bluuebunny/crossref_metadata_2025 huggingface dataset:
18F‐MK‐6240 Tau PET as a Biomarker for Chronic Traumatic Encephalopathy: Case Series of 10 Symptomatic Former National Football League Players
Authors: Alosco Michael L , Iaccarino Leonardo , Asken Breton M. , Nowinski Christopher , Mundada Nidhi S. , Smith Karen , Culhane Julia E , Shankar Ranjani , Windon Charles , Tripodis Yorghos , Mercier Gustavo , Stein Thor D. , Grinberg Lea Tenenholz , McKee Ann C. , Stern Robert A , Kowall Neil W , Miller Bruce L. , Mez Jesse B. , Killiany Ronald J , Rabinovici Gil D.
Published: December 2022

Background

The pathognomonic lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of neuronal phosphorylated tau (p‐tau). Patchy p‐tau deposits initially accumulate in frontotemporal cortices. Medial temporal lobes (MTL) become involved in late stage. Validated in vivo biomarkers for CTE p‐tau do not exist. 18F‐MK‐6240 is a second‐generation tau PET ligand with improved imaging properties compared with first‐generation ligands, but its utility in CTE is unknown. We report initial results from an ongoing proof‐of‐concept study investigating MK‐6240 in people at risk for CTE.

Method

Ten older adult male symptomatic former National Football League (NFL) players completed tau (MK‐6240) and amyloid (florbetapir) PET imaging and neuropsychological testing. MK‐6240 data were acquired from 36 cognitively unimpaired males without traumatic brain injury history (but unknown contact sport history) from the Wisconsin Registry for Alzheimer’s Prevention (mean age=66.3, SD=6.3; mean MMSE=29.6, SD=0.5). Using cerebellar gray matter reference, 70‐90 min MK‐6240 SUVR images were created. W‐score (age‐adjusted z‐scores) maps were generated using the control data and thresholded at w>1.65 to visualize high binding voxels. Images and scatter plots of uptake in NFL players and controls were qualitatively assessed due to the small sample size.

Results

Sample characteristics are in Table 1 (age range:51‐72, 5/10 Black). All NFL players had a negative florbetapir PET. 9/10 were cognitively impaired, particularly in memory and executive functions (Table 2). One former NFL player (case 4) had MTL MK‐6240 uptake greater than all controls, along with focal low intensity uptake in the superior frontal cortex (Figure 1). Two NFL players (cases 6 and 9) had mildly elevated MTL MK‐6240 uptake, particularly in entorhinal cortex and parahippocampus, though similar binding was seen in some controls (Figure 2). There was minimal MTL uptake in the remaining NFL players. Cortical uptake was complicated by contamination from off‐target meningeal binding.

Conclusions

Existing data suggests current radioligands (e.g., flortaucipir) developed for Alzheimer’s disease might have restricted utility to late stage CTE. This might be true for MK‐6240 and off‐target meningeal binding complicates detection of cortical p‐tau. Data collection is ongoing and the larger data set will inform on MK‐6240 as a biomarker for CTE.
Determining Etiologic Diagnoses in Patients with Rapidly Progressive Dementia
Authors: Day Gregory S , Tipton Philip W , Lazar Evelyn , Martens Yuka A , Dunham S Richard , Geschwind Michael D , Bu Guojun , Morris John C. , Graff‐Radford Neill R.
Published: December 2022

Background

Overlap in the presenting clinical features and test results in patients with rapidly progressive dementia (RPD) confounds the etiologic diagnoses of RPD, contributing to diagnostic delays, missed treatment opportunities, and poorer outcomes. There is a need to improve diagnostic accuracy in patients with RPD, with particular emphasis on identifying patients with potentially treatment‐responsive causes of RPD early in the symptomatic course.

Method

Patients with RPD were prospectively enrolled and evaluated in inpatient settings and outpatient subspecialty (memory) clinics at Washington University (Saint Louis, MO; 2016–2019) and Mayo Clinic (Jacksonville, FL; 2020–2021). Etiologic diagnoses were independently assigned by two dementia specialists integrating clinical features and the results of widely accessible diagnostic testing and referencing established diagnostic criteria. Diagnostic disagreements were resolved via blinded review by a third specialist. Clinicopathologic correlation was evaluated using neuropathological and genetic data when available.

Result

160 patients with RPD were assessed, with average age‐at‐symptom onset 60.0±15.9 years; 50% were female. Diagnostic inter‐rater reliability (91% agreement; Cohen’s κ = 0.88, p<0.001) and clinicopathologic correlation were excellent (100% agreement in 24 patients with neuropathologic or genetic data). Autoimmune encephalitis was the leading cause of RPD (39%), followed by Alzheimer disease and related dementias (29%—i.e., frontotemporal dementia, Lewy body dementia, vascular cognitive impairment), Creutzfeldt‐Jakob disease (15%), and other causes (15%—e.g., neurosarcoid, metabolic disruptions, neoplastic disease). The average age of patients with potentially treatable causes (AE and selected “other” causes; 54.4±18.2) was younger than those with neurodegenerative dementing illnesses (67.3±9.5) or CJD (67.4±7.9; p<0.001). Patients with potentially treatable causes were more likely to present with altered level of consciousness and seizures (p<0.05). CSF pleocytosis (>5 WBC/hpf) was more common in AE patients (p<0.05).

