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Browsing by Author "Nudelman, Kelly"
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Item Adult neurogenesis and neurodegenerative diseases: A systems biology perspective(Wiley, 2017-01) Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.; Medical and Molecular Genetics, School of MedicineNew neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research.Item Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort(Wiley, 2023) Polsinelli, Angelina J.; Wonderlin, Ryan J.; Hammers, Dustin B.; Pena Garcia, Alex; Eloyan, Anii; Taurone, Alexander; Thangarajah, Maryanne; Beckett, Laurel; Gao, Sujuan; Wang, Sophia; Kirby, Kala; Logan, Paige E.; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Griffin, Percy; Iaccarino, Leonardo; Kramer, Joel H.; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Soleimani-Meigooni, David N.; Rumbaugh, Malia; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Womack, Kyle; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of MedicineIntroduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Methods: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD. Keywords: early-onset Alzheimer's disease; early-onset dementia; mild cognitive impairment; neuropharmacology; neuropsychiatric symptoms; psychotropic medications.Item Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach(MDPI, 2017-08-17) Padmanabhan, Kanchana; Nudelman, Kelly; Harenberg, Steve; Bello, Gonzalo; Sohn, Dongwha; Shpanskaya, Katie; Tiwari Dikshit, Priyanka; Yerramsetty, Pallavi S.; Tanzi, Rudolph E.; Saykin, Andrew J.; Petrella, Jeffrey R.; Doraiswamy, P. Murali; Samatova, Nagiza F.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineAlzheimer’s disease (AD) is a major public health threat; however, despite decades of research, the disease mechanisms are not completely understood, and there is a significant dearth of predictive biomarkers. The availability of systems biology approaches has opened new avenues for understanding disease mechanisms at a pathway level. However, to the best of our knowledge, no prior study has characterized the nature of pathway crosstalks in AD, or examined their utility as biomarkers for diagnosis or prognosis. In this paper, we build the first computational crosstalk model of AD incorporating genetics, antecedent knowledge, and biomarkers from a national study to create a generic pathway crosstalk reference map and to characterize the nature of genetic and protein pathway crosstalks in mild cognitive impairment (MCI) subjects. We perform initial studies of the utility of incorporating these crosstalks as biomarkers for assessing the risk of MCI progression to AD dementia. Our analysis identified Single Nucleotide Polymorphism-enriched pathways representing six of the seven Kyoto Encyclopedia of Genes and Genomes pathway categories. Integrating pathway crosstalks as a predictor improved the accuracy by 11.7% compared to standard clinical parameters and apolipoprotein E ε4 status alone. Our findings highlight the importance of moving beyond discrete biomarkers to studying interactions among complex biological pathways.Item Combined neuropathological pathways account for age-related risk of dementia(Wiley, 2018-07) Power, Melinda C.; Mormino, Elizabeth; Soldan, Anja; James, Bryan D.; Yu, Lei; Armstrong, Nicole M.; Bangen, Katherine J.; Delano-Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura; Gross, Alden L.; Mungas, Dan; Widaman, Keith F.; Schneider, Julie; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia. METHODS: We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. RESULTS: At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%). INTERPRETATION: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies.Item Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls(MDPI, 2023-05-23) Nudelman, Kelly; Nho, Kwangsik; Zhang, Michael; McDonald, Brenna C.; Zhai, Wanting; Small, Brent J.; Wegel, Claire E.; Jacobsen, Paul B.; Jim, Heather S. L.; Patel, Sunita K.; Graham, Deena M. A.; Ahles, Tim A.; Root, James C.; Foroud, Tatiana; Breen, Elizabeth C.; Carroll, Judith E.; Mandelblatt, Jeanne S.; Saykin, Andrew J.; Medical and Molecular Genetics, School of MedicineBackground: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10-8), and rs78786199 (chromosome 2, p = 1.925 × 10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.Item Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology(Wiley, 2020-08-05) Nho, Kwangsik; Nudelman, Kelly; Allen, Mariet; Hodges, Angela; Kim, Sungeun; Risacher, Shannon L.; Apostolova, Liana G.; Lin, Kuang; Lunnon, Katie; Wang, Xue; Burgess, Jeremy D.; Ertekin-Taner, Nilüfer; Petersen, Ronald C.; Wang, Lisu; Qi, Zhenhao; He, Aiqing; Neuhaus, Isaac; Patel, Vishal; Foroud, Tatiana; Faber, Kelley