2023 ADRD Poster Gallery

This poster gallery features research from students and early career Pitt researchers. Their research stretches across basic, psychosocial/behavioral, clinical, and translational research on a broad range of topics related to Alzheimer’s disease and related disorders (ADRD).

Topic Areas

Posters are labeled with the following color-coded topic areas.
Basic Science & Pathogenesis Clinical Manifestations Psychosocial Public Health Translational

On campus Poster Session on November 16th

All live interactions will take place with presenters at the Poster Session on campus at the William Pitt Union, Ballroom on 11/16; register to attend via the event page.

1Race, Meaning & Purpose in Life, and Markers of Brain Health for Alzheimer’s Disease

Presented by Aishwarya Mukundan, MPH, BS
Research Mentor: C. Elizabeth Shaaban, PhD, MS, MPH

Background: Meaning and purpose in life (M&P) represents goal direction and life meaning. Higher M&P is related to better cognition. We aimed to assess racial differences while testing the association of M&P with brain health markers. We hypothesized that higher M&P scores would be associated with better markers, moreso in Black compared to White individuals.

Methods: 206 (50-89 years) adults were included. M&P was measured by the National Institutes of Health Toolbox. Brain health was characterized as general cognition by the Montreal Cognitive Assessment, cortical thickness from magnetic resonance imaging, and beta-amyloid (Aβ) burden from positron emission tomography scans. Race was self-reported. Linear regression, adjusted for years of education, sex, age, and M&P*race interaction terms were tested. Race-stratified models were tested when the interaction p<0.10.

Results: Although M&P was not associated with Aβ nor cortical thickness (both p>0.10)– among cognitively normal participants, higher M&P scores were related to better global cognition (β=0.090, p=0.022). In the whole sample, results varied by race (interaction p=0.073), with higher M&P scores associated with better global cognition for Black (β=0.11, p=0.011), but not White participants (β=0.0081, p=0.83). There was no effect modification for amyloid or cortical thickness (interaction p’s all>0.10).

Conclusion: Greater M&P is associated with better global cognition in Black adults. Studies should examine other brain health markers and the likelihood of M&P improving health outcomes.

 2Enhancement in Sleep Induced by Repetitive TMS

Presented by Yue (Coco) Dong, RN
Research Mentor: Kristine Wilckens , PhD

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and non-pharmacological measure for cortical function. rTMS has also been used to trigger slow wave activity, relating to memory consolidation and brain restoration. This is a secondary analysis aiming at looking at the change of different sleep parameters as a function rTMS in people with moderate-to-severe worry.

Methods: fMRI-directed intermittent Theta Burst Stimulation (iTBS), which is a form of rTMS, was delivered to patients with moderate to severe worry, targeting at the right superior parietal gyrus, for about 5-6 minutes, five days a week for two consecutive weeks for this study. Participants were asked to complete some sleep measurements, including sleep diary and actigraphy, at least four days prior to the initiation of TMS session (pre-TMS) and  throughout the night. The first four nights of TMS sessions were deemed as adjustment period to avoid any bias. Linear mixed effect modeling was used, with compound symmetry as covariance type and parameter estimates for fixed effects as Model Statistics, to illustrate the potential interaction effect between timepoints and progression of days. One-way within subject ANOVA and post-hoc pairwise comparison with LSD correction was also used to identify potential sleep trend between pre-TMS session, adjustment period, and 4-day post-TMS. Point biserial correlation was used to examine the effect of employment status, stratified as active and inactive, on sleep variables. The primary sleep measures were total sleep time (TST), time in bed (TIB), sleep latency (SL), wakefulness after sleep onset (WASO), and sleep efficiency (SE).

Results: There are 22 participants with 306 datapoints available for diary analysis, and 20 participants with 280 datapoints available for actigraphy analysis. Significant interaction effect was examined for TST and SE, but it stopped being significant once removing multivariate outliers. Significance of the main effect of both TIB and TST was identified. What is more, both the TST and SE were identified to be quadratic in trend analysis with significant increase from adjustment period. No interaction effect nor main effect was discovered in actigraphy dataset. Significant correlation between employment status and SL, TST, and TIB, indicating a lower SL, TST, and TIB for participants who are active compared to who are inactive.

Conclusion: Compared to sleep before TMS initiation, SE is enhanced after 4 days of TMS session while controlling for days, which is a promising direction for future sleep-TMS-related study. However, there are limitation in this study as well. Firstly, this is a pilot study (n=22); hence it lacks statistical power. Secondly, the target population might have effect on sleep solely, which could act as a moderating effect. Thirdly, this is a secondary analysis, so no sleep measures day after TMS sessions were collected, allowing for a pre-post comparison, which could enhance statistical power.

Funding Source: R01MH108509/STUDY1905150 (PI: Carmen)

 3Unfair Treatment, Social Cohesion, and Cognition in Black Adults Living in Urban Neighborhoods

Presented by Erica Fan, MPH
Research Mentor: Andrea Rosso, PhD

Background: Exposure to discrimination has been associated with poorer cognitive function but this association may be influenced by broader social factors.

Methods: We investigated the associations between unfair treatment, social cohesion, and cognitive function in 226 participants ≥50 years, recruited from urban, primarily Black neighborhoods in Pittsburgh, PA. Neuropsychological assessments were conducted in 2018 to create six cognitive domain z-scores, adjusted for age, sex, and education level. Social cohesion was assessed in 2013 and 2018. Change in social cohesion scores over time categorized participants into four groups: consistently high, consistently low, increasing, and decreasing scores. Unfair treatment was assessed via questionnaire in 2018. Adjusted generalized linear models assessed associations between unfair treatment and cognition.