Conclusion

Etiologic diagnoses can be reliably established in RPD patients using available clinical data. Treatment‐responsive causes of RPD are common warranting consideration, particularly in younger patients with altered consciousness, seizures, and CSF pleocytosis.
Factors associated with Alzheimer’s disease patients’ caregiving status and family caregivingburden in China
Authors: Leng Fangda , Li Yuxian , Sun Wei , Wang Huali , Jin Haiqiang , Sun Yongan
Published: December 2022

Background

The increasing prevalence of Alzheimer’s disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current study aims to provide understanding of the current status of caring given to AD patients in China and the underlying factors with a large multicenter cross‐sectional observational approach.

Method

A total of 1675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socioeconomical and medical factors.

Result

90.87% of the patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427–0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373–0.884),patients’ income (OR 0.511; 95% CI, 0.330–0.789) and self‐care ability (OR 0.329; 95% CI, 0.183–0.588).

Conclusion

Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China.
Applying Variational Autoencoder to Explore Changes in Clock Drawing With Hip Fracture Surgery
Authors: Chapin Benjamin Albert , Bandyopadhyay Sabyasachi , Rodriguez Katie , Amini Shawna , Radhakrishnan Nila , Tighe Patrick , Rashidi Parisa , Price Catherine C.
Published: December 2022

Background

Older adults with acute hip fractures are particularly vulnerable to delirium and postoperative cognitive decline. Hospital staff, however, do not screen preoperative cognition or systematically monitor for delirium in these at‐risk individuals. Using the clock drawing test (CDT) our team demonstrated the potential for semi‐supervised deep learning using Variational Autoencoder (VAE) to extract clock drawing anomalies predictive of dementia (Bandyopadhyay, in review). We applied the VAE technique to assess preoperative to postoperative changes in CDTs in patients with acute hip fractures.

Methods

Post‐injury, pre‐operative hip fracture patients completed screening including the CDT to command and copy, and a baseline delirium assessment with the Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU). Postoperatively, delirium was assessed twice daily. Post‐surgery CDTs were collected after two consecutive negative CAM‐ICUs. A VAE with two latent dimensions was trained using 13,580 unlabeled clocks in an unsupervised manner to create a parsimonious 2D latent space to encode the constructional aspects of the CDT. This latent space was operationalized using a k‐Nearest Neighbor Classifier on a classification dataset consisting of 71 Dementia and 80 Control samples using 3‐fold cross validation. This separated the latent space into the “Red” and “Blue” areas corresponding to “Dementia” and “Control” groups, respectively. We projected the pre and postoperative hip fracture dataset CDTs onto this latent space to investigate changes in CDT relative constructional features post‐surgery for those with and without postoperative delirium.

Result

27 participants completed our study (age 82.96 ± 9.28; education 13.19 ± 2.90; 85% female). 2 were delirious preoperatively and excluded from analysis, and 4 developed delirium postoperatively (16%). All preoperative command and copy clocks were in the “Dementia” region of the VAE latent space. Copy, but not command clocks moved further into the “Dementia” region. Error type changed in the post‐operative command condition to resemble the copy condition more closely. Trends suggest preoperative copy clock performance may predict delirium risk after surgery.

Conclusion

Semi‐supervised deep learning with VAE applied to the CDT, particularly the copy condition, shows promise for automated preoperative cognitive screening and postoperative monitoring in at‐risk hip fracture patients. Future studies are needed with larger participant samples.
Developing an Ethnographic Community‐Based Participatory Research Dementia Study with Diverse Indigenous Populations: Indigenous Cultural understandings of Alzheimer’s disease and related dementias – Research and Engagement (ICARE) project
Authors: Blind Melissa J , Warry Wayne , Lambrou Nickolas H. , Pitawanakwat Karen , Ketcher Dana , Pederson Collette , Johnson January , Hill Annamarie , Dertinger Melinda , Koski Jessica , Trudeau Rhonda , Strong Lois , Summers Marlene , Martin Wesley , Lewis Jordan P , Zuelsdorff Megan , Gleason Carey E. , Jacklin Kristen
Published: December 2022

Background

Dementia diagnoses have been increasing in Indigenous populations for over a decade and have now surpassed rates in non‐Indigenous populations in both Canada and the U.S. Prevalence rates of Alzheimer’s Disease and Related Dementias (ADRD) are approximately 3 times higher in Indigenous populations compared to White populations, with a 10‐year earlier onset . The ICARE project (NIH –5R56‐AG‐62307‐2) qualitatively explores the impact of ADRD in Indigenous populations across four diverse sites in Canada and the United States.

Method

We used a community‐based participatory research (CBPR) approach and a two‐eyed seeing framework to establish research partnerships with four Indigenous communities/regions: 7 Anishinaabe First Nations on Manitoulin Island, Ontario Canada; Red Lake Tribal Nation, Minnesota; Grand Portage Tribal Nation, MN; and the Oneida Nation, Wisconsin. The community engagement strategy supported the infrastructure needed to conduct dementia research in a culturally safe and appropriate way that respects Tribal Sovereignty.

Result

Indigenous community‐based researchers were hired at each site and each underwent research training designed by the ICARE team. With guidance from local leadership, we established 8–12‐member community advisory groups at each site to serve as partners to guide the research. We collected preliminary ethnographic data on social determinants of health, demographics, community health, aging and dementia specific services. We demonstrated feasibility with pilot data collection of key informant interviews with Traditional Knowledge Keepers, Administrators, and Providers (n = 54) and sequential focus groups with local health care staff and formal caregivers that work with Indigenous older adults (n = 17).