M.; Lovestone, Simon; Simmons, Andrew; Weiner, Michael W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer’s disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N=1,440) of blood-based microarray gene expression profiles as well as neuroimaging and CSF endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid-β accumulation, especially in the entorhinal cortex region. cis-eQTL mapping analysis of CREB5 detected five significant associations (p<5x10−8), where rs56388170 (most significant) was also significantly associated with global cortical amyloid-β (Aβ) deposition measured by [18F]Florbetapir PET and CSF Aβ1-42. DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to AD. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity and learning and memory.Item Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort(Springer, 2022-10-22) Simuni, Tanya; Merchant, Kalpana; Brumm, Michael C.; Cho, Hyunkeun; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Chahine, Lana M.; Alcalay, Roy N.; Nudelman, Kelly; Foroud, Tatiana; Mollenhauer, Brit; Siderowf, Andrew; Tanner, Caroline; Iwaki, Hirotaka; Sherer, Todd; Marek, Kenneth; Parkinson’s Progression Marker Initiative Authors; Medical and Molecular Genetics, School of MedicineWe examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.Item The Longitudinal Early-onset Alzheimer’s Disease Study (LEADS): Framework and methodology(Wiley, 2021) Apostolova, Liana G.; Aisen, Paul; Eloyan, Ani; Fagan, Anne; Fargo, Keith N.; Foroud, Tatiana; Gatsonis, Constantine; Grinberg, Lea T.; Jack, Clifford R., Jr.; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; Murray, Melissa E.; Nudelman, Kelly; Rumbaugh, Malia; Toga, Arthur; Vemuri, Prashanthi; Trullinger, Amy; Iaccarino, Leonardo; Day, Gregory S.; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Rogalski, Emily; Salloway, Steve; Wolk, David A.; Wingo, Thomas S.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; LEADS Consortium; Neurology, School of MedicinePatients with early‐onset Alzheimer's disease (EOAD) are commonly excluded from large‐scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial‐ready network. LEADS will follow 400 amyloid beta (Aβ)‐positive EOAD, 200 Aβ‐negative EOnonAD that meet National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age‐matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post‐mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.Item Transcriptomic Profiling in Mild Cognitive Impairment and Alzheimer's Disease Using Neuroimaging Endophenotypes(2022-12) Bharthur Sanjay, Apoorva; Yoder, Karmen K.; Apostolova, Liana G.; Risacher, Shannon L.; Gao, Sujuan; Nudelman, KellyAlzheimer’s disease (AD) is a devastating neurodegenerative disease affecting more than 6 million Americans and 50 million people worldwide currently. It is an irreversible neurodegenerative disease which causes decline in memory, cognition, personality, and other functions which eventually lead to death due to complete brain failure. Recently there has been a lot of research that has focused on enabling early intervention and disease prevention in AD which could have a significant impact on this disease, be crucial for life management, assessment of risk for future generations, and assistance in end-of-life preparation. For a late-life complex multifactorial disease, such as AD, where both genetic and environmental factors are involved, integrating multiple layers of genetic, imaging, and other biomarker data is a critical step for therapeutic discovery and building predictive risk assessment tools. The multifactorial nature of AD suggests that multiple therapeutic targets need to be identified and tested together. Hence, we need a systems-level approach to build biomarker profiles which can be used for drug discovery and screening/risk assessment. The research presented in this dissertation focuses on utilizing a systems level approach to identify promising imaging genetics biomarkers that provide insight into dysregulated biological pathways in AD pathogenesis and identify critical mRNA measures that can be investigated further within the scope of novel therapeutics, as well as input variables in predictive models for AD risk, screening, and diagnosis. The overall research goal was the development of systems level, imaging genetics biomarker signatures to serve as tools for risk analysis and therapeutic discovery in AD. The specific outcomes of the analyses were characterization of patterns in gene expression at systems level using neuroimaging endophenotypes, and identification of specific driver genes and genotypic variants, which can inform predictive modeling for diagnosis, risk, and pathogenic profiling in AD.