Results: Unfair treatment was associated with executive function (β=-0.044, p=0.01) and with language (β=-0.032, p=0.05). Additionally, social cohesion moderates the association between unfair treatment and executive function. In those with consistently low social cohesion, more unfair treatment was associated with worse executive function (β=-0.085, p=0.02). Both increasing and decreasing social cohesion showed a similar negative association between unfair treatment and executive function at a trend level (β=-0.09, p=0.07 and β=-0.123, p=0.07, respectively). When changing groups are combined, there is a significant negative association between unfair treatment and executive function (β=-0.100, p=0.005). There was no association for those with consistently high social cohesion. Individuals experiencing unfair treatment and consistently low levels of neighborhood social cohesion had lower executive function.

Conclusion: These findings highlight the importance of intervening at multiple levels and addressing interpersonal discrimination and structural sources.

 4Neighborhood Disadvantage and the Association Between Imaging Biomarkers of Alzheimer’s Disease and Cognition in a Cohort of Diverse Older Adults

Presented by Erica Fan, MPH
Research Mentor: Ann Cohen, PhD

Background: Neuroimaging biomarkers of Alzheimer’s disease (AD) are well-validated in White populations. However, it remains unclear how these biomarkers are associated with cognition in non-White populations disproportionately affected by systemic socioeconomic discrimination.

Methods: We investigated whether neighborhood disadvantage modifies associations of neuroimaging biomarkers with cognition in a diverse cohort of 198 adults ≥50 years, 50% of whom are Black. Outcomes included cognitive impairment and neuropsychological test scores. Predictors were indices of neurodegeneration, vascular damage, and brain amyloid burden, quantified using MR-based measures of cortical thickness and white matter hyperintensities (WMH) and [¹¹C]PiB PET, respectively.  We measured neighborhood disadvantage using area deprivation index (ADI), a composite measurement of socioeconomic conditions in a census tract.

Results: In linear models, higher ADI, neurodegeneration, and WMH were separately associated with worse cognition. We found an ADI*neurodegeneration interaction on delayed recall memory (p=0.08). Neurodegeneration-positive participants had worse story delayed recall compared to neurodegeneration-negative regardless of ADI (β=-1.57, p=0.01). In neurodegeneration-negative participants, higher ADI is associated with worse delayed recall (β=-0.04, p=0.004): those with a high ADI exhibited low delayed recall, comparable to neurodegeneration-positive participants. ADI was not associated with cognition in neurodegeneration-positive participants. WMH and ADI interacted in models of impairment, visual memory, and visual copy (interaction p’s<0.10). In those with high ADI, greater WMH was associated with worse cognition (β=-0.30, p=0.02) while participants with low ADI scored well regardless of WMH volume.

Conclusion: Taken together, the relationship between neuroimaging biomarkers and cognition differs by neighborhood socioeconomic conditions, highlighting the need for clinical strategies that acknowledge structural disadvantage.

 5DNA Damage and Neuronal Senescence: Differential Vulnerabilities of Neurons in Different Cortical Layers

Presented by Gnanesh Gutta, BSc
Research Mentor: Karl Herrup, PhD

Background: Alzheimer’s disease (AD) is an aging-related disease with the disease’s risk and the accumulation of unrepaired DNA damage increasing with age. The increased accumulation of this genomic damage leads to increased pressure to re-enter a cell cycle and the expression of senescence markers. Cellular senescence is a phenomenon seen in cells that results in a state of permanent arrest in cell growth and division as a protective mechanism from external stressors.

Method: Through fluorescent staining techniques for amyloid-β accumulation, cellular senescence markers, and DNA damage in human post-mortem brain samples and primary cultured neurons, we are assessing the spatial correlations in the cortex between these three phenomena.

Results: Overall, cellular DNA damage is significantly increased in the BA9 region of the Alzheimer’s Disease cortex when compared to this region in the unaffected control (UC) cortex. This increase is uniform across all cortical layers with a trend towards increased density of cells with DNA damage with increasing distance from the pial surface in the gray matter. This pattern in DNA damage is overlaid with an uncoupled pattern of cellular senescence density across the cortex. Through inducing cellular senescence via a known pathway without DNA damage in primary culture, an increase in DNA damage was observed along with the increased expression of senescence-associated proteins in neurons.

Discussion: This work suggests that the hyperinsulinemia pathway in cellular senescence previously thought to be involved in AD may not present in the neurodegeneration of AD.

 6Understanding the Female Advantage in Verbal Memory Among Individuals with Unimpaired Cognition and Mild Cognitive Impairment

Presented by Hannah Dewhurst, BS
Research Mentor: Beth Snitz, PhD

Sex differences in cognitive abilities has been receiving increasing attention over the past decade. It has been frequently reported that females score better on verbal memory tasks than males. Therefore, it is important to account for sex differences when evaluating memory in older adults and to use sex specific norms to account for this memory advantage, especially when diagnosing memory impairment. The present study examines differences in verbal memory scores in a sample of older adults (N = 342, Female n = 184, 51.8%; Male n = 177, 48.2%). After adjusting for age (M = 78.39, SD = 9.01), race (White n = 286, 83%; African American n = 56, 16.4%), and education (M = 15.46, SD = 2.7) delayed recall scores from the California Verbal Learning Test (CVLT) were compared between sexes in cognitively unimpaired individuals (n= 110) and participants diagnosed with MCI (n = 231). Using ANOVA, long delay recall scores of the CVLT were higher in females than males (p = .011) in the unimpaired group, even when accounting for age (p = .017), race (p = .22), and education (p = .11). However, scores were not significantly different (p = .158) in the MCI group accounting for age, (p = .124), race (p = .463), and education (p = .600). In agreement with previous research, results from the present study indicate an advantage in verbal memory in females before impairment, with implications for testing hypotheses about cognitive reserve and considering beyond demographic variables in memory evaluation.

