2022 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 Drug Development Psychosocial Public Health Translational

On campus Poster Session on June 16th

All live interactions will take place with presenters at the Poster Session on campus at the William Pitt Union, Lower Lounge on 6/16; register to attend via the event page.  Please note that to allow for maximum space around posters during the in-person sessions, the poster sessions are divided between odd-numbered and even-numbered posters; you will note this arrangement under the Poster Sessions below.

1Reducing MRI Inter-Scanner Variability Using 3D Superpixel ComBat.

Presented by Chang-Le Chen, MS
Research Mentor: Dana Tudorascu, PhD

Background: Aggregating structural MRI data across sites enables us to address the biological heterogeneity in Alzheimer’s disease. However, inter-scanner variability hinders the direct comparability of multi- site/scanner MRI data. We aim to explore the feasibility of extending a statistical harmonization method called ComBat to the voxel level; we propose a framework that incorporates ComBat on three- dimensional superpixels, improving the computational efficiency and stability of harmonization.

Methods: Eighteen subjects (10 patients with Alzheimer’s disease and 8 controls; age: 68.0 [9.3] years; 10 females) participated in this study. For each subject, T1-weighted images were acquired on each of four 3T scanners with different manufacturers or models. After the standard image preprocessing including two-step registration, the individuals’ cross-scanner unharmonized scans (Raw images) were parcellated into ten-thousands of superpixels based on local contrasts, and then ComBat was applied to each superpixel to harmonize voxel-wise signal distributions. The harmonized scans were used to estimate gray matter volume and cortical thickness by employing voxel- and surface-based morphometries, and the coefficients of variation of neuroanatomical measures were calculated to evaluate the harmonization performance.

Results: The harmonized images provided similar contrasts across scanners compared to the Raw images in visual inspection. The structural similarities between harmonized brain tissue maps were significantly improved across scanners (p < 0.001). Also, our method can significantly reduce the coefficients of variation in terms of volumetric and cortical thickness measures (both p-values < 0.001).

Conclusion: The proposed harmonization approach can significantly reduce the inter-scanner variation and improve the structural similarities between cross-scanner brain scans.

 3Emotional impacts on care partners of patients receiving results of biomarker testing for Alzheimer’s disease.

Presented by Rеbеkаh Chеոg
Research Mentor: Jennifer Lingler, PhD, CRNP

Introduction: With new developments in the identification and prevention of early signs of Alzheimer’s disease, we examined the emotional burden on care partners regarding disclosure of biomarker testing results.

Methods: Qualitative interviews were conducted with 33 pairs of amyloid PET scan recipients and care partners. These pairs were assigned to the scan group of a randomized controlled trial. After disclosure of their PET scan results, patients and care partners were separated and individually interviewed to assess changes in lifestyle, healthcare, and perspective toward the future, as well as give participants space to elaborate on their emotions and provide feedback regarding the test and disclosure process.

Results: Themes that emerge from this data include acceptance of scan result implications on risk factors for Alzheimer’s disease from the care partner perspective and insight regarding best practices for test result disclosure. Furthermore, this data suggests that care partners play an important role in decisions related to lifestyle changes after receiving test results.

Discussion: These findings implicate the importance of care partners in the process of identifying biomarkers and preparing patients for treatment of chronic illness. They suggest the importance of identifying supportive factors and counseling for both patients and care partners before, during, and after medical testing. Findings demonstrate a risk of disproportionate focus on possible benefits of testing among amyloid scan candidates and suggest a need to clearly emphasize the limitations of amyloid PET when counseling cognitively impaired patients and their families before testing. Future research should focus on key factors contributing to care partner burden.

 5Sex Moderates the Relationship between Functional Connectivity and Remission in Late-life Depression.

Presented by Andrew Gerlach, PhD
Research Mentor: Carmen Andreescu, MD

Background: Given the high prevalence of depression and aging population, modest success rates of treatment in late-life depression (LLD) are a growing concern. Neuroimaging may identify biomarkers of treatment response, though sex differences are inadequately addressed.

