Kelly N.H. Nudelman
Indiana University
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Publication
Featured researches published by Kelly N.H. Nudelman.
American Journal of Medical Genetics | 2017
Emrin Horgusluoglu; Kelly N.H. Nudelman; Kwangsik Nho; Andrew J. Saykin
New 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 Alzheimers disease and Parkinsons 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.
PLOS ONE | 2014
Kelly N.H. Nudelman; Yang Wang; Brenna C. McDonald; Susan K. Conroy; Dori J. Smith; John D. West; Darren P. O'Neill; Bryan P. Schneider; Andrew J. Saykin
Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors.
Frontiers in Physiology | 2014
Kelly N.H. Nudelman; Shannon L. Risacher; John D. West; Brenna C. McDonald; Sujuan Gao; Andrew J. Saykin
Epidemiological studies show a reciprocal inverse association between cancer and Alzheimers disease (AD). The common mechanistic theory for this effect posits that cells have an innate tendency toward apoptotic or survival pathways, translating to increased risk for either neurodegeneration or cancer. However, it has been shown that cancer patients experience cognitive dysfunction pre- and post-treatment as well as alterations in cerebral gray matter density (GMD) on MRI. To further investigate these issues, we analyzed the association between cancer history (CA±) and age of AD onset, and the relationship between GMD and CA± status across diagnostic groups in the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort study. Data was analyzed from 1609 participants with information on baseline cancer history and AD diagnosis, age of AD onset, and baseline MRI scans. Participants were CA+ (N = 503) and CA− (N = 1106) diagnosed with AD, mild cognitive impairment (MCI), significant memory concerns (SMC), and cognitively normal older adults. As in previous studies, CA+ was inversely associated with AD at baseline (P = 0.025); interestingly, this effect appears to be driven by non-melanoma skin cancer (NMSC), the largest cancer category in this study (P = 0.001). CA+ was also associated with later age of AD onset (P < 0.001), independent of apolipoprotein E (APOE) ε4 allele status, and individuals with two prior cancers had later mean age of AD onset than those with one or no prior cancer (P < 0.001), suggesting an additive effect. Voxel-based morphometric analysis of GMD showed CA+ had lower GMD in the right superior frontal gyrus compared to CA− across diagnostic groups (Pcrit < 0.001, uncorrected); this cluster of lower GMD appeared to be driven by history of invasive cancer types, rather than skin cancer. Thus, while cancer history is associated with a measurable delay in AD onset independent of APOE ε4, the underlying mechanism does not appear to be cancer-related preservation of GMD.
Alzheimers & Dementia | 2018
Kelly N.H. Nudelman; Kelley Faber; Colleen M. Mitchell; Chris C. Hobbick; Tae-Hwi Schwantes-An; Catharine M. Wyss; Kristi Wilmes; Madeline Potter; K. Rose Case; Michael C. Edler; Stephen R. Dlouhy; Tatiana Foroud
the Brains for Dementia Research cohort, was aligned to hg19 using TopHat. The aligned files were QC’d and interrogated for the presence of single nucleotide polymorphisms against the reference genome (hg19). Known polymorphisms with rs# nomenclature were filtered out, along with none A/G changes. Those remaining represented potential A-to-I RNA editing sites. A number of these sites were investigated by Sanger sequencing on a total of 12 (including the original 3) DNA samples and with RNA extracted from the same five brain regions of each individual (n1⁄460) to confirm or refute the presence of RNA-editing as called by the bioinformatics pipeline. Results: The potential RNA-editing site located within the HMP19 gene locus was confirmed to be a false positive; no other individuals or brain regions tested displayed RNA-editing at this point. The sample which had displayed potential editing in the RNA-sequencing data was in fact due to a novel A/G polymorphism in the DNA that had been reflected in the RNAsequence. The potential editing site within the MEG3 gene locus, proved to be a true editing site, in accordance with previous literature. Furthermore, a number of the samples used for verification were from Alzheimer’s disease tissue, in these tissues a more variable pattern of editing was observed in comparison to control samples. Conclusions:The bioinformatics pipeline developed using the Galaxy platform and data fromRNA-sequencing data has identified numerous potential RNA-editing sites in human post-mortem brain. Our data suggest that variation in RNA-editing might be associated with disease and warrants further investigation.