 7Creating Inclusive Research Through Culturally Aware Data Collection Sites

Presented by Hector Salazar, BSN
Research Mentor: Carey Gleason, PhD

Background: Ethnic and racial diversity in clinical research is critical for developing generalizable treatments and caregiving strategies. Barriers to participation among persons from underrepresented groups (URG) are systemic in clinical research. To increase URG research participation, we designed a community-based data collection site where study participants complete full research visits.

Method: For an Alzheimer’s disease study, we established the first community-based data collection site in Madison, WI, forging connections with Black community leaders and campus outreach staff. The site is proximal to diverse neighborhoods, public transportation, and is a hub for multi-ethnic businesses. We rent space in the South Madison Partnership Office, an established community outreach center. This allowed us to cultivate a consistent presence in the Black community, which evolved into a full data-collection site. Staff include research specialists, community liaisons, nurse practitioners, and clinicians who are culturally-aware and members of the Black community. The site is decorated with art from local Black and Indigenous artists, and food served is from a local Black-owned business.

Result: We established proof of concept by successfully launching a fully-equipped research site in the community, used for memory testing, biometric readings, blood draws, and one-on-one conversations with clinicians. Initial comments suggest participants prefer this comfortable, familiar setting over that of a hospital setting.

Conclusions: Researchers can use culturally-aware and convenient data collection sites. Our site prioritizes the needs of participants toward the goal of achieving representation of racialized groups in research. This model has potential for broad implementation across aging and biomedical research.

 8Assessing the Correlations Between LATE Pathology and Amygdala Volume in Neurodegenerative Diseases Using 7T Postmortem MRI

Presented by Jaehoon Noh, BSc
Research Mentor: Julia Kofler, MD

Abstract

 9Predictors of Decisional Capacity in AD Biomarker Test Candidates

Presented by Jeong Eun Kim, BSN
Research Mentor: Jennifer Lingler, PhD, MA, CRNP, FAAN

Background: Understanding and evaluating one’s Alzheimer’s disease (AD) biomarker status can be complex, particularly for individuals with cognitive impairment and their family care partners. This study aimed to identify predictors of decisional capacity in an amyloid PET disclosure study involving persons with Mild Cognitive Impairment (PwMCI) and their family care partners (CPs).

Methods: This analysis utilized baseline data from an RCT of amyloid PET results disclosure. Decisional capacity was assessed using the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC), and predictors included sociodemographic characteristics, knowledge about MCI/AD/normal aging, cognitive function (Mini Mental Status Exam), and neuropsychological tests among PwMCI (n=82). Dyadic analyses were performed on CP data (n=82) to examine partner effects among key variables.

Results: Participants and CPs were mostly White (91.5%,90.2%), highly educated (16.5,15.5 years average), with mean age 72.7 and 66.8 years, respectively. MMSE (b=0.215,SE=0.082,p=0.011) and MCI/AD knowledge scores (b=0.241,SE=0.101,p=0.020) positively predicted decisional capacity for PwMCI. Dyadic analysis showed that MCI/AD knowledge scores (p=0.019) were highly correlated within the dyad. Furthermore, analyses revealed significant positive correlations for MCI/AD knowledge for actor relations for decisional capacity for both PwMCIs (a11=0.328,p=0.005) and CPs (a22=0.262,p=0.025). CP’s level of MCI/AD knowledge had negative association for partner effects for decisional capacity (p21=-0.207,p=0.043) of the PwMCI.

Conclusion: Assessment of decisional capacity is imperative when considering participation in AD research, including biomarker studies involving results disclosure. Our findings highlight that not only do individual characteristics put PwMCI at risk for lower decisional capacity, but dyadic effects from CPs may also be present.

10Age- and Sex-Related Morphological Changes in Cerebral Blood Vessels: A 7T TOF MRA Study

Presented by Jiatai Li, BSc
Research Mentor: Minjie Wu, PhD

Background: In this study we evaluated age- and sex-associated morphological changes of cerebral blood vessels using 7T Time-of-flight (TOF) magnetic resonance angiography (MRA).

Methods: Our study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole-Brain TOF images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number=354, voxel size=0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images. For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.

Results: We found age-related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02 Fig. 1 blue). This age-related difference is driven by small vessels (p=0.002, Fig. 1 left, red) rather than large vessels (p=0.7, Fig. 1 left, green). Further, women showed greater age-related increase in mean arterial tortuosity, compared to men (age*sex interaction p=0.04, Fig. 1 right).

Discussion: Our findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD-related AD risk in women.

Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N=25). Future study with a large balanced sample and a longitudinal design are required to confirm our findings.