Methods: Resting state fMRI scans at baseline and one day after commencing antidepressant treatment were collected from 81 participants with LLD. Differential FC was calculated by subtracting the region-to-region baseline FC from the day 1 FC. Edgewise differential FC, demographics, and clinical variables were entered in a random forest model. This model was repeated for males and females separately and combined. Models were assessed with area under the curve metrics, and predictive value of the connectivity features was evaluated by Gini importance.

Results: Sensitivity and specificity of remission prediction were significantly increased by fitting separate models for males and females. Further, the connectivities carrying predictive importance for males and females differed substantially. Collpasing the connectivities to region-wise summaries revealed a more substantial role for the parietal lobe in females and temporal lobe in males, while the frontal regions and caudate carried predictive importance for both sexes.

Conclusions: Early FC indicators of antidepressant treatment response in LLD differ fundamentally between males and females, and overall prediction is significantly improved when considering males and females separately. Simply including sex as a covariate in the model is insufficient to capture these difference, as there is a clear moderating effect of sex. Separate models for males and females or interaction terms may be necessary to provide sufficient sensitivity and specificity.

 7Exploratory Analysis of the Influence of Individual Characteristics on Trust in Clinical Researchers within African American Community.

Presented by Coco (Yue) Dong, BSN
Research Mentor: Jennifer Lingler , PhD, CRNP

Background/Purpose: Despite African American adults being disproportionately impacted by Alzheimer’s disease (AD), researchers face significant challenges in recruiting such individuals due, in part, to a long-standing history of distrust in clinical researchers. While distrust is a well-established barrier to research participation, little is known of which individual-level factors influence trust in researchers among African Americans. This secondary analysis examined the association between participant characteristics and trust in researchers.

Methods: Data were extracted from 500 African American respondents to the survey of Recruitment Innovations for Diversity Enhancement in AD research study, including sociodemographic characteristics, family history of AD, perceived personal risk of AD, and trust that was measured by Trust in Medical Researchers Scale. Multiple linear regression model was performed to examine factors associated with trust in researchers.

Results: Participants were predominately female (77%) and most (73%) reported being either divorced, widowed, separated, or single. After adjusting for age, sex, education, and AD family history, we found that individuals who had previous research experience had higher trust than those who had not (β=1.84, P=0.007); Participants reporting having enough income to meet their basic needs had higher trust than those who did not (β=1.66, P=0.08).

Conclusion: In our analyses, previous participation in research and financial well-being emerged as the main individual-level factors impacting trust among African Americans. Efforts to tailor recruitment to enhance diversity in AD research should therefore focus on building trust, particularly with those who have limited research experience or maybe financially struggling.

 9Low sleep efficiency is associated with greater white matter hyperintensity burden in individuals without dementia or significant cortical atrophy.

Presented by Kristine Wilckens, PhD
Research Mentor: Ann Cohen, PhD

Background: Preliminary evidence suggests that poor sleep is associated with both cerebrovascular disease and Alzheimer’s disease pathology. However, it is unclear whether associations between sleep and cerebrovascular disease depend on extent of Alzheimer’s disease pathology. Addressing this question is important to identify the individuals in which sleep interventions may be most effective for mitigating cerebrovascular disease.

Aim: Test cross-sectional associations between actigraphically-assessed sleep time and sleep efficiency and white matter hyperintensities among individuals characterized on amyloid-beta (Aβ).

Method: 47 participants with normal cognition or mild cognitive impairment (MMSE > 24) completed a 11C-PiB- positron emission tomography to assess Aβ status (29 Aβ negative and 18 Aβ positive) and a T2-weighted magnetic resonance imaging scan for white matter hyperintensities. Partial correlation analyses were controlled for age and sex.