Alzheimers & Dementia | 2018
Aparna Vasanthakumar; Justin Wade Davis; Kenneth Idler; Elizabeth Asque; Bridget Riley-Gillis; Sungeun Kim; Kwangsik Nho; Kelly N.H. Nudelman; Kelley Faber; Yuchen Bai; Yu Sun; Tatiana Foroud; Karol Estrada; Liana G. Apostolova; Qingqin S. Li; Andrew J. Saykin; Jeffrey F. Waring
Background: Mutations in the SPG4/SPAST gene are the major cause of hereditary spastic paraplegias (HSPs), a group of genetic disorders leading to progressive spasticity and weakness of the lower limbs. Alzheimer’s disease (AD) is a degenerative disorder of the central nervous system. Early-onset familial AD (EOFAD) accounts for 3-5% of all AD cases and denotes families in which onset is reliably before age 60 to 65 years and sometimes before age 55 years. Two SPG4/SPAST Italian families with pure HSP and AD and one Japanese family with complicated HSP and AD were previously described by our research team. Methods:Whole exome sequencing (WES), Sanger sequencing, Multiplex Ligation dependent Probe Amplification (MLPA) analysis, bioinformatics, neurological evaluation, diagnostic imaging, and pathological assessment. Results: One Italian man was diagnosed as certainly affected by slowly progressive autosomal dominant HSP, according to the Harding criteria. The age at onset of the first motor symptoms was 32 years. At 57 years, the phenotype was complicated by cognitive impairment; a diagnosis of EOFAD based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria was formulated. The case was definite Alzheimer’s disease (autopsy proven): the brain pathology showed plaques with a congophilic core and neuritic pathology. Additional four affected subjects revealed the same initial symptoms of dementia and HSP was diagnosed. Additional clinical signs, such as hearing impairment, seizures, and pes cavus, were present in the affected individuals. WES revealed in all patients a new heterozygous change in SPG4/SPAST. MLPA analysis excluded the presence of deletions/duplications in SPG4/SPAST. Bioinformatic analyses and population study confirm a pathogenetic role of such mutation. Screening of PS1, PS2, and bAPP genes did not reveal any coding mutation. No affected subject carried out APOE genotype ε4/ε3 or ε4/ε4. Conclusions: To our knowledge, this work describes the first Italian family with a new SPG4/SPAST mutation and association of a complicated form of HSP and EOFAD.
Alzheimers & Dementia | 2017
Andrew J. Saykin; Kwangsik Nho; Jingwen Yan; Kelly N.H. Nudelman; Shannon L. Risacher; Sungeun Kim; Liana G. Apostolova; Li Shen; Rima Kaddurah-Daouk
tomics and plasma proteomics data was available. The EMIF-AD biomarker discovery cohort consists of 1221 AD, MCI and control subjects, selected from the EMIF catalogue. All subjects had existing amyloid measures (CSF Ab or amyloid-PET), structural MRI and clinical data, and furthermore plasma proteomics (targeted and untargeted), CSF proteomics (targeted), metabolomics, genomics and epigenetics data were generated. For both studies univariate and multivariate statistics were utilised to identify candidate biomarkers of AD pathology (neurodegeneration and/or brain amyloid burden), rates of cognitive decline, and MCI progression to dementia. pQTL-eQTL-mQTL analyses, network/pathway analysis, andmultimodal classifiers were employed to detect multimodal signatures. Results: Initial analyses indicate that in the ANM-MMB study a serum and urine derived 15 metabolite classifier predicts MCI progression to AD with 72% accuracy, and the biological significance of the metabolites included in the biomarker panel was identified. Further analyses will examine whether a multimodal classifier is able to predict with even greater accuracy. We will then seek to replicate this in the EMIF-AD biomarker discovery study. Further analyses will also examine single and multimodal biomarker classifiers of other endophenotypes. Conclusions:These two studies could be used to identify novel and replicate previously identified single modality biomarker findings. Furthermore the impact of combining the additional modalities with these findings will be discussed. Computational and technical challenges encountered and the bioinformatics pipeline devised in the multimodal analysis of the ANMMMB cohort will be used to inform the analysis pipeline of the EMIF-AD biomarker discovery study as a replication.