11Assessing the Correlations Between Pathology and Hippocampal Volume in Neurodegenerative Diseases Using 7T Postmortem MRI

Presented by Jr-Jiun Liou, PhD
Research Mentor: Tamer Ibrahim, PhD

Background: The hippocampus, crucial for memory, is among the earliest areas damaged compromised in neurodegenerative diseases. In limbic-predominant age-related TDP-43 encephalopathy (LATE), the severity of LATE pathology can be classified into three stages based on TDP-43 proteinopathy distribution. While previous studies have focused on hippocampal volume and cognition, their relationship to LATE stages remains unreported.

Methods: In this study, ex vivo postmortem MRI scans of the formalin -fixed left hemisphere were acquired at 7T in Down Syndrome, Alzheimer’s Disease/ Lewy Body Disease and Other Diagnosis cases (n=77). Manual segmentation of the hippocampus was performed, and the hippocampal volume was correlated to clinical information and neuropathological results.

Results: The ex vivo hippocampal volume obtained from manual segmentation was significantly correlated with the volume in vivo (p=0.0066). The hippocampal volume had a positive correlation with whole brain weight measured at autopsy (p<0.001) and a negative correlation with Thal phase (p<0.0001) and Braak stage (p=0.0005), LATE pathology (p<0.0001), as well as dementia duration (p=0.0064). Down syndrome cases had a significantly lower hippocampal volumes than non-down syndrome cases (p=0.0025). In Alzheimer’s disease/ Lewy body disease cases, a significant difference was detected between LATE and non-LATE cases (p<0.0001); LATE stage 2 (p<0.0001) and stage 1 (p=0.0494) hippocampi were significantly smaller than stage 0 hippocampi. Additionally, the hippocampal volume was lower in those diagnosed with hippocampal sclerosis (HS) when compared to those without (p=0.0091) and the volume of LATE cases without HS was lower than that of non-LATE cases (p=0.0125).

Discussion: We present a novel postmortem imaging protocol, utilizing ultra-high field MRI and a feasible acquisition time of three hours per brain, and demonstrate accurate measurement of hippocampal volumes and correlation with postmortem measures of neuropathology burden.

12Psychosocial Factors are Associated with Physical Activity in Older Adults with Musculoskeletal Pain: Cross-Sectional Findings from the Cardiovascular Health Study

Presented by Kailyn Witonsky, BA
Research Mentor: Caterina Rosano, MD

Background: Musculoskeletal pain is common and limits physical activity in older adults. However, some older adults with musculoskeletal pain are also physically active. Psychosocial factors are emerging as predictors of physical activity and may explain why some older adults with pain are physically active.

Methods: We investigated the cross-sectional association of psychosocial factors with leisure time physical activity (kcal/week) in adults over the age of 64 with musculoskeletal pain from the Cardiovascular Health Study. Psychosocial factors included: social network score from the Lubben Social Network scale and three questions from the Center of Epidemiologic Studies Depression Scale (CES-D): perceived effort, difficulty getting going, and trouble concentrating. Separate multivariable ordinal regression models estimated the association between these indicators and physical activity, while controlling for demographics and other contributors of physical activity: number of medications, number of pain sites, body mass index, gait speed, digit substitution symbol test, brain white matter hyperintensities, and mood.

Results: Among 902 participants (65% female, 14% Non-White) with pain and complete data, higher social network score (β = 0.02, p <0.01), and no self-reported “difficulty getting going” (β = 0.4, p <0.01) were associated with higher levels of physical activity, independent of covariates. Associations with perceived effort or trouble concentrating were not statistically significant.

Conclusions:  Our research suggests that lower physical activity is not an inevitable result of pain and psychosocial factors might be important targets to support physical activity. Studies should investigate the role of psychosocial states on physical activity among older adults with pain.

13The Functional Role of ENPP6 in the Pathogenesis of Psychosis in Alzheimer’s Disease

Presented by Khushi Rai, BSc
Research Mentor: Robert Sweet, MD

Objective: Psychosis occurs in 41% of patients diagnosed with Alzheimer’s disease. Our lab conducted a genome-wide association meta-analysis in over 12,000 Alzheimer’s disease subjects with psychosis (AD+P) and without psychosis (AD-P). One genome-wide significant locus associated with AD+P was ectonucleotide phosphodiesterase 6 (ENPP6), a choline-specific phosphodiesterase involved in choline metabolic processes necessary for myelin synthesis in oligodendrocytes. The normal expression of ENPP6 mRNA peaks as oligodendrocytes progenitor cells (OPCs) proliferate and declines during differentiation into mature oligodendrocytes. This study investigates whether the maturation of OPCs is impaired in AD+P because of the reduced expression of ENPP6.

Methods: OPC/Oligodendrocytes are generated from OLIG2+ progenitors derived from an iPS cell line using a T3 (triiodothyronine) protocol. The generation of OPC/ Oligodendrocytes are examined by using four stage-specific markers at different time points to ensure that the differentiation is proceeding successfully. Antisense oligonucleotides (ASO) are designed to determine their efficacy in silencing the target gene and will be delivered into cells through lipofectamine. The impact of silencing the target gene is examined through quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Results: Five ASOs (506, 745, 1484, 2732, and 3766) were screened to determine their knockdown efficiency in the cell line SH-SY5Y. The ASO’s closer to the five-prime end had greater effects. 506 and 745 were shown to individually knockdown ENPP6 expression. 1484 was shown to upregulate ENPP6 expression.

Conclusion: OPC/Oligodendrocytes were successfully generated from iPSCs. Two ASOs (506 and 745) were identified to successfully knockdown ENPP6. Our lab is currently exploring lentiviral-mediated knockdown of ENPP6 in OPCs/Oligodendrocytes.