Conclusion

NIH/NIA R56 funding resulted in the establishment of the community‐based infrastructure to support on‐going ADRD research in the four diverse communities. We demonstrated the feasibility of supporting community‐engaged dementia research partnerships with Indigenous communities who have differing cultural, political and historical contexts. This foundation is supporting the expansion of ICARE into a 5‐year ethnographic research study aimed at creating a foundational ethnographic database of AI/FN lived experience of ADRD across the disease trajectory that can be examined to inform the creation of culturally appropriate and safe approaches to improve dementia diagnostics, care, and outreach (NIH‐R01‐AG‐62307‐2).
Impact of α‐synuclein RNA interference on Neuropathological and Clinical Phenotypes in a mouse model of Alzheimer’s Disease
Authors: Leitao Andre D. G. , Spencer Brian , Wu Chengbiao , Conroy Abigail , Amalraj Jessica N , Mante Michael N , Masliah Eliezer , Rissman Robert A.
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathologic accumulation of beta amyloid (Aβ), Tau and α‐synuclein (α‐syn). The role of α‐synuclein has been extensively studied in Parkinson’s disease, but less so in AD. Recent studies have shown that α‐syn may also play a role in AD and its downregulation could be protective against the toxic effects of Aβ accumulation. First, we hypothesized that selectively knocking down α‐syn improves the neuropathological, biochemical, and cognitive findings in AD. Second, we tested whether α‐syn ablation could enhance AD treatments with donepezil (pro‐cholinergic) and memantine (glutamate antagonist), which are currently ineffective at slowing progression of disease.

Method

PSAPP transgenic mice were used to model AD and knockdown of a‐syn was performed by RNA interference. 43 non‐transgenic and 33 PSAPP mice were used in this study. We have selectively knocked‐down α‐syn by two different

methods

a) first, by stereotaxic bilateral injection of either LV‐shRNA (pan) α‐syn or LV‐shRNA‐luc (control) into the hippocampus and striatum; b) second, by intraperitoneal injection of a complex of ApoB11 and shRNA‐α‐syn, which was previously shown to cross the BBB. Water maze and open field testing were used to measure cognitive deficits. Biochemistry and immunohistochemistry were performed on each hemibrain.

Result

We have successfully utilized these two strategies to down‐regulate α‐syn as shown by lower levels of α‐syn through biochemistry and immunohistochemistry. Importantly, this correlates with a significant reduction in the number of Aβ plaques and tau peptides, suggesting the overlap between Aβ, tau and α‐syn in pathology. Other findings include a reduction in Iba1 staining in mice injected with LV‐shRNA‐α‐syn suggesting involvement of microglia in pathology. Open field testing indicates that α‐synuclein reduction could restore context dependent memory. Moreover, injection of LV‐shRNA‐α‐syn into the hippocampus of mice treated with memantine rescues cognitive deficits to a non‐disease level, as shown by all variables analyzed during water maze trials with an invisible platform (time, entrances and passes in correct zone).

Conclusion

Overall, this study provides evidence that α‐synuclein knock‐down improves some of the neuropathological and cognitive deficits and could be of therapeutic value in AD, especially when combined with a glutamate antagonist.
The California Face‐Name Associative Memory Exam (C‐FNAME)
Authors: Hall Kathleen , Williams Garrett , Geraci Kristin , Blank Michael , Baldo Juliana , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Herron Tim , Wyma‐Hughes John , Woods David L.
Published: December 2022

Background

The Face‐Name Associative Memory Exam (FNAME) is a sensitive measure of associative memory and age‐related cognitive decline, with FNAME scores declining in parallel with increasing amyloid and tau burden in preclinical Alzheimer’s disease (Rentz et al., 2011). Here we describe the California FNAME (C‐FNAME), a fully automated, brief (8.8 min) computerized test designed for at‐home administration under telemedical supervision.

Method

PARTICIPANTS. The C‐FNAME was remotely administered to 435 healthy adults (42.8% female, M = 64.8, ±14.7) in their homes via tablet computer. Participants underwent two C‐FNAME test sessions on successive days.

TECHNOLOGY. C‐FNAME administration was automated, with instructions delivered using text‐to‐speech and responses scored with automatic speech recognition. Examiners monitored participant performance via video and audio feeds using a web‐browser interface that displayed recall scores in real time.

TASK. Participants saw 6 faces with associated first names, last names, and occupations (encoding). Faces were presented individually, and participants repeated the names and occupations before the next face appeared. After each encoding trial, participants were asked to recall the associations when presented with the face alone (Figure 1a and 1b). After 30 minutes, participants saw the faces again one at a time and repeated the recall portion of the task (delayed recall).

Result

The C‐FNAME showed excellent test‐retest reliability (r = 0.83 for total recall scores, r = 0.82 for delayed recall scores). Multiple regression analysis revealed highly significant effects of age (Figure 2), education, gender, and vocabulary on total recall (p < 0.001 for all comparisons), with these variables aggregately accounting for 28.2% of variance. Performance significantly improved by 1.23 standard deviations on repeated testing (p< 0.001). As in previous FNAME studies (Papp et al., 2014), participants recalled occupations more accurately than names (Figure 3).