Results/Conclusions: Across all participants, there were no significant associations between sleep efficiency and white matter hyperintensities. Analyses stratified by Aβ status demonstrated significant associations between higher sleep efficiency and lower white matter hyperintensities in Aβ negative participants, across the whole brain, r=0.48, p = 0.014, and in periventricular, r= 0.50, p = 0.010, and bilateral temporal regions, r’s > 0.4, p < 0.05. In Aβ positive participants, there were no significant associations between sleep and white matter hyperintensity burden. We conclude that sleep may be more related to cerebrovascular disease in individuals at low risk for Alzheimer’s disease, or before Aβ pathology develops. Future studies should examine these associations in Aβ positive individuals with a broader range of cognitive impairments and dementia.

 11Discreet protein networks mediate age-related loss of large dendritic spines in the precuneus.

Presented by Josh Krivinko, MD
Research Mentor: Robert Sweet, MD

Background: Dendritic spine density (DSD) loss in neocortical areas is a correlate of cognitive decline in Alzheimer Disease (AD), while preservation of DSD in subjects containing AD-related pathology is associated with cognitive resilience. Because aging is itself associated with DSD loss, identifying upstream mediators of DSD may facilitate development of pharmacotherapies which enhance cognitive resilience and prevent dementia onset.

Method: The right precuneus was isolated postmortem from 98 subjects, ages 20-96 years, none of whom had a documented neurocognitive disorder. DSD was estimated by detecting spinophilin and actin colocalization with immunohistochemistry and confocal microscopy. Protein abundance in homogenate and synaptosome fractions was quantified by liquid chromatography/mass spectrometry. Correlated protein networks were generated with Weighted Gene Co-expression Network Analysis and proteins which mediated the effect of age on DSD were identified with mediation analysis. Gene ontology term enrichment within protein networks was evaluated in WebGestalt.

Result: The density of large dendritic spines negatively correlated with age (Pearson R=-0.36, p<0.001). 1839 of 5032 proteins in homogenate and 914 of 4754 proteins in synaptosomes were correlated with age (q<0.05). Proteins segregated into 19 network modules; five modules mediated the effect of age on DSD. Modules which mediated the effect of age on DSD were enriched for “positive regulation of excitatory postsynaptic potential” (enrichment=11.0, p=0.034), “neurotransmitter transport” (enrichment=3.9, p=0.003) and “myelination” (enrichment=21.5, p=<0.001).

Conclusion: The density of large dendritic spines declines linearly with age within the precuneus. Network analysis revealed a novel role for myelination in DSD loss, nominating a potential target to augment cognitive resilience during aging.

 13Optimization of Protocols for Producing iNSCs and Neurons from Common Marmoset Dermal Fibroblasts via hSOX2 and Small Molecule Treatment.

Presented by Stephanie Hachem
Research Mentor: JungEun Park, PhD

Abstract
Alzheimer’s disease (AD), the most common form of dementia in older adults, affects over 50 million people worldwide. The primary symptoms of AD are memory loss, cognitive impairment, mood/behavioral changes, and death. Despite intensive research, AD pathology is still poorly understood, and, to date, there is no cure. There’s a strong need to identify better animal models to bridge the translational gap and identify potential treatments. We hypothesize that the common marmoset (Callithrix jacchus) is the ideal non-human primate model for AD. We used CRISPR/cas9 gene-editing techniques to engineer marmosets harboring mutations in the presenilin-1 gene that causes familial AD in humans. Compared to age/sex-matched wild-type non-carrier marmosets, these animals express elevated plasma levels of beta-amyloid (Ab). In the present work, we want to develop in vitro neuronal cultures as a testbed for AD phenotypes and therapies without the cost and time of in vivo research. Like induced pluripotent stem cells derived from somatic cells, induced neuronal stem cells (iNSCs) can generate neuronal cultures, but with less non-neuronal tumorigenic potential. We optimized a protocol to produce iNSCs from fibroblasts by treating WT and AD marmoset fibroblasts with human SOX2 lentivirus and small molecules. The iNSCs had clustered or dendritic morphologies and were positive for the iNSC markers SOX2, NESTIN, and PAX6. Our next steps are to achieve higher iNSC confluencies and characterize iNSCs and their derived neurons for AD phenotypes. This work will allow the testing of disease mechanisms and extend the usefulness of marmosets as translational AD models.

