Clinical Trials for ADRD (IMPACT‐AD): An update after two years of conduct.
Authors: Grill Joshua , Berkness Tyler , Carrillo Maria C. , Snyder Heather M. , Aisen Paul , Sperling Reisa A. , Petersen Ronald C. , Aggarwal Neelum T. , Bell Karen L. , Burns Jeffrey M. , Donohue Michael C. , Dodge Hiroko H , Espeland Mark A. , Gillen Daniel L. , Geldmacher David S. , Heidebrink Judith L , Jicha Gregory A , Olichney John M. , Rafii Michael S , Rentz Dorene M. , Salloway Stephen P. , Sethuraman Gopalan , Smith Amanda G , Raman Rema
Published: December 2022

Background

We developed the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) to address the shortage of qualified investigators with adequate training and expertise to conduct Alzheimer’s Disease (AD) and AD Related Dementias (ADRD) clinical trials.

Method

We describe the experience of the first two years of funding of the IMPACT‐AD course, specifically the rates of applications to the course, descriptive summaries of the accepted trainees, and the measures of participant satisfaction and learning.

Result

Over the first two years of the course, we received 195 eligible applications to the course. Most (n = 121, 62%) applicants were female and nearly half self‐reported as being African American/Black, Asian, or Pacific Islander race and/or Hispanic/Latino ethnicity. Forty‐one applicants (21%) indicated that they were the first in their family to attend college

Of 69 total trainees accepted to the course (36% acceptance rate), a majority (n = 44, 64%) were female. Twenty‐eight (41%) self‐reported as being African American/Black, Asian, or Pacific Islander race and eleven (16%) were of Hispanic ethnicity. Fourteen trainees (20%) identified as being the first person in their family to attend college. Among trainees, 24 (35%) were MDs, 30 (43%) were PhDs, and 9 (13%) held master’s degrees.

Course lecture topics were rated, on average, as “essential” or “valuable” by 98% of trainees. Across lecture topics, on average, 48% of trainees rated their prior knowledge of topics as “very strong” or “strong,” and 11% of trainees rated their prior knowledge as “weak.” Overall, 52% of trainees evaluated their change in knowledge based on the lectures as “very much increased,” 46% as “somewhat” or “slightly” increased, and 2% as “no change.” Results were similar for the two tracks. Based on pre‐ and post‐course assessments, trainees improved their knowledge of covered content (from 62% to 79% correct responses on knowledge assessments).

Conclusion

The IMPACT‐AD course is achieving its mission of educating and diversifying the next generation of ADRD trialists.

We thank Dr. Laurie Ryan and Dr. Kristina McLinden from the National Institute on Aging for their key contributions in leadership and scientific guidance of IMPACT‐AD.
NIAGADS Alzheimer’s Genomics Database: version GRCh38
Authors: Greenfest‐Allen Emily , Kuksa Pavel P. , Kuzma Amanda B , Valladares Otto , Lee Wan‐Ping , Wheeler Nicholas R. , Bush William S. , Leung Yuk Yee , Stoeckert Christian J , Wang Li‐San
Published: December 2022

Background

The Alzheimer’s Genomics Database (GenomicsDB) is an interactive knowledgebase for Alzheimer's disease (AD) genetics that offers a platform for data sharing, discovery, and analysis to accelerate research on AD and AD related dementias (ADRD). The resource provides unrestricted access to GWAS summary statistics datasets, variant annotations, and meta‐analysis results deposited at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Here we introduce an updated version of the GenomicsDB, now mapped against the latest human genome assembly, GRCh38.

Method

The GenomicsDB allows users to interactively mine AD/ADRD summary statistics datasets or visually inspect them and compare with annotated variant tracks and GRCh38 aligned functional genomics tracks from the FILER functional genomics repository (Kuksa et al. 2022). Available tracks include key AD datasets from large‐scale sequencing projects such as IGAP (Lambert et al. 2013; Kunkle et al. 2019) and the ADGC (e.g., Naj et al. 2011) that have been lifted over from earlier genome builds. Available annotated variants include those from the AD Sequencing Project’s (ADSP) Release3 WGS, called from nearly 17k samples. All variants reported in the GenomicsDB are annotated using an assembly specific version of ADSP annotation pipeline (Butkiewicz et al. 2018). The GenomicsDB provides a REST API for programmatic access. Supported queries return complete annotations for single or bulk lookups of GenomicsDB entries (genes, variants, genomic loci) and ranged queries of datasets as JSON documents.