Conclusion

At‐home computerized administration of the C‐FNAME demonstrated excellent psychometric properties and produced results similar to those obtained with FNAME assessments administered in the laboratory. The design of the C‐FNAME allows for rapid, remote administration and scoring, which encourages the participation of populations that may be sometimes excluded from research protocols in laboratory settings.
Chemotherapy as a risk factor for Alzheimer’s disease
Authors: Escarcega Rocio Diaz , Patil Abhijeet A , Manchon Jose Felix Moruno , Urayama Akihiko , Dabaghian Yuri A. , Morales Rodrigo , McCullough Louise D. , Tsvetkov Andrey S.
Published: December 2022

Background

Cognitive impairments may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity (chemobrain) can be subtle or disabling and frequently include disturbances in memory, attention, executive function, and processing speed. Cognitive impairments may go away soon after chemotherapy is over or may persist for years and yet, there is a paucity of effective treatments. Research has shown that chemotherapy drugs such as doxorubicin promote neurotoxicity and cognitive disturbances. Critically, some studies demonstrated that dementia occurs more commonly in cancer patients who had chemotherapy treatment compared to individuals never exposed to chemotherapy. Understanding whether and how chemotherapy may promote dementia later in life is needed.

Method

To establish new insights into chemotherapy‐induced cognitive impairments, we use wild‐type and Tg2576 mice (a model of Alzheimer’s disease (AD)) treated with Doxil, a liposomal form of doxorubicin. Mice are injected intraperitoneally with saline or Doxil for six weeks. These conditions recapitulate a dosing schedule used in human patients and are the same as those used in similar studies in mice. Mice are then tested with cognitive and behavior assays, and their brains are analyzed for aging and AD phenotypes.

Result

In our studies, we discovered that Doxil promotes cognitive impairment in wild‐type mice. We also found that the brains of young mice exposed to Doxil contain lipofuscin—a mixture of oxidized proteins and lipids that is usually found only in the aged or diseased brains. DNA damage occurred with Doxil treatment in mice, confirming Doxil accelerated features of brain aging. Critically, Doxil enhances the deposition of amyloid in Tg2576 mice.

Conclusion

Our study demonstrates evidence of accelerated brain aging in wild‐type mice and amyloid deposition in AD mice due to Doxil treatment. Our data provide a foundation for investigating chemotherapy as a potential risk factor for AD that warrants further study. This research is being pursued in our laboratory.
REM sleep is associated with the integrity of the cholinergic basal forebrain in aMCI participants
Authors: André Claire , Martineau‐Dussault Marie‐Ève , Daneault Véronique , Blais Hélène , Lorrain Dominique , Hudon Carol , Bastien Célyne , Petit Dominique , Lafrenière Alexandre , Legault Julie , Thompson Cynthia , Montplaisir Jacques , Gosselin Nadia , Carrier Julie
Published: December 2022

Background

The basal forebrain cholinergic system (BFCS) degenerates in Alzheimer’s disease (AD) before the onset of dementia. Interestingly, rapid‐eye movement (REM) sleep is highly dependent on cholinergic activity. In AD patients, REM sleep duration is reduced but the underlying brain mechanisms are still unclear. Our objective was to investigate the associations between REM‐sleep quantity and BFCS integrity in participants with amnestic mild cognitive impairment (aMCI) compared to healthy controls.

Method

Sixty‐two participants (31 cognitively healthy: 66.8 ± 7.2 years old, 13 women; 31 aMCI: 68.3 ± 8.8 years old, 7 women) underwent polysomnography and structural magnetic resonance imaging examinations. REM sleep duration (number of minutes) and proportion (%) were computed. All participants had a REM sleep apnea‐hypopnea index <15. T1‐weighted images were preprocessed using CAT12 and the DARTEL algorithm, and the mean intensity of BFCS subregions (i.e., Ch1‐2‐3, Ch4 and total BFCS) was extracted using the JuBrain Anatomy Toolbox. Multiple regressions were performed between BFCS subregional intensities and REM sleep indices controlling for age, sex and total intracranial volume, in the whole cohort and in the two groups separately.

Result

In the whole cohort, REM sleep duration and proportion were positively associated with Ch4 intensity (duration: r = 0.31, p = 0.017; proportion: r = 0.35, p = 0.007; Figure 1A and B) and total BFCS intensity (duration: r = 0.31, p = 0.016; proportion: r = 0.29, p = 0.024). Analyses stratified by cognitive status showed the same pattern in aMCI participants: REM sleep duration and proportion were positively associated with both Ch4 intensity (duration: r = 0.44, p = 0.018; proportion: r = 0.49, p = 0.009; Figure 1C and D) and total BFCS intensity (duration: r = 0.46, p = 0.014; proportion: r = 0.46, p = 0.013). No significant association, nor trend, was found in cognitively healthy participants (Figure 1C and D).

Conclusion

In aMCI participants, lower REM sleep duration and proportion were associated with a decreased integrity of the BFCS, especially the Nucleus Basalis of Meynert. Our results support the notion that REM sleep alterations are an early marker of the degeneration of the BFCS in prodromal AD, before the onset of dementia.
Air pollution and dementia using longitudinal electronic health record data from the Indian Health Service
Authors: Zhu Yachen , Shi Yuxi , Manson Spero , O'Connell Joan , Jiang Luohua
Published: December 2022

Background

Air pollution has been identified as an important risk factor for dementia in previous studies. As a unique population with a history of colonization, American Indians have long been disproportionately affected by air pollution. However, few studies have investigated the effects of air pollution on the risk of developing dementia in American Indians. This study aims to address this important knowledge gap.