 15G protein-coupled receptor kinases modulate tau phosphorylation and optogenetic tau aggregation.

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

Abstract
Aggregation of the hyperphosphorylated tau protein in neurofibrillary tangles (NFTs) is a pathological hallmark of Alzheimer’s Disease (AD) brains. Several kinases contribute to the pathological phosphorylation of tau; however, kinase-targeted therapies for AD have failed in clinical trials due to low efficacy and severe side effects. Critically, kinases responsible for numerous identified tau phosphorylation sites remain unknown. G protein-coupled receptor (GPCR) kinases (GRKs) have been implicated in neurological disorders, such as Parkinson’s Disease, via phosphorylation of non-GPCR substrates, e.g., α-synuclein. Previously, we characterized the expression profile of the GRKs in the human brain and showed that two members of this family, GRKs 2 and 3, are abundantly expressed in neurons, positively correlated with tau levels, and associated with NFTs in the AD brain. These findings provided a significant premise for the putative involvement of GRKs 2 and 3 in neuronal tau phosphorylation and aggregation. We used an inducible optogenetic system (optoTAU) to control the expression and temporal aggregation of tau. We show that optoTAU aggregation is reduced in HEK293 cells following genetic deletion of Grk2 or Grk3. Interestingly, GRK2 overexpression, but not GRK3, increases tau aggregation and phosphorylation (pTau). In turn, Grk3 knockout significantly decreases pTau levels. Lastly, dual pharmacological inhibition of GRKs 2 and 3 substantially decreases pTau levels in HEK293 cells and differentiated human neurons. Collectively, these studies causally implicate GRKs 2 and 3 in tau pathogenesis and support further investigation of targetable mechanisms through which these GRKs may differentially impact tau phosphorylation and aggregation in AD.

 17DNA damage increases secreted Aβ40 and Aβ42 in neuronal progenitor cells: relevance to Alzheimer’s Disease.

Presented by Starr Welty, PhD
Research Mentor: Arthur Levine, MD

Background: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s Disease (AD).

Objective: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation.
Methods: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 and Aβ42. Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology.

Results: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 hours after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 hours and 4 hours after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons.

Conclusion: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD.

2University of Pittsburgh Brain Bank for Contact Sports Participants.

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

Abstract
Contact sports players are at increased risk for developing progressive psychiatric and neurocognitive deficits later in life. Autopsies of many of the symptomatic individuals have shown accumulation of hyperphosphorylated tau in the cortical sulci of the brain with perivascular accentuation. Collectively, this combination of progressive neurocognitive decline and tau pathology has been termed chronic traumatic encephalopathy (CTE). To date, the study of CTE has been limited by overall small sample size, significant selection bias for symptomatic individuals, and second-hand collection of head injury exposure. To further our understanding of this emerging neurodegenerative disease, longitudinal cohort studies are needed to examine the incidence of CTE pathology in retired contact sports players with and without cognitive and psychological symptoms. To address this goal, we aim to create a database to collect and share extensive epidemiological and clinicopathological data for a non-selective cohort of retired contact sports players. We have selected surveys to collect pre-mortem data on head injury exposure, medical history, and cognitive and behavioral measures directly from study participants, as well as annual surveys to track the development and progression of clinical symptoms. These surveys will be administered through the Research Electronic Data Capture (REDCap) system. Study participants will be asked to consider provisional consent for brain donation, and when possible, a full neuropathologic exam will be performed to correlate with the clinical and historical findings. The results of this study will help to clarify the clinical significance of the pathologic findings in patients with a history of repetitive head trauma in both symptomatic and asymptomatic populations.