Result

The GenomicsDB currently hosts >70 datasets and reports >150 million annotated variants from the ADSP and 23 AD/ADRD GWAS studies, mapped to GRCh38. Keeping up with community standards allows this resource to provide ongoing support for AD/ADRD research by making it possible to integrate AD/ADRD relevant `omics datasets generated by the ADSP and others who have adopted GRCh38 as their reference genome.

Conclusion

The NIAGADS Alzheimer’s Genomics Database v. GRCh38 (www.niagads.org/genomics) provides an up‐to‐date and accessible platform that facilitates unrestricted sharing of genetic knowledge underpinning AD/ADRD. To best serve our user community, NIAGADS will continue to provide the GRCh37.p19 version of the Alzheimer’s Genomics Database (including programmatic access) in archival format.
Leveraging Natural Language Processing to Identify Caregiver Availability for Patients with ADRD from Electronic Medical Records
Authors: Mahmoudi Elham , Wu Wenbo , Najarian Cyrus , Aikens James , Bynum Julie , Vydiswaran V. G. Vinod
Published: December 2022

Background

Prior literature has posited that caregiver availability can potentially prevent adverse health events such as hospital readmissions in the ADRD population. Identifying caregiver availability for patients with Alzheimer’s disease and related dementia (ADRD) can inform healthcare systems and hospital administrations on appropriate discharge planning. Caregiver availability is an important and influential domain in assessing risk of hospital readmissions. However, caregiver availability data is not systematically collected in our healthcare system. Our main objective was to use medical notes (from physicians, nurses, or social workers) to assess caregiver availability and types of caregivers for hospitalized patients with ADRD.

Method

We used 2016‐2019 telephone‐encounter medical notes from a single institution. Rule‐based natural language processing (NLP) was used to develop an algorithm to identify whether the patient (1) resides at home; (2) resides at an institution; (3) has a formal caregiver; and (4) has an informal caregiver. We evaluated the data at the patient level. We used chart abstraction as the “gold standard,” and examined the validity of the algorithm for both training (n = 749) and test sets (n = 227).

Result

The result from our test set indicated a high level of accuracy and reliability for identifying an informal caregiver (F1 = 0.942; accuracy = 0.947, sensitivity = 0.970, and specificity = 0.928). Identifying whether the patient lived at an institution was the least reliable measure (F1 = 0.638, accuracy = 0.899, sensitivity = 0.512, specificity = 0.978). The most common causes of misclassifications were: (1) incomplete or misspelled names of the facilities; (2) past/uncertain/undecided situations; (3) lack of specificity; (4) use of uncommon abbreviations; and (5) irregular use of templates.

Conclusion

Our NLP algorithm was able to identify whether the patient lived at home vs. an institution and whether the patient had a formal or informal caregiver. There is merit in continuing the NLP approach to identify more granular, caregiver‐related information (e.g., type, hours available, etc.). More effort is needed towards generalizing the algorithm. This information can be used by other healthcare systems to detect ADRD patients who do not have a caregiver at home and may be at risk of adverse events including readmission.
Cross‐ancestry effect of APOE on cognitive performance
Authors: Harerimana Nadia V. , Li Clara , Zhu Carolyn W , Sano Mary , Grossman Hillel , Goate Alison , Andrews Shea J
Published: December 2022

Background

Alzheimer's disease (AD) is more prevalent in populations of non‐European ancestry, with Black and Hispanic adults 1.5 and 2.5 times more likely to develop AD respectively. Health disparities in AD could be explained by race and ancestry, where race captures risk factors due to socio‐economic aspects of health and ancestry captures the biological mechanisms influenced by genetic variation. The APOE ε4 allele is the most significant genetic risk factor for AD; however, the risk conferred by APOE ε4 differs across populations. Here, we investigate the interactive effect of race, ancestry and APOE on episodic memory performance.

Methods

Episodic memory at last assessment was measured using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Memory Task in ∼500 participants from the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), including 82 African American, 118 Hispanics, 117 Asian Americans, and 275 White participants. Genetic ancestry was determined using principal component analysis; global ancestry proportions using ADMIXTURE; and local ancestry in the APOE locus using RFMix. The interactive effect of APOE and genetic ancestry, global ancestry proportions, and local ancestry locus on episodic memory performance was evaluated using linear regression models adjusting for age, sex, education, telehealth/in‐person visit, and year of visit.