14Transcriptomic Profiling of Astrocytes in Alzheimer’s Disease: Revealing Cellular States and Molecular Alterations

Presented by Kimia Ghafari, BS
Research Mentor: Hansruedi Mathys, PhD

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder associated with aging, marked by cognitive deterioration with known astrocyte changes in response to disease progression. New findings support the notion that different transcriptomically defined astrocyte states are linked to different stages of AD.

Methods: The emergence of transcriptomics technologies has facilitated rapid advancements in understanding and characterizing these abnormal astrocyte states associated with the disease. In this study, we analyzed over 340,000 astrocytes from more than 600 aged, prefrontal cortex (PFC) brain samples exhibiting varying degrees of AD pathologies revealing multiple transcriptomically distinct astrocyte cell states and gene modules.

Results: Using a pseudobulk-based differential gene expression analysis approach, we identified genes that are differentially expressed in high-resolution cell states across various measures of AD pathology including global AD pathology, neurofibrillary tangle burden, tangle density, overall amyloid level, neuritic plaque burden, diffused plaque burden and cognitive and lifestyle measurements. We also explored the associated biological and functional ontologies, revealing that genes and gene modules related to DNA damage, RNA metabolism, Cholesterol, and Lipid metabolism are altered in AD astrocytes. We also analyzed sex differences across the high-resolution cell types and their association with multiple AD pathologies.

Overall, this large transcriptomic atlas has yielded valuable insights into pathology-associated astrocyte states and their respective gene alterations.

15Social Characteristics of Racial Minority Stroke Survivors and Perceived Discrimination: A Secondary Analysis

Presented by Lilcelia Williams, PhD
Research Mentor: Elizabeth Skidmore, PhD

Abstract

African American and Black persons experience significant disability after stroke. They also experience high external stressors, including discrimination, which may attenuate stroke recovery. Further understanding of the associations among external stressors, disability severity, and attenuated recovery are important to reduce healthcare disparities and improve patient outcomes. However, persons of the same race may not have the same lived experiences due to variations in social characteristics such as age or education. Associations between these social characteristics and perceived discrimination may offer insights into the recovery of older adult African American and Black stroke survivors. We conducted a secondary analysis of 11 poststroke patients who were recruited to participate in the Black Lived Experiences of Stroke Study (female=10, age=67±11, ≥2 years post-secondary education=63%) to assess the frequency of perceived discrimination. Perceived discrimination was measured with the Everyday Discrimination Scale survey. We examined correlations between age and education and perceived discrimination using Cramer’s V tests. Semi-structured participant interviews were also examined for examples of perceived discrimination during poststroke healthcare. Nine participants reported perceived discrimination post-stroke. Analyses revealed a clinically meaningful but not statistically significant relationship between chronological age and perceived discrimination (Cramer’s V=0.62, p=0.12). There was no meaningful relationship between educational level and perceived discrimination. All participants reported challenges with communication, missed diagnoses and poor delivery of care poststroke. Findings support the need for additional research to examine the relationships between participants’ social characteristics and perceived discrimination among Black and African American stroke survivors, and the impact on stroke recovery. 

16Subjective Memory and Perceived Risk of Alzheimer’s Disease among African American Adults

Presented by Lilcelia Williams, PhD
PI: Research Mentor: Jennifer Lingler, PhD, MA, CRNP, FAAN

Objectives: Given the disparities in access to diagnoses and treatment in cognitive decline, there is more reason to take note of subjective memory complaints among African American adults. One way to better understand its relevance is through further exploration into how important memory complaints are to one’s perceived risk of AD. Therefore, the objective of the current study was to investigate the associations among subjective memory complaints and perceived risk of AD among older African American adults. 

Methods: This secondary data analysis included 341 African American adults aged 45 and older. Subjective memory complaints were measured with the Frequency of Forgetting Scale. Multiple linear regression models were used to examine the relationship between perceived AD risk and total score of subjective memory assessment after controlling for demographics. The interaction between subjective memory assessment with sex and education were also investigated. 

Results: Mean age of participants was 60, male participants reported better subjective memory performance than female participants, and females reported a slightly higher chance of developing AD in the next 10 years than male participants. Regression analyses showed that reporting female sex moderated the association between perceived AD risk and subjective memory complaints. 

Conclusion: Results indicate that perceptions of AD risk were strongly associated with sex and subjective memory complaints or potential presence of cognitive symptoms. Future research should be expanded to include race-based cognitive ability, as well as gender-based cognitive ability. 

17The Alzheimer’s Disease-Associated TREM2 R47H Exacerbates Ferroptosis through GPX4

Presented by Lili Lu, PhD
Research Mentor: Gang Li, PhD

Abstract

Genome-wide association studies (GWAS) have identified the R47H allele of triggering receptor expressed on myeloid cells 2 (TREM2) R47H as one of the most significant genetic risk factors for Alzheimer’s disease (AD). However, the mechanism by which it contributes to AD remains largely unknown. Ferroptosis is a programmed cell death caused by the abnormal increase in iron-dependent lipid peroxidation. Increasing evidence suggests that ferroptosis could be one of the mechanisms involved in the development of AD, but, so far, no genetic evidence has been discovered. Here, we report that rs75932628, an exonic SNP encoding TREM2 R47H, is also part of a cis-regulatory element that modulates TREM2expression by recruiting at least two iron chaperones, namely Poly(rC) Binding Protein 1 (PCBP1) and PCBP2. Further analysis revealed that iron suppresses TREM2 expression by disrupting the binding of these proteins to rs75932628, and that downregulation of TREM2 by iron, as well as other heavy metals, inhibits the expression of glutathione peroxidase 4(GPX4). Decreased GPX4, an enzyme capable of converting lipid peroxide to lipid alcohol, results in ferroptosis, due to the accumulation of lipid peroxide. Thus, our results reveal how iron, the most abundant heavy metal in nature, can regulate ferroptosis by interacting with the AD-associated TREM2 R47H allele. These data provide human genetic evidence supporting the ferroptosis hypothesis of AD pathogenesis.