4Sex Differences in Amyloid Deposition using Rectilinear Neural Networks.

Presented by Linghai Wang, BS
Research Mentor: Howard Aizenstein, MD, PhD

Background: Amyloid deposition is a biomarker of prodromal Alzheimer’s disease that can be measured by the Pittsburgh compound B (PiB) PET. In this study, we use artificial neural networks to investigate the relation between sex, age, education, and White Matter Hyperintensities using a data driven approach.

Method: Older adults without dementia were recruited from the community for this longitudinal neuroimaging study (n=124, age 65-95, 67.2% female). We use the voxel counts of regional WMH, age, one-hot encoded sex, and education to predict the regional PiB using a multilayer perceptron network. We project the gradients from each layer onto the inputs to compute a percentage contribution for each variable. These values are averaged for all inputs in the test set to evaluate the contribution of each variable. To compensate for the sex imbalance in the dataset we compared the results when oversampling males and undersampling females.

Results: When comparing the two resampling methods we found there was no significant difference between model accuracy and feature relevances. With every feature included, we found that variables that contributed the most to the final prediction were being female (21%), followed by age (16%), being male (12%), education (9%), and finally WMH (average 4%). Being female was significantly higher than all other variables.

Conclusions: We believe that the predictive contribution of being female seems to support the hypothesis that sex is important in the accumulation of amyloid. The contribution of age with amyloid has been extensively studied in the literature and is reflected in our results.

6Late-life worry and amyloid burden: a role for stressor-evoked brain networks.

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

Introduction: Worry is a transdiagnostic symptom common to many neuropsychiatric disorders and implicated in Alzheimer’s disease. Worry has been linked to preclinical amyloid burden, yet the pathways underlying this link are not well understood. The present study examined stressor-evoked brain networks and cardiovascular reactivity as potential pathways linking worry to amyloid burden.

Methods: Eighteen amyloid-negative older adults (age 60 to 80), stratified on worry severity, underwent positron emission tomography and functional magnetic resonance imaging. We examined associations of worry severity and amyloid burden with brain activation, effective connectivity, and cardiovascular reactivity to a cognitive stressor task. Multivariable regression analyses accounting for age and sex examined associations within a priori brain regions of interest.

Results: Greater worry severity was associated with greater amyloid burden in the anterior cingulate cortex but was not associated with global amyloid burden. Greater worry severity was associated with greater stressor-evoked activity in the right amygdala, as well as greater effective connectivity between bilateral anterior insula and several brain regions, including the amygdala, hippocampus, anterior cingulate cortex, and periaqueductal gray. By contrast, global amyloid burden was associated with greater stressor-evoked activity in the right amygdala, as well as greater effective connectivity between regions including the midcingulate cortex, amygdala, and hypothalamus. Finally, neither worry severity nor global amyloid burden was statistically associated with stressor-evoked cardiovascular reactivity.

Conclusions: These preliminary findings suggest that late-life worry and preclinical amyloid burden relate to altered processing in brain networks important for stress appraisal and physiological regulation.

8Differences in Perceived Risk of Alzheimer’s Disease Among African Americans of Different Demographics.

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

Background/Purpose: Despite efforts to combat racial health disparities, the African American community remains disproportionately impacted by Alzheimer’s Disease (AD). Lower perceptions of one’s risk for AD has been associated with better cognitive and physical function. However, few studies focus on perceived AD risk among African Americans. The purpose of this study is to examine differences in perceived AD risk among African Americans with different sociodemographic characteristics.

Theoretical Framework: This study is a secondary analysis of data from surveys administered as part of the Recruitment Innovations for Diversity Enhancement (RIDE) in AD research study. RIDE is guided by Larkey and Hecht’s Culture-Centric Model of Health Promotion.