Results

Admixed American and African genetic ancestry assignments showed an interaction with APOE (African: p‐value=0.023 and Amerindian: p‐value=0.002). In addition, higher proportion of African and Admixed American global ancestry showed significant interactions with APOE (African: p‐value=0.032 and Admixed American: p‐value=0.029). Lastly, ancestry local to APOE region showed an interaction with the APOE e4 allele in Admixed Americans such that an Admixed American background was associated with better cognitive performance in comparison to a European ancestral background (p‐value=0.008).

Conclusions

Our study showed that ancestry modifies the effect of APOE on cognitive performance. Future work needs to evaluate potential confounders associated with social determinants of health and ascertainment bias during enrollment, including age at assessment and visit type. In sum, this study corroborates a role of ancestry in modifying APOE associated AD risk.
Sleep, self‐reported ocular health, and cognition in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL‐Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Mahanna‐Gabrielli Elizabeth , Kuwayama Sayaka , Tarraf Wassim , DeBuc Delia Cabrera , Cai Jianwen , Daviglus Martha L , Joslin Charlotte , Lee David J , Mendoza‐Santiesteban Carlos , Stickel Ariana M , Zheng Diane , González Hector M , Ramos Alberto R
Published: December 2022

Abstract/Proposal

Background

Visually impaired individuals may experience increased frequency of sleep/wake disorders, fragmented sleep, insomnia, and short sleep duration. Visual impairment and sleep disorders can have downstream effects on cognitive functioning.

Method

Sample included n = 590 (unweighted) HCHS/SOL Miami Field Center participants ages 45‐74 at baseline who returned for cognitive examination on average 7‐years later (SOL‐INCA). Participants completed validated ocular (National Eye Institute Visual Functioning Questionnaire; NEI‐VFQ), validated sleep questionnaires for sleepiness, insomnia, sleep duration and objective measures of sleep apnea visit‐1 (2008‐2011). They also completed a battery of neurocognitive tests for verbal episodic learning and memory (Brief Spanish English Verbal Learning Test), verbal fluency (Controlled Oral Word Association), processing speed and executive function (Digit Symbol Substitution) at visit‐1 and at SOL‐INCA. Two additional measures of processing speed/executive functioning were added at SOL‐INCA(Trails‐A, ‐B). We examined global cognitive performance and change using a regression‐based reliable change index, adjusting for the time lapse between visit 1 and SOL‐INCA (all measured in z‐score units). We used regression models to test whether (1) participants with sleep disorders have an increased risk for visual impairment, (2a) ocular health is associated with worse baseline and average 7‐years cognitive function and/or cognitive decline, and (2b) sleep attenuates any of these associations.

Result

Sleepiness (β = 0.04; p<0.01) and insomnia (β = 0.03; p<0.001) were linked to worse ocular health, and the associations were robust to adjustment for sociodemographic characteristics, acculturation, behavioral risk measures, and health conditions. Worse ocular health was linked to lower global cognitive function at baseline (β = ‐0.14; p<0.001) and on average 7‐years later (β = ‐0.16; p<0.01). The associations were consistent across all considered cognitive domains and robust to demographic adjustments. Ocular health was also associated with a change in verbal fluency (β = ‐0.17; p<0.05), but no change was observed in other cognitive domains. Sleep disorders did not attenuate any of the reported associations.

Conclusion

Self‐reported ocular health was independently associated with worse language, memory, and executive function and predicted 7‐year cognitive decline in the language domain.
Is in‐home saliva collection of cortisol and DHEA‐S effective to measure stress in dementia care dyads?: A comparison between music‐based intervention group and comparison group
Authors: Kim Hyejin , Theorell Töres , Engström Gabriella , Berglund Lars , Hallinder Helena , Emami Azita
Published: December 2022

Background

Despite the fact that music provides a wide array of benefits for dementia care dyads (persons with dementia and family caregivers), the increased attention to music for stress reduction in dementia care dyads has sparked questions about whether and how to effectively measure changes in stress throughout the interventions. The purpose of this study was to explore the feasibility of collecting salivary cortisol and dehydroepiandrosterone sulfate (DHEA‐S) as stress biomarkers to assess the short‐term effects of music among dementia care dyads living at home.