18University of Pittsburgh National Sports Brain Bank for Contact Sports Participants: An overview of data collected during the first 6 months

Mary Gantz Marker, PhD
Research Mentor: Julia Kofler, MD

Abstract

19Neuron-Preserving Tau Coincides with Distribution of HSV-1 Proteins in Alzheimer’s Disease

Presented by Vanesa Hyde
Research Mentor: Or Shemesh, PhD

Abstract

Alzheimer’s disease (AD) is diagnosed via postmortem detection of extracellular amyloid beta (Aβ) plaques or oligomers and intracellular hyperphosphorylation tau. These canonical pathologies are key players in AD etiology. A complementary line of research suggests that common human pathogens serve as the initial seeding agents which facilitate the pathologies of AD. We used expansion microscopy (ExM), a tissue manipulation method which enables the imaging of biological samples at 40nm resolution. For our purposes, we used a novel version of ExM, decrowding expansion pathology (dExPath), which exposes inaccessible protein epitopes to antibody staining while enabling super resolution imaging.  Using dExPath, we visualized pathogen-related proteins within human brain samples. We discovered a clear colocalization between AD pathologies and pathogen-derived proteins. Utilizing human brain organoids and rodent cultures as model systems for the human brain, we used pathogen infection to replicate the AD pathologies observed in the AD human brain. Our results suggest that (1) neurons exposed to pathogens produce human AD pathologies, (2) AD pathologies may be antimicrobial, and (3) AD pathologies may be neuron protective. With these important roles in mind, our continued research focuses on isolating the mechanism from which the proposed neuron-protective strategy operates.

20Change in Alzheimer’s Disease Gray Matter Cortical Signature is Associated with Treatment Response in Late-Life Depression

Presented by Saurab Faruque, MPH
Howard Aizenstein, MD, PhD

Background: Alzheimer’s disease (AD) cortical signature is a novel MRI indicator reflecting mean cortical thickness of 9 brain regions of interest and has been associated with dementia progression. Brain morphology has also demonstrated utility in predicting antidepressant treatment efficacy. Although dementia and late-life depression (LLD) often overlap clinically and cortical atrophy is implicated in both, the predictive value of AD cortical signature—a composite biomarker for cortical neurodegeneration—has not been explored for LLD pharmacotherapy.

Methods: 39 patients with LLD received first-line antidepressant therapy (SNRI Levomilnacipran or SSRI Escitalopram) and underwent structural MRI at baseline and after 12 weeks of treatment. Linear models including MRI-related and demographic covariates were constructed for the relationship between AD cortical signature and treatment response.

Results: 18 responders and 5 non-responders had complete imaging data. There were no baseline differences between responders and non-responders. Change in AD cortical signature was significantly different between the groups (t(21)=-2.5, p<0.05).  Treatment non-response was associated with a significant decline in AD cortical signature (average 4.9% decrease from baseline, p<0.05), while treatment response was not associated with a significant change.

Discussion: The significant association between change in AD cortical signature and non-response to antidepressant treatment suggests either a deleterious effect of this unique atrophy pattern on antidepressant response or a neuroprotective effect of successful treatment for older adults. Change in AD cortical signature may be a useful factor for understanding pharmacotherapy efficacy in LLD. Future studies should consider AD cortical signature changes prior to treatment initiation as a predictor of LLD treatment response.

21Transcriptomics Atlas of Aged Human Brain Immune Cells: Unraveling Pathology-Associated Changes in Alzheimer’s Disease

Presented by Shihan Wang, MD candidate
Research Mentor: Hansruedi Mathys, PhD

Background: Alzheimer’s disease (AD) is a major neurodegenerative disorder characterized by cognitive decline and hallmark pathologies. Microglia play a major role in central nervous system homeostasis. However, microglia activation can promote AD by activating complement, leading to plaque formation, tangles, neurites, and synaptic loss.

Methods:Transcriptomic studies have revealed different microglial states in AD, but more research is required. In this study, we analyzed over 150000 prefrontal cortical immune cells from more than 600 aged post-mortem brain samples exhibiting varying levels of AD pathologies.

Results: Differential gene expression analysis identified genes that were differentially expressed in high-resolution cell states across various measures of AD pathology including global AD pathology, neurofibrillary tangle burden, tangle density, overall amyloid level, neuritic plaque burden, and diffuse plaque burden. We also explored the associated biological and functional ontologies, revealing that genes and gene modules related to cell activation and innate immune response. Additionally, cell-type compositional analysis revealed specific microglia cell states that are associated with AD pathologies. Furthermore, our analysis of sex differences across the high-resolution cell types revealed distinct immune responses. We also analyzed the temporal changes of microglia across multiple stages of Alzheimer’s disease progression.

In summary, our analysis of a transcriptomic atlas has yielded insights into detailed cell states, pathology-associated types, and genes/pathways affected in AD. 