Method

County‐level average air pollution data in 2003‐2007 were downloaded from the land‐use regression models developed by the Center for Air, Climate, & Energy Solutions (CACES) and merged with data from the Indian Health Service (IHS) National Data Warehouse and related electronic health record databases between fiscal year (FY) 2007‐2013. We assigned air pollution exposure to IHS users based on their county of residence and calculated 5‐year averages of PM2.5, O3, CO, and NO2 in each county. A total of 14,910 American Indians who were 65+ years old in FY2007, used IHS services at least once each year, and were dementia free between FY2007‐2009 were included in the main analysis. Cox proportional hazard models with age as the time scale were employed to examine the association of air pollution with dementia incidence, adjusting for potential confounders.

Result

The PM2.5 levels in the IHS counties were lower than those in all US counties during 2003‐2013, while the levels of other air pollutants were similar to the US (Figure 1). More dementia incident cases were found in IHS counties with higher O3 levels (Figure 2). In multivariable Cox regression models (Table1), we found a significant positive association between dementia and O3 with a hazard ratio (HR) of 1.26 (95% CI: 1.02‐1.55) per 1 ppb standardized O3, while the associations between dementia and PM2.5, and CO were not statistically significant. We found similar results in sensitivity analyses using longer lags between air pollution and dementia or replacing CO by NO2 in the regression model.

Conclusion

Our study suggests that exposure to O3 is associated with the higher risk of dementia in American Indians. Future efforts to reduce exposure to air pollution might help lower dementia risk in American Indian communities.
Inhibition of Inflammasome Activation through the Modulation of b‐hydroxybutyrate Levels In vivo Decreases Alzheimer’s Disease Pathology
Authors: Shippy Daniel , Hanslik Kendra , Wilhelm Connor , Patel Viharkumar , Zarbock Katie R , Bendlin Barbara B. , Rey Federico E. , Raife Thomas , Ulland Tyler K.
Published: December 2022

Background

Using gnotobiotic models, our research group has demonstrated that specific changes in the gut microbiome modulate serum and brain b‐hydroxybutyrate (BHB) levels. BHB levels measured in blood also differ in Alzheimer’s disease (AD), and BHB has been linked with immune function. Recently, microglial activation of the nod‐like receptor family pyrin domain containing protein 3 (Nlrp3) inflammasome—a multi‐protein complex that when activated results in apoptosis specks‐like protein containing a caspase recruitment domain (Asc)‐speck accumulation—has been recognized as feature of AD (extracellular Asc‐specks can nucleate Ab plaques and enhance AD pathology). Given that gut microbiome modulates immune function and may impact inflammasome activation, here we tested the extent to which BHB differs in AD brain, impacts the Nlrp3 inflammasome and impacts AD pathology.

Methods

Brain samples and red blood cells from N = 10 individuals with AD and N = 10 controls were obtained from the Wisconsin ADRC and subjected to untargeted metabolomics. For mouse experiments 5XFAD mice, a model for Ab plaque formation, and wild type controls were treated with oral BHB in drinking water. Mice were maintained on BHB drinking water from 8 weeks of age until 4 months of age. Upon harvest half of each mouse brain was fixed, sectioned, stained, and imaged on a confocal microscope. The levels of BHB in the other half of each brain were assessed.

Results

We found that individuals with AD have lower levels of BHB in both their red blood cells and their brains. As BHB is known to inhibit Nlrp3 inflammasome activation we hypothesized that increasing BHB levels would result in the inhibition of the Nlrp3 inflammasome and subsequent reduction in AD pathology in vivo. To test this, we administered BHB orally to 5XFAD mice. BHB administration increased brain BHB levels, reduced plaque load, microgliosis, inflammasome activation, and Asc‐spec formation.

Conclusions

Our findings demonstrate that BHB levels are lower in the brains of individuals with AD and BHB administration in 5XFAD mice reduces AD pathology by inhibiting Nlrp3 inflammasome activation and Ab plaque formation. Taken together, our data suggest future studies exploring the role of BHB in humans with AD are warranted.
Comparison between plasma, serum and cerebrospinal fluid glial fibrillary acidic protein in Alzheimer’s Disease and Dementia with Lewy bodies and the effect of age and sex on diagnostic performance
Authors: Honey Madison I. J. , Wesenhagen Kirsten E. J. , Willemse Eline A.J. , Verberk Inge M.W. , Boonkamp Lynn , Killestein Joep , Visser Pieter Jelle , Tijms Betty M. , Teunissen Charlotte E.
Published: December 2022

Background

Glial fibrillary acidic protein (GFAP) is a novel Alzheimer’s Disease (AD) biomarker that associates with amyloid pathology and pathology‐related changes can be detected in different biofluids. We studied how the performance of GFAP to distinguish between controls, AD and dementia with Lewy bodies (DLB), depends on the studied biofluid (cerebrospinal fluid (CSF), serum or plasma) and the confounding effects of age or sex.