Method

Participants who were recruited from the memory evaluation center collected their saliva three times a day, five days a week, over the eight weeks of in‐home online music intervention. In this non‐randomized open study, we examined concentrations of endpoints morning cortisol and DHEA‐S, evening cortisol, and the ratio of cortisol to DHEA‐S. Mean values of logarithmically transformed endpoints during the last available week were compared between the intervention and comparison groups with adjustment for baseline mean values in linear regression models or non‐parametric Willett’s residual method.

Result

A total of 34 dyads (34 persons with dementia and 34 family caregivers; n = 24 dyads [intervention group], n = 10 dyads [comparison group]) were included. We did not find statistically significant differences between the intervention group and the comparison group in persons with dementia. Caregivers in the intervention group had lower concentrations of morning saliva cortisol (geometric mean: 3262 pg/ml) compared to the comparison group (geometric mean: 5271 pg/ml) (p = 0.013).

Conclusion

The in‐home daily saliva collection of cortisol and DHEA‐S may be feasible to examine the short‐term effects of music on stress among dementia care dyads. The findings suggest that our in‐home music intervention may help reduce stress among family caregivers who provide care to persons with dementia. Considering the small sample with high intra‐individual variation of salivary biomarkers, a randomized controlled trial with a larger sample is needed in future research.
Case Study: New Site Development Program Aimed at Improving Access and Enrollment in Clinical Trials for Traditionally Underrepresented Populations (TUP)
Authors: Rodgers Tamiko MaGee , Zisko Leigh , Dwyer John , Sipchen Julie , Brown Christina M. , Soza Aida L. , Falcon James A. , Falcon Antonio
Published: December 2022

Background

Increased awareness and access to clinical trials is essential for recruitment of traditionally Underrepresented Populations (TUPs) into Alzheimer’s disease clinical trials. Identifying trusted physicians in diverse communities and helping build new Alzheimer’s research sites is an effective approach to materially increasing UP participation in clinical research. Global Alzheimer’s Platform (GAP) partnered with two Primary Care Physicians in Rio Grande City, Texas to open a new Alzheimer’s research facility.

Method

GAP identified the Rio Grande Valley area to open an Alzheimer’s disease trial site for multiple reasons: high prevalence (∼20%) of Alzheimer’s, significant (98%) Hispanic/Latino population, trusted community physicians with a large geriatric patient population, and lack of access to research opportunities. GAP worked with the physician(s) to develop a project plan to open the clinical trial site. Areas addressed included space, staff, supplies, subjects, and sponsors. Several obstacles to overcome included tracer availability, finances, raters, and training for a clinically sound, but research‐naïve team.

Result

After 7 months of site development, El Faro Health & Therapeutics (El Faro) opened in November 2021. The site was approved for their first trial in January 2022. The site has completed feasibility or has initiated onboarding for up to 5 additional projects and intends to activate in up to 3 more trials by Q2 2022. In their first three months, the site has completed ∼85 memory screens and reviewed more than 200 charts to begin developing a potential participant database. El Faro successfully leveraged their strong community relationships gaining media attention from over 10 media sources. Additional updates on referrals, prescreens, screens and randomizations will be provided at the conference.

Conclusion

Members of the Hispanic/Latino community are 1.5 times more likely to develop Alzheimer’s disease; however, they make up ∼1% of AD clinical trial participants. By establishing an AD research center in Rio Grande City, TX, barriers to participation are being removed, which will result in an increase in trial enrollment of UPs. The success of El Faro will demonstrate that true equity can be achieved in Alzheimer’s research with collaboration from local leaders in diverse communities.
Longitudinal Blood Biomarker Trajectories in Preclinical Alzheimer’s Disease
Authors: Yakoub Yara , Ashton Nicholas J. , Karikari Thomas K , Strikwerda‐Brown Cherie , Montoliu‐Gaya Laia , Meyer Pierre‐François , St‐Onge Frederic , Schöll Michael , Breitner John , Zetterberg Henrik , Blennow Kaj , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: December 2022

Background

Blood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET.

Method

We included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups.

Result

Amyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups.