Methods: Data were pooled from 500 African American participants who completed an online screening for RIDE, including age, sex, education, financial status, and perceived risk of AD. Kruskal-Wallis tests were performed to examine the difference in perceived AD risk between age groups and education levels. Mann-Whitney U tests were conducted to investigate the difference in perceived risk by gender and financial status.

Results: Participants were predominately female (77%) and most (73%) reported being divorced, widowed, separated, or single. On average, the perceived risk of developing AD was 35.24 (SD=26.36) on a 100 point scale. Perceived AD risk differed significantly by age (p=0.0005) and was higher for individuals at age 40-59 (median =35) and those 60 and above (median = 45), as compared to younger adults (age 18-39, median=30). Perceived AD risk was also significantly higher among individuals who self-reported struggling to meet their basic needs as compared to those reporting no difficulty (P =0.048). No significant differences were observed by education or gender.

Conclusion: This study affirms the sentiment that African Americans are not a monolithic group by demonstrating wide variability in perceived AD risk among African American adults based on other sociodemographic factors.

10Aberrant accumulation of age- and disease-associated factors following neural probe implantation in an AD mouse model.

Presented by Steven Wellman, BS
Research Mentor: Takashi Kozai, PhD

Abstract
Alzheimer’s disease (AD) is a gradually progressive and age-dependent neurological disorder afflicted by currently unidentified causes of local inflammation, vascular abnormalities, and glial dysfunction, ultimately contributing to large-scale neurodegeneration that precedes cognitive and behavioral impairment. In some ways, brain trauma induced by neural interface technologies, such as penetrating microelectrode arrays, produces similar neuropathology while also suffering from end-stage neuron loss and tissue failure. To understand whether there may be parallel neurodegenerative mechanisms at play between device-implanted brains and those of neurological disease, we used two-photon microscopy to visualize the aggregation, if any, of age- and disease-associated factors around implanted devices in both wild-type (WT) mice and genetically susceptible AD models. With this method, we observed that device injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in both older WT and AD subjects. Furthermore, we observed a tendency for amyloid plaques near the electrode to increase in size compared to more distal plaques in aged AD mice. Interestingly, we saw that probe implantation accelerates the appearance and deposition of amyloid-like pathology even within young AD mice (2 m.o.), months before the typical phenotype onset within the AD model. Overall, these results suggest that the trauma sustained from brain implants can promote and even hasten neuropathology typically associated with age- and disease-related conditions. Future work improving our understanding of fundamental biological mechanisms occurring at the intersection of brain injury and disease will have a profound impact on development of future treatments and intervention strategies for both implantable technologies and dementia.

12Age and sex-specific neurovascular dysfunctions in Alzheimer’s disease mouse model.

Presented by Noah Schweitzer, BS
Research Mentor: Bistra Iordanova , PhD

Background: Approximately two-thirds of the people diagnosed with Alzheimer’s Disease (AD) are women. The pathways, severity and presentation of vascular contributions to cognitive impairment and dementia appear to be sex-specific. Understanding those sex differences will lead to more accurate diagnostics and better treatment of AD.

Aim: We quantified the longitudinal changes in neurovascular coupling and vascular reactivity in male and female wild-type (WT) and AD mice. We then correlate these measures with amyloid plaques and cerebral amyloid angiopathy (CAA) deposition.

Method: We injected AAV-Syn-GCaMP6f into transgenic AD mice (B6C3.Tg.APPswe-PSEN1de9, n=5 male, n=5 female, 3-16 months, and age-matched controls). We followed the longitudinal trajectory of neurovascular responses in the somatosensory cortex through whisker stimulation. In a separate experiment, we decoupled the vascular from the neuronal response by inducing hypercapnia with 10% CO2. Dual-wavelength wide-field optical imaging simultaneously recorded hemodynamic and neuronal responses. Amyloid plaques and CAA were labelled in vivo with Methoxy-04.