Method

From the Amsterdam Dementia Cohort and a local repository of healthy controls we included 372 cognitively normal individuals (CN), 255 patients with AD and 120 patients with DLB (Table 1) and GFAP levels were measured in one (n=322), two (n=416) or three (n=9) biofluids. GFAP was measured using Simoa in CSF (n=473), plasma (n=257) and serum (n=451) samples. For individuals with DLB, GFAP was measured in CSF and serum only. Effects of clinical diagnosis, age and sex on GFAP levels in each body fluid were estimated with linear models. Estimated differences between diagnostic groups were corrected for age and sex, age effects were corrected for sex and diagnostic group, and sex effects were corrected for age and diagnostic group.

Result

GFAP levels were increased in AD relative to controls in all biofluids (fold change (FC): 1.6(CSF), 1.9(plasma) and 1.4(serum), p‐values<0.001) and increased in AD relative to DLB (FC: 1.7(CSF) and 1.3(serum), p‐values<0.001, Figure 1). No difference was found between DLB and controls. CSF GFAP levels increased with age in all clinical groups (range of standard deviation protein level increase per year (SD/year): 0.020‐0.024), while plasma GFAP levels increased with age only in CN (SD/year: 0.032). Serum GFAP levels increased with age in CN and DLB (SD/year: 0.058(CN) and 0.074(DLB), Figure 2). CSF GFAP showed sex effects in AD only (FC in males compared to females: 1.1), whereas serum GFAP showed sex effects in all clinical groups (FC in males: 0.83(AD), 0.85(NC) and 0.72(DLB)), and plasma GFAP showed no sex effects (Figure 3A‐C).

Conclusion

Differences in GFAP levels between clinical diagnoses showed the same trend for all three matrices. With older age, differences in GFAP levels between controls and AD become harder to detect.
A systematic approach to reduce cultural bias: An illustration from the adaptation of the Addenbrooke’s Cognitive Examination III for the Bengali speaking population in India
Authors: Dutt Aparna , Nandi Ranita , Rao P.Sulakshana , Bhargava Pallavi , Gopalkrishnan Subha , Bose Arpita , Ghosh Amitabha , Evans Jonathan J.
Published: December 2022

Background

A systematic approach is vital for adapting neuropsychological tests developed and validated in the western, educated and English populations. However, rigorous and uniform methods are often not implemented during adaptation of neuropsychological tests and cognitive screening tools across different languages and cultures. This has serious clinical implications. The naming test from the Addenbrooke’s Cognitive Examination (ACE) III will be presented as an example to illustrate a systematic approach for selecting culturally appropriate and psychometrically reliable items for a literate Bengali speaking population in India.

Method

Two studies were conducted in seven phases for adapting the ACE III naming test. Twenty‐three items from the naming test in the English and the different Indian ACE‐R versions were administered to healthy Bengali speaking literate adults for determining image agreement, naming and familiarity of the items. Eleven items were identified as outliers. We then included 16 culturally appropriate items that were semantically close to the items in the selected ACE‐R versions of which 3 were identified as outliers. The final corpus consisting of 24 items was administered to 30 patients with mild cognitive Impairment, Alzheimer’s disease and vascular dementia, and 60 healthy controls matched for age and education to determine which items in the corpus best discriminated patients and the controls, and also their difficulty levels.

Result

The ACE III Bengali naming test with an internal consistency of .87 included 12 psychometrically reliable, culturally relevant high naming‐high familiarity and high naming‐low familiarity living and non‐living items. Item difficulty ranged from .47 to .88 and had discrimination indices ≥.44.

Conclusion

A systematic approach helps to determine whether a test is appropriate for the cultural context (within nations also) in which it is intended to be used, and also the possible reasons if inappropriate, which subsequently determines the principle/framework for test adaptation. Adaptation of neuropsychological tests based on familiarity driven approach helps to reduce cultural bias at the content level. This coupled with appropriate item selection statistics helps to improve the validity of the adapted tests and ensure cross‐cultural comparability of test scores both across and within nations.
Structural Basis and Mechanism of Cyclophilin A‐Tau Interaction in Alzheimer’s Disease and Neuroinflammation
Authors: Murray Anqesha L , Wang Chunyu , Gibson James
Published: December 2022

Background

Tau protein that comprises neurofibrillary tangles in Alzheimer’s Disease (AD) interact with the abundant immunophilin protein Cyclophilin A (CypA) due to its peptidyl‐prolyl cis‐trans isomerase activity.

Method

Using surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and cell culture, structural details of CypA/tau interaction and its functional consequences are characterized.

Result

Using SPR, we observed a binding equilibrium constant (KD) of full‐length tau at ∼10 µM and identified the tau binding pocket on CypA using NMR. CypA and tau uptake by microglia was measured by immunofluorescence microscopy and flow cytometry. CypA‐tau interactions within microglia cell lines affect neuroinflammation by altering proinflammatory and anti‐inflammatory cytokine secretion responses.

Conclusion

CypA binds to tau with high affinity and specificity, which has functional significance in tau conformation, interaction, aggregation, and in neuroinflammation.
The Lived Experience Of Latinx‐Americans And How Researchers Can Build Stronger Partnerships To Improve Research
Authors: Flores Melissa , Walter Sarah , Seshadri Sudha
Published: December 2022

Background

The Latinx population is growing in the United States, and yet recruiting participants at representative rates into research for dementia is an ongoing challenge. This group is additionally facing the largest increase in Alzheimer’s Disease and related dementia diagnoses; however, literature indicates their contribution is regularly absent from related research and clinical trials. Representative recruitment to research is critical to ensure the outcomes of research are applicable and generalizable to this large population group. Hearing and understanding the lived experience of individuals from Latinx communities is key to addressing barriers to participation. Literature around increasing minority participation notes approaches of personalization are essential in reaching Latinx groups. This session will assist researchers in tailoring strategies of recruitment and methods of engaging with the latinx population by providing the necessary platform and direct connection to this community.