Conclusion

We observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.
Biomarkers and neuropathology in posterior cortical atrophy: an international, multi‐site study
Authors: Chapleau Marianne , La Joie Renaud , Mundada Nidhi S. , Fumagalli Giorgio G , Formaglio Maïté , Grinberg Lea Tenenholz , Hromas Gabrielle , Kasuga Kensaku , Lacombe‐Thibault Mégane , Levin Netta , Lladó Albert , Miklitz Carolin , Perani Daniela , Rodriguez‐Porcel Federico , Seeley William W. , Spina Salvatore , Tousi Babak , Vandenberghe Rik , Walker Jamie M. , Wu Liyong , Yong Keir X X , Pelak Victoria S , Ossenkoppele Rik , Rabinovici Gil D.
Published: December 2022

Background

Posterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer’s disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker and neuropathological correlates of PCA in a large‐scale international cohort.

Method

We contacted 55 research centers conducting PCA research identified in a literature review (n=1353 papers) as well as additional sites recruited through the ISTAART Atypical AD Professional Interest Group (n=7 sites) requesting deidentified, single‐subject data from PCA patients (published and unpublished). Inclusion criteria were: 1. clinical diagnosis of PCA, 2. availability of AD biomarkers (PET or CSF) or 3. availability of autopsy diagnosis. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected.

Result

As of January 2022, we have collected individual patient data from 390 participants evaluated at 14 sites in 10 countries (Table 1). In the preliminary sample, mean age at symptom onset was 63.1 ± 8.8 years, 62.3% of participants were female, and 78.3% presented with a “PCA‐pure” clinical syndrome by Crutch 2017 diagnostic criteria. APOE4 genotype was present in 45.6% (n=125). Preliminary results show that 82.9% (n=270) display predominant MRI atrophy and 91.9% (n=185) predominant FDG hypometabolism in posterior cortical regions. CSF amyloid markers were positive in 80.2% participants (n=187), while CSF phosphorylated tau markers were positive in 61.4% (n=184). Amyloid PET was positive in 85.2% (n=129) while tau PET was only available in 65 patients (positive in all, and all were amyloid positive). At autopsy (n=36, data from 4 centers), high AD neuropathologic changes were found in all but one patient, who had primary frontotemporal lobar degeneration with TDP‐43 type A pathology. Lewy bodies, argyrophilic grains and cerebral amyloid angiopathy were common co‐pathologies (Figure 1).

Conclusion

In a large international cohort, PCA is strongly associated with positive AD biomarkers and neuropathology. Data collection is ongoing, and we further aim to identify clinical features associated with non‐AD underlying causes of PCA.
Inhibition of mitochondrial carbonic anhydrases reduces Amyloid β induced cell death in cerebral endothelial cells
Authors: Lemon Nicole L , Ilies Marc A , Fossati Silvia
Published: December 2022

Background

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS) which has been observed to become dysfunctional in Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA). Cerebrovascular amyloid disrupts the function of brain endothelial cells (ECs). Previous findings from our lab demonstrated that Acetazolamide (ATZ) and methazolamide (MTZ), both pan‐carbonic anhydrase (CA) inhibitors, prevent NVU cell death in models of AD and CAA. Although these FDA‐approved pan‐CA inhibitors are protective, a more specific targeting of the isoforms involved in AD pathology may not only reduce side effects, but also increase the efficacy of pan‐CA inhibition. We have shown that CAIs reduce Aβ‐induced cytochrome C release from the mitochondria, caspase‐9 activation, and mitochondrial H2O2 production in NVU cells. Therefore, we hypothesize that mitochondrial CA‐VA/B are the main isoforms involved in these mechanisms and we anticipate that using inhibitors selective for CA‐VA/B will prevent cerebral EC apoptosis, thereby reducing NVU dysfunction and AD progression.

Method

Human cerebral microvascular EC were treated with the vasculotropic Aβ40‐Q22 Dutch mutant, alone and in combination with a number of CA‐V inhibitors. Cell viability was measured with WST‐1 reagent and apoptosis was measured as the amount of fragmented nucleosomes. To assess mitochondria‐mediated apoptotic pathways, the expression of BAX BCL‐2 and caspase 9 activation were evaluated. The levels of different CA enzymes in cerebral EC was also assessed following Aβ treatment.