22Big Five Personality Characteristics, Neuropsychological Performance, and Subjective Cognitive Functioning in Older Adults

Presented by Taylor Lazzari, BS
Research Mentor: Kirk Erickson, PhD

Background: Cognitive decline in older adults can become recognized through memory complaints from the individual, usually made when asked about their cognition. However, not everyone is equally vocal about their cognitive abilities or aware of their level of cognition. Also, the alignment of these complaints to neuropsychological testing performance can vary from individual to individual.

Methods: This study examined the association between neuropsychological test performance and subjective cognition ratings with the Big Five Inventory (44 Item) of personality among older adults 60 years and older in the Intervention Trial of Exercise (IGNITE) study (N = 642) in older adults, sixty years of age and up (x = 69, SD = 3.75). We assessed neuropsychological test performance through Hopkins Verbal Learning Task (HVLT) and Trailmaking B Time, while subjective cognition was examined through the Everyday Cognition Questionnaire (ECOG).

Results: In demographics and health-adjusted regression, we found higher extraversion was negatively associated with neuropsychological performance in Trailmaking B (unstandardized B = .646, p = .175), and negatively associated with subjective cognitive function (unstandardized B = -.017, p < .001). Additionally, higher openness to new experiences was negatively associated with subjective cognitive function (unstandardized B = -.007, p = .017). No significant results were found for conscientiousness, neuroticism, or agreeableness personality traits, and HVLT performance scores.

Discussion: These findings suggest if this relationship is further examined through longitudinal study, this information can be added to current etiology of early cognitive decline and dementia and allow for potential use of personality tests as an early identification method. 

23G Protein-Coupled Receptor Kinase 2 Modulates Tau Pathogenesis In Human Neurons

Presented by Thais Rafael Guimarães, BS
Research Mentor: Amantha Thathiah, PhD

24Do Cardiovascular, Metabolic, or Inflammatory Risk Factors Relate to Brain Age in Late Life?

Presented by Thomas Kraynak, PhD
Research Mentor: Carmen Andreescu, MD

Abstract

An individual’s so-called ‘brain age’ can be estimated using patterns of brain morphology derived from structural magnetic resonance imaging (MRI) and used in cross-validated models to predict their chronological age. Individuals whose predicted brain age appear older than their chronological age may be at elevated risk for Alzheimer’s Disease. Having elevated cardiovascular, metabolic, and inflammatory risk factors is reliably associated with greater brain age during midlife, yet the importance of these factors on predictions of brain aging in late life are not well understood. We tested cross-sectional and longitudinal associations of cardiovascular, metabolic, and inflammatory risk factors (blood pressure, dyslipidemia, adiposity, insulin resistance, systemic inflammation) with predictions of brain age in a cohort of community-dwelling older adults, the Healthy Brain Project of the Health Aging and Body Composition study (N = 268, age 79 to 92, 58% women, 40% black). In this cohort, the predictions of brain age were modest (predicted-observed correlations < .30, mean absolute errors > 4.9 years). Adjusting for chronological age, sex, race, education, smoking status, medication use, and MRI quality, there were significant sex and race differences in predicted brain age, with men and whites having older-looking brains than women and blacks (β’s > .23 and .55, respectively). Only circulating interleukin-6(IL-6), a marker of systemic inflammation, was associated with greater brain age in both models (β’s > .12, p’s < .05). Markers of dyslipidemia (triglycerides, high-density lipoprotein) were associated with brain age in one of the two models (β = .12, p < .05 and β = -.22, p = .001, respectively). These findings extend prior research on midlife brain aging and suggest that systemic inflammation may relate to accelerated brain aging in late life, but associations with other risk factors are not as consistent. 

25Investigating Non-Canonical SUMF1 in Alzheimer’s Disease with Psychosis

Presented by Tiffany Ku, MS
Research Mentor: Robert Sweet, MD

Introduction: In Alzheimer’s disease (AD), genetic factors play a crucial role in the development of psychotic symptoms, as demonstrated by a recent Genome-Wide Association Studies linking an alternate (non-canonical) transcript of sulfatase modifying factor 1 (SUMF1) to AD with psychosis. The role of non-canonical SUMF1 in the brain and in the pathogenesis of psychosis in AD patients remains unexplored. This study aims to uncover non-canonical SUMF1‘s role by investigating its expression in HEK293T cells and exploring its potential involvement in AD with psychosis.

Methods: By utilizing western blotting on overexpression of non-canonical SUMF1, we confirmed its presence. Antisense oligonucleotides (ASOs) targeting the non-canonical SUMF1 mRNA are designed and optimized. Then, using qPCR method, we quantified the expression levels of both canonical and non-canonical SUMF1 after lipofectamine transfection of HEK293T cells with ASOs.

Results:We identified the overexpression of non-canonical SUMF1 in HEK293T cells through western blotting. We identified two ASOs from exon13, that selectively knock down the non-canonical SUMF1 while not affecting the canonical form (ASO1, p=0.01; ASO2, p=0.000002). Finally, in the context of neuronal maturation from iPSCs, our findings indicated that the non-canonical SUMF1 exhibited its peak expression around day 54.

Conclusions: These findings may pave the way for a better understanding of the molecular mechanisms underlying AD with psychosis and offer new avenues for developing therapeutic interventions targeting SUMF1-related pathways. Further investigation is warranted to unravel the intricacies of non-canonical SUMF1, including whether it interacts with canonical SUMF1 to alter its function. 