Method

The panelist, selected by the Biggs Institute research team, will share their lived experience with ADRD diagnosis, care, and/or research participation. As part of the South Texas ADRC, the Biggs Institute selected panelist will provide the perspective of Latinxs living in south Texas and along the border, specifically addressing the unique challenges faced in accessing care and research. They will communicate their connection to research, personal and potential cultural barriers to research involvement, and share what researchers can do to build better partnerships with Latinx communities.

Result

This session will highlight the Latinx perspective related to dementia research and will offer the opportunity for further understanding around the experience of individuals in minoritized communities. Attendees will hear the perspective of the Latinx community to prompt improved methods of inclusion. This session aims to benefit researchers, and those in the field of aging and dementia research, by providing perspectives crucial to the development of strategies to facilitate engagement with a more demographically diverse community.

Conclusion

The voice of Latinx individuals is essential to include when discussing research priorities and addressing the challenges to increase diverse research participation. Improving inclusivity in ADRD research will improve relevance of findings, and sharing diverse perspectives is a first step to build meaningful partnerships with the latinx community.
Why and how to engage with African American faith communities in brain health research?
Authors: Epps Fayron , Moore Miranda , Chester Mia , Gore Janelle , Aycock Dawn
Published: December 2022

Background

Disparities in brain health outcomes often involve African American individuals. To achieve the highest impact for health care initiatives; effectively engaging with African American communities is crucial. One method to reach African American communities is to effectively collaborate with churches. Churches are often seen as the cornerstone of African American communities and should be regarded as a key partner in health care research. Churches have opportunities to respond to the health needs of their respective congregation and communities. For this presentation, we will outline effective strategies for engaging African American churches in promoting behavior change to enhance health equity for health care research.

Methods

Strategies include: a) Learning the history of the church, b) Selecting the best person to represent your organization, c) Having a clear ask, d) Engaging in honest conversations with leadership, e) Being persistent and engaging in church sponsored activities, and f) Offering a sustainability plan.

Results

The implementation of these strategies requires planning, time, and commitment. For example, Alter (nurse‐led dementia‐friendly congregation program) has implemented these strategies over a 2‐year period and excelled in promoting brain health and reducing dementia stigma in African American communities.

Conclusion

Health professionals and researchers can use these strategies within their practices and research to improve health and promote health equity for African American individuals and communities.
APOE e4 dependent deficits in brain DHA phospholipids and mfsd2a in Alzheimer’s disease patients with severe cerebral amyloid angiopathy
Authors: Nkiliza Aurore , Evans James , Ringland Charis , Daniel Niedospial , Huguenard Claire , David Roderick , Ojo Joseph , Crawford Fiona , Mullan Michael , Bachmeier Corbin , Abdullah Laila
Published: December 2022

Background

The apolipoprotein E e4 allele (APOE4) is a major risk factor, contributing to vascular pathologies in AD which include CAA, BBB dysfunction and reduced cerebral vascular integrity. The diminished capacity of APOE4 to transport docosahexaenoic acid (DHA), an essential fatty acid required for the structural and functional maintenance and vascular integrity of the brain, could also contribute to AD pathogenesis. However, it remains undetermined if changes in the brain DHA content of phospholipids (PL) and DHA transporters exist in relation to APOE4, AD diagnosis and CAA pathology.

Method

We performed liquid chromatography/mass spectrometry‐based PL analysis of the cerebrovascular and parenchymal fractions from autopsied human brain of pathologically confirmed AD cases and controls. We performed an antibody‐based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects and brain homogenates from transgenic mice with human APOE (APOE‐TR) and APOE‐TR crossed with mice with five AD mutations (EFAD). We performed proteomic analyses of the cerebrovascular and parenchymal fractions of the brains from 50‐week‐old APOE‐TR.

Result

In the cerebrovasculature and parenchyma, DHA containing PL species were lower in ε4 carriers with AD compared to control ε4 carriers. We observed an ε4‐dependent decrease in mfsd2a level in the cerebrovasculature of ε4 carriers compared to non‐carriers. Stratification of DHA containing PL by CAA showed that these PL levels were reduced in ε4 positive AD patients with severe CAA. In addition, brain levels of DHA containing PC species and mfsd2a were lower in APOE4‐TR and E4FAD mice compared to other genotypes in each mouse model. Furthermore, protein levels of glucose transporter 1 (Glut1) and a metabolite transporter, monocarboxylate transporter 1 (MCT1), were lower in the cerebrovasculature of APOE4‐TR relative to APOE3‐TR and APOE2‐TR mice.