Results/Conclusions: We observe sex-differences in the longitudinal trajectories of vascular reactivity to hypercapnia in AD mice. Young AD females have a larger response to hypercapnia compared to males, but with aging, their vascular response diminishes quicker. The vascular response in elder AD vs. WT mice (>10 months) is also significantly decreased. As the AD mice age, we observe that plaques grow linearly whereas CAA grows exponentially. The neuronal response to whisker stimulation has a stronger decrease due to tissue plaque load, while the BOLD response has a stronger decreases from CAA accumulation.

14In situ hybridization-Informed Digital Image Analysis to Investigate Excitatory Neuron Population Loss in Alzheimer’s Disease (AD) with Psychosis.

Presented by Dana Julian, BS
PI: Research Mentor: Julia Kofler, MD

Abstract
Alzheimer’s Disease with psychosis (AD+P) affects ~50% of AD patients and is characterized by visual hallucinations and delusions. Psychotic symptoms often co-exist with other adverse symptoms such as agitation, aggression, and depression and coincide with greater functional impairment, worse general health, and increased mortality. Bulk and single cell RNASeq data has revealed an increased loss of excitatory neurons (ExN) in the dorsolateral prefrontal cortex of AD+P versus AD-P patient tissue. The goal of this study was to develop in situ hybridization (ISH) methodology to evaluate the excitatory neuron populations in AD+P postmortem human tissue and validate ISH results. We leveraged existing bulk and single cell RNASeq data to establish mRNA targets that precisely capture ExN in both AD+P and AD-P. Using a probe combination of SCL17A7/VGLUT1 to identify ExN, synaptophysin to label overall neuron populations and a nuclear counterstain for total cell numbers, we have successfully established a protocol to detect and count these cell populations within postmortem formalin-fixed, paraffin-embedded tissue sections. We are currently developing image analysis algorithms using the QuPath software of ISH whole slide images to quantify excitatory neurons loss in AD+P patient tissue and allow for automated and higher-throughput data collection. This methodology will allow us to further interrogate the cellular composition of ExN sub populations that are specifically vulnerable in AD+P that may contribute to symptoms. Understanding these subpopulations is critical to developing therapeutic targets to minimize the debilitating psychotic symptoms suffered by many AD patients.

16Number Two When Feeling Blue: Characterizing Microbiome Alterations in Mild Cognitive Impairment and Late Life Depression.

Presented by Antonija Kolobaric, BS
Research Mentor: Carmen Andreescu, MD

Background: Over 30% of patients with mild cognitive impairment (MCI) have a comorbid diagnosis of late life depression (LLD). Individuals with both MCI and LLD perform worse on cognitive assessments and have higher rates of progression to dementia when compared to nondepressed patients with MCI. Numerous studies suggest that gut microbiome plays an important role in cognitive abilities and overall wellbeing. In this project, we establish novel associations between the microbiome, cognitive impairment, and mental illness in participants with MCI and varying levels of depression. This area of research may open new therapeutic options, which is of critical importance given the low rates of response and high rates of relapse in LLD.

Methods: We collected cognitive, clinical, and demographic assessments, and stool samples from participants with MCI (N=50 not depressed, N=151 depressed). Microbial community diversity, structure, and composition was assessed using high-resolution 16S rRNA markers gene sequencing. We implemented alpha diversity analysis to characterize microbiome richness and evenness, beta diversity analysis to characterize group differences, and taxonomic analysis to identify individual taxa with different abundances between the two groups.

Results: We found that LLD comorbid with MCI is associated with significantly increased microbiome community diversity. Furthermore, we identified 20 taxa with significantly different abundances between depressed and non-depressed MCI participants, indicating a unique microbial profile in LLD

Conclusions: Our study demonstrated that LLD comorbid with MCI is associated with significant changes in the microbiome composition. These findings may aid in the development of future targeted interventions to ameliorate depressive symptoms in late life.