26APOE Stratified Genome-Wide Meta-Analysis of Cognitive Decline across Neurocognitive Domains in Older Adults

Presented by Vibha Acharya, PhDc
Research Mentor: M. Ilyas Kamboh, PhD

Abstract

APOE, one of the robust genetic risk factors for AD, has also been associated with cognitive decline, especially with the decline of memory, executive function, and global cognitive function. APOE genotype stratified analysis can help to identify other genetic loci which might be masked due to strong effect of APOE 4. Hence, APOE genotype stratified (APOE23/22, APOE33, APOE34/44) genome-wide meta-analyses  was conducted using slopes across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function derived from ~3,000 individuals aged 65 and above leveraging three longitudinal cohorts: Gingko Evaluation of Memory (GEM), Monongahela-Youghiogheny Heathy Aging Team (MYHAT), and Monongahela Valley Independent Elders Survey (MoVIES). A linear mixed effect model was used to determine the individual cognitive domain change across time by using baseline age, education, and sex as covariates. APOE genotype stratified genome-wide association analyses were then conducted using common and low frequency variants ( ≤1 % minor allele frequency) for each cognitive phenotype adjusting for four genetic principal components in each cohort and later meta-analyzed using inverse-variance method in METAL software. In the APOE 33 group, we identified a novel genome-wide significant (GWS) signal for decline of global cognitive function on Chr6q12 (β= -0.507; P=1.44E-09). A previously described novel signal for decline of attention on Chr9q21.32 in this sample without APOE genotype stratification (PMID: 37089073) was found to be confined in the APOE 33 group at GWS level (β= -0.288; P=9.95E-09). In the APOE 34/44 individuals, we observed a second novel signal for decline of language on Chr5q23.1 (β= 0.693; P=3.79E-08). In conclusion, the APOE genotype stratified GWAS analyses have enabled us to identify additional novel signals associated with cognitive decline in older adults. 

27GRK2 Activity Promotes Aβ Generation by Altering GPR3 Signaling and Intracellular Trafficking

Presented by William Lu, BS
Research Mentor: Amantha Thathiah, PhD

Background: Biased G protein-coupled receptor (GPCR) signaling preferentially activates G protein- or β-arrestin-mediated signaling pathways and presents opportunities to develop more selective and safer therapeutics but remains largely unexplored in Alzheimer’s Disease (AD). Recently, we developed a G protein-biased GPR3 AD mouse model, which does not recruit β-arrestin 2, that displays reduced amyloid-β (Aβ) pathology without adverse cognitive effects associated with elimination of both G protein and β-arrestin signaling.

Methods: We investigated how G protein-biased GPR3 signaling ameliorates Aβ accumulation in amyloid precursor protein-expressing HEK293 cells (HEK-APP) using biochemical and immunocytochemical methods.

Results: We first validated that biased GPR3 signaling reduces Aβ generation in HEK-APP cells. To gain mechanistic insight into how biased GPR3 affects Aβ generation, we determined that biased GPR3 displays reduced binding to APP relative to wild-type GPR3. We also found that, in contrast to APP, biased GPR3 exhibits reduced localization to Golgi. To explore how GPR3 phosphorylation by GPCR kinases (GRKs) may influence GPR3 signaling, we determined that Grk2 deficiency leads to reduced β-arrestin 2 recruitment to GPR3 and decreased Aβ generation in HEK-APP cells. Further pharmacological studies reveal that inhibition of GRK2 activity replicated the effect of Grk2 deficiency on Aβ generation in both HEK-APP cells and familial AD neurons.

Discussion: These results suggest that inhibition of GRK2 activity may play a similar role as G protein-biased GPR3 in reducing Aβ generation. Future studies will further elucidate how GRK2 activity impacts GPR3-mediated Aβ generation and could reveal novel targets for the development of AD therapies.

28Dignity in People with Dementia: A Concept Analysis

Presented by Yuchen Zhang, RN, BSN
Research Mentor: Jennifer Seaman, PhD, RN

Background: Dignity is a core human value with nebulous nature that can serve as a guiding principle for healthcare delivery. Alzheimer’s disease and related dementias (ADRD) are chronic neurodegenerative diseases that lead to progressively worsening capacities, which increases vulnerability in people with dementia (PwD) when receiving inappropriate or insufficient care that compromise dignity. Considering the increased prevalence of ADRD and continuously escalating care-related costs, establishing a productive dignity-driven, value-based guideline for dementia care not only preserves personhood of PwD but also prevents unnecessary suffering and promotes general quality of life (QoL).

Method: We conducted a concept analysis using Walker and Avant’s eight-step process. A comprehensive search was conducted using the PubMed and CINAHL databases and searching the keywords “dignity”, “dementia”, “Alzheimer’s disease”, and “dementia care”.

Results: 39 out of 4,910 found articles were identified and utilized for this concept analysis. The concept of dignity in PwD is operationalized as the promotion of worthiness and the accordance of respect that allow the presence and expression of a person’s sense of self with autonomy, regardless of health status. Specific antecedences are empowerment, non-maleficence, and adaptive environmental scaffolding. As the consequence of facilitating dignity in PwD, their QoL is enhanced.

Discussion: This concept analysis yields actionable targets for facilitating dignity among PwD who have potential capacities to live dignified lives with appropriate external supports. As a foundational and necessary value in humanity, the incorporation of dignity in dementia care has potential to promote efficient and effective care that optimizes the QoL for PwD throughout their disease progression.