Result

Inhibition of CA‐VA/B significantly increased cerebral EC viability in the presence of Aβ40‐Q22. CA‐VA/B inhibitors also significantly reduced Aβ40‐Q22 induced DNA fragmentation in a dose dependent manner. The inhibition of CA‐VA/B attenuated Aβ40‐Q22 induced caspase‐9 activation as well as the increase in expression of the pro‐apoptotic protein BAX in cerebrovascular ECs. Interestingly, we detected changes in the expression of mitochondrial isoform, CA‐VB, after treating cerebral ECs with Aβ.

Conclusion

These results indicate that the targeted inhibition of CA‐V is protective against Aβ‐challenge in cerebral ECs through the inhibition of mitochondria‐mediated cell death and suggest that the efficacy of these new compounds should be explored in animal models of cerebrovascular amyloidosis.
Cerebrospinal Fluid Lactate Levels along the Alzheimer’s Disease Continuum and Associations with Blood‐Brain Barrier Integrity, Age, Cognition and Biomarkers
Authors: Zebhauser Paul Theo , Berthele Achim , Goldhardt Oliver , Diehl‐Schmid Janine , Priller Josef , Ortner Marion , Grimmer Timo
Published: December 2022

Background

Cerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death or microglial activation. A small number of studies have examined CSF lactate levels in dementia due to Alzheimer’s disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remains unclear.

Methods

We examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well‐defined sample of patients with AD at the stage of mild cognitive impairment (MCI‐AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD).

Results

Contrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI‐AD compared to those with ADD and to HC in univariate analysis, as well as for MCI‐AD compared to ADD when controlling for age and blood‐brain barrier integrity. CSF lactate levels were associated with age and blood‐brain barrier integrity but not with clinical severity or CSF biomarkers of AD.

Conclusion

CSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and healthy controls or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.
Neuroimaging‐based Biomarkers of Brain Aging in Healthy Older Adults
Authors: Nemati Samaneh , Newman‐Norlund Roger , Newman‐Norlund Sarah , Sayers Sara , Busby Natalie , Bonilha Leonardo , Fridriksson Julius
Published: December 2022

Background

With increasing longevity, the incidence of age‐associated functional decline and dementia is on the rise, with Alzheimer’s disease, the third most common type of dementia, projected to affect 13.8 million people by 2050. Previous studies on aging populations have reported that while people chronologically age at the same rate, an individual’s brain maturation/aging trajectory, which can be quantified by measuring the deviation of their brain’s structure and function from normative data, can be predictive of more serious forms of cognitive decline. Software capable of accurately computing this trajectory based on commonly acquired clinical scans, such as BrainAGE R, could provide reliable biomarkers of pre‐clinical disease states thereby enhancing clinicians’ ability to make early diagnosis of cognitive decline. In this study, we evaluate the relationship between resting‐state functional connectivity (rsFC) and BrainAGE measures in healthy older adults.

Method

Sixty participants (40 Female, 20 Male) aged between 60‐80 (M = 66.78, SD = 6.98) were recruited as part of the Aging Brain Cohort dataset at the University of South Carolina (ABC@UofSC). Participants completed structural T1‐weighted (T1w) and resting‐state fMRI (rsfMRI) scans. Preprocessing of the data was done using default preprocessing steps specified by the CONN toolbox. Following image preprocessing and denoising, ROI‐to‐ROI connectivity matrices in CONN were created for each participant. Individual brain age was estimated using BrainAGE R computer algorithm based on their T1w scans. BrainAGE difference scores were then calculated by computing the difference between each participant’s chronological age and their estimated brain age. Finally, a univariate general linear model analysis was used to identify significant relationships between BrainAGE difference scores and rsFC while controlling for participants’ chronological age.

Result

Our analysis revealed a significantly negative association between BrainAGE scores and rsFC of several brain networks. In particular, higher BrainAGE scores were associated with decreased connectivity between 1) default mode and salience networks, 2) default mode and fronto‐parietal networks (bilateral), and 3) visual and salience networks.