Conclusion

These findings demonstrate that brain DHA deficiencies in ε4 carriers may be due to reduced mfsd2a expression and partly associated with severe CAA. Thus, targeting this transport mechanism may improve the bioavailability of DHA into the brains of ε4 carriers who are at risk of developing AD.
Different atrophy profiles detected in AD patients who carry APOE4 versus non‐carriers: An ENIGMA‐VBM Multicohort Analysis (N=1,893)
Authors: Rajagopalan Priya , Tennant Victoria R , Thomopoulos Sophia I , Owens‐Walton Conor , Kempton Matthew , Si Shuqing , Thompson Paul M
Published: December 2022

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and apolipoprotein E (APOE) ε4 allele is the greatest common genetic risk factor for late‐onset AD. In one of the largest multi‐cohort VBM analyses to date, we aimed to a) map regional brain cortical volume deficits in people with dementia vs controls (CTL) and b) investigate how atrophy patterns in AD were modulated by carrying the APOE4 genotype.

Method

The ENIGMA voxel based morphometry (VBM; https://sites.google.com/view/enigmavbm) pipeline was used to perform a mega‐analysis and a multi‐cohort meta‐analysis on T1‐weighted brain MRI data from 1,893 subjects (Table 1) across four different cohorts, namely the Alzheimer’s Disease Neuroimaging Initiative (ADNI), phases 1, GO/2, 3, and the Open Access Series of Imaging Studies (OASIS3). 488 participants with AD had APOE genotype data with 172 non‐carriers (ε3/3) and 316 carriers (ε3/4, ε4/4). Protective APOE ε2 carriers were excluded. Within the 488 participants with AD, effects of carrying the APOE4 allele were tested using a VBM analysis adjusting for age, sex, intracranial volumes and differences in cohorts.

Result

As expected, compared to controls (CTL), participants with dementia demonstrated cortical brain volume deficits in medial temporal lobes, notably the bilateral hippocampus, entorhinal cortex, amygdala and fusiform gyrus in Mega‐ & Meta‐analysis (Fig. 1). In those with AD, APOE4 carriers demonstrated relatively higher gray matter volumes in the primary motor cortex, medial frontal gyrus and posterior middle temporal gyrus, compared to non‐carriers (P<0.001, uncorrected; Fig. 2). As expected, APOE ε4 carriers demonstrated lower medial temporal lobe and precuneal gray matter volumes.

Conclusion

An expected strong pattern of medial temporal lobe volume reduction was noted in the dementia group compared to CTL. Interestingly, within the dementia group, APOE ε4 carriers showed higher gray matter density in the primary motor cortex, a region not routinely associated with AD nor with amyloid deposition, as shown in a smaller prior study. APOE ε4 carriers showed typical medial temporal and precuneal volume reductions which commonly show amyloid deposition, consistent with the notion that APOE ε4 mediates atrophy mainly via an amyloid dependent mechanism.

References: 1) Ashburner J, Friston KJ. doi:10.1006/nimg.2000.0582. 2) Liu, Ying. doi:10.1016/j.neuron.2014.11.020. 3) La Joie, Renaud. doi:10.1126/scitranslmed.aau5732. 4) Gutiérrez‐Galve L. doi:10.1159/000258100 et al. 2009;28(5):461‐70.
Cellular network perturbations point to a new microglia‐astrocyte community accelerating Alzheimer’s disease progression
Authors: Green Gilad Sahar , Fujita Masashi , Yang Hyun‐Sik , McCabe Cristin , Taga Mariko , Cain Anael , Zeng Lu , Regev Aviv , Bennett David A , Menon Vilas , Habib Naomi , De Jager Philip L
Published: December 2022

Background

Alzheimer’s Disease (AD) is a fatal neurodegenerative disease where abnormal accumulation of amyloid‐β and tau aggregates drive neurodegeneration and leads to cognitive impairment, dementia and eventually death. Combining results from recent studies, each finding a novel AD‐associated cell state of different non‐neuronal cell types, suggests a system level change of the cellular environment of the AD brain and its potential role in disease outcome.

Method

To better understand the dynamics of the cellular environment in aging human brains and AD, we applied single‐nucleus RNA‐sequencing to profile 424 aging brains of individuals across different clinicopathological characteristics. We characterized the cellular diversity within the aging human prefrontal cortex, resulting in a detailed atlas of ∼1.7 million cells classified into 95 cellular subsets of different cell types, including rare populations of microglia and astrocytes.

Results

Quantifying variations across individuals, we uncovered multiple cell subsets associated with disease pathologies and cognitive impairment. Of these, we prioritize an uncommon Microglial subset 13 (Mic.13, average 3.2% of microglia) and Astrocyte subset 10 (Ast.10, average 3.8% of astrocytes). Mic.13 expresses AD risk gene TREM2 and microglial markers linked to AD (e.g. APOE, SPP1), and its proportion is strongly associated with AD pathologies, amyloid‐β plaques and neurofibrillary tangles, and cognitive decline. Applying a mediation model, we showed that Mic.13 partially mediates the effect of amyloid‐β on tau (proportion mediated [p.m.] = 18%). While the impact of Mic.13 on cognitive decline is largely mediated by tau (p.m. = 43%), an additional subset highlighted by our analysis Ast.10, associated with both tau and cognitive decline, partially mediates the impact of tau and Mic.13 on cognitive decline (p.m. = 7.2% and p.m. = 12% respectively). Integration of all cellular states revealed an intricate network of multi‐cellular communities, each composed of multiple states of different cell types. Investigating the dynamics of the cellular communities in the aging brain and along disease progression, uncovered unique trajectories spanning from a healthy to diseased brains.

Conclusion

Our charted atlas of the cellular environment and modelling of the cellular dynamics supports a system level change underlying AD, with an active role for multiple cell types in disease progression, and highlights novel research directions and potential therapeutic targets.