Alzheimers & Dementia | 2017
Aparna Vasanthakumar; Justin Wade Davis; Kenneth Idler; Sungeun Kim; Kwangsik Nho; Kelly N.H. Nudelman; Kelley Faber; Yuchen Bai; Tatiana Foroud; Karol Estrada; Qingqin Li; Andrew J. Saykin; Jeffrey F. Waring
explore differential cerebral amyloid burden between carriers and non-carriers of APOE-Ɛ4 and Ɛ2. Linear regression model was applied to investigate the correlation between APOE allele dosage and FBB-PET. Statistical analyses and Meta-analysis were performed using SPSS and OpenMeta, respectively. In case of heterogeneity between studies, DerSimonian and Liard method was used. Results:We found a significant association between APOE Ɛ4 and SCD diagnosis [OR1⁄41.61(1.21 – 2.16); p1⁄40.001]. Meta-analysis of the present results with prior studies (n1⁄49,567), identified heterogeneity in the APOE Ɛ4 effect among series (I21⁄453%, p1⁄40.03), reaching nominal statistical significance [OR1⁄41.23 (1.01 – 1.51]; p1⁄40.05]. In addition, SCD individuals carriers of APOE-Ɛ4 presented higher risk to suffer AD than non-carriers [OR1⁄41.95(1.47 – 2.60); p1⁄42.69e-06]. Furthermore, significant differences were found in cerebral amyloid burden between carriers and non-carriers of APOE-Ɛ4 (p1⁄41.62e-05). However, APOE allele dosage only explained 9% of FBB-PET levels variation. Conclusions: Our study points out to the existence of a preclinical AD subgroup within the SCD population. We proposed that the variation in cerebral amyloid levels is partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this trait. Poster Presentation
Alzheimers & Dementia | 2017
Kelly N.H. Nudelman; Kwangsik Nho; Brenna C. McDonald; Debomoy K. Lahiri; David A. Bennett; Andrew J. Saykin
Background:Even though APP, PSEN1 and PSEN2 are major causative genes for Alzheimer’s disease (AD), they are relatively rare. We are perusing to find other novel genes in the disease progression. Since SORL1 gene was suggested in playing a protective role against amyloid beta secretion, mutation in SORL1 could be involved in the disease progression.Methods:We performed a complex genetic screening by NGS for 50 genes, including SORL1 gene. NGS data was confirmed by standard sequencing. We performed PolyPhen2, SIFT and 3D protein structure prediction for the rare mutations. Results:We found several rare probable novel SORL1variants, such as V277I, G511R, D862E, R1159Q, T1483A, G1524R and V2097I. We also detected the common A528T mutation among our patients. Most of them were predicted as possible damaging from the predictions. Conclusions: It is too early to say that these mutations in SORL1 could be involved in disease progression. Mutations in SORL1 may be involved in loss-offunction mechanisms. Previous segregation analyses revealed that rare SORL1 mutations could be also associated with early onset familial AD.
Supportive Care in Cancer | 2016
Noah R. Zanville; Kelly N.H. Nudelman; Dori J. Smith; Diane Von Ah; Brenna C. McDonald; Victoria L. Champion; Andrew J. Saykin
Archive | 2014
Kelly N.H. Nudelman; Shannon L. Risacher; John D. West; Kwangsik Nho; Vijay K. Ramanan; Brenna C. McDonald; Li Shen; Tatiana Foroud; Bryan P. Schneider; Andrew J. Saykin