Conclusion

Our results provide novel evidence that accelerated brain maturation/aging, as indexed by BrainAGE scores, is associated with specific patterns of decreased rsFC in healthy older adults.
Artificial Intelligence Tools to Evaluate Language and Speech Patterns in Alzheimer's Disease
Authors: Favaro Anna , Motley Seneca , Samus Quincy M , Butala Ankur , Dehak Najim , Oh Esther S , Moro‐Velazquez Laureano
Published: December 2022

Background

Speech and language problems are one of the earliest signs of neurodegenerative diseases including Alzheimer’s disease (AD), but they are often difficult to detect especially in the early stages. Utility of assessing speech and language problems using artificial intelligence (AI) has been examined in the past. However, the accuracy of different methods has been variable, preventing incorporation of these techniques in clinical use. In this study, we present different speech‐based machine learning techniques. We focused on the automatic extraction of a wide array of interpretable features from the speech signals, then compared these features across different neurological disorders.

Method

Spoken responses to four different tasks (i.e., Cookie Theft Picture (CTP) and Stroop Task) were recorded from 80 participants, 5 with AD, 28 with Parkinson's disease (PD), 18 normal controls (NCs), and the remaining with other neurological diseases (OTRs). We automatically extracted several acoustic and linguistic features using speech and language technologies. We conducted pairwise Kruskal–Wallis tests to assess how speech and language abilities differed between different neurodegenerative disease vs. control groups. We used SciPy Python library.

Result

The total amount of speech time and pauses as well as the average duration and the variance of the number pauses significantly differed between AD and NC and between PD and NC in almost every task (p <0.05). Prosodic features based on F0 contour and F0 on the first and last voiced segment resulted in significant differences across tasks between AD and NC, AD and PD, AD and OTR (p <0.05). The phonological posterior for the phonological classes of consonantal, voiced, labial, nasal, velar, trill, and close significantly differed in almost every task between AD and NC, AD and PD and AD and OTR (p <0.05). Moreover, from the transcriptions of the CTP task, the number of sentences and noun phrases differed significantly between AD and NC, whereas the number of contrastive connectives and the moving average type‐token ratio were significant between NC and OTR (p <0.05).

Conclusion

Automated analysis of speech employing machine learning techniques can provide objective assessment of patients with AD that may be useful in distinguishing AD from other neurological disorders.
Patient Self‐Reported Cognitive Ability and Self‐Reported Confidence in Symptom/Medication Management in People with Dementia Disorders: Twin Pillars of Truth or Illusion for Clinicians?
Authors: Baek Steven , Kaczmarek Olivia , Peraza‐Bonilla Sophia , Bumstead Barbara , Zarif Myassar , Gudesblatt Mark
Published: December 2022

Background

Dementia associated diseases (DAD) refers to clinical conditions characterized by progressive impairment of cognition that interferes with an individual’s ability to function independently due to such cognitive impairment (CI). Clinically, CI can vary in degree and combination across multiple important cognitive domains (CD). Clinician and patient with DAD (PwDAD) self‐awareness/recognition of such varied types/degrees of CI might not only be sub‐optimal or inaccurate, but unable to recognize subtle change or provide quantitative information across multiple CD. Patient self‐reported outcome measures (PRO) are now often incorporated into routine care to gauge cognitive impairment, disability progression and participation in self‐management of symptoms, medications and shared decision making. Clinicians rely on patient provided information/history to treatment decisions. Incorporating PRO measures into routine care has increased and impacts care plans and decision‐making. Both accurate and reliable information is needed by clinicians to improve clinical decision‐making and outcomes as well as to avoid unanticipated/adverse outcomes.

Method

Retrospective cross‐sectional analysis of PwDAD who have completed PRO on the same day for both the Self‐Efficacy for PROMIS Managing Symptom s‐SF 8a (MS‐SF) and Neuro‐QOL Cognition Function‐SF (CF‐SF) in the course of routine care. Linear regression analysis of relationship was explored with significance (p<0.05)

Results

205 PwDaD, 65% female, average age 70 +/‐ 15 years. A significant positive correlation was found between the MS‐SF and CF‐SF reflecting the patient’s perceived cognition abilities and self‐reported self‐confidence in managing their symptoms (r2 = 0.5, p‐value<0.01).

Conclusion

PwDaD who report higher self‐efficacy/confidence with managing medications on MS‐SF also report higher self‐perception of cognitive functioning on CF‐SF. Low perceived cognitive ability tracks with low confidence in managing symptoms. However, CF‐SF does not track with actual measures of cognitive performance suggesting that clinicians can be misled by relying on patient self‐reported confidence of symptom management. Accurate measurements of both cognitive ability and patient ability to self‐management symptoms are needed in real world care to intervene proactively and improve outcomes.