Browsing by Author "McDonald, Brenna C."
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Item Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury(Elsevier, 2016-09-06) Shee, Kevin; Lucas, Alexandra; Flashman, Laura A.; Nho, Kwangsik; Tsongalis, Gregory J.; McDonald, Brenna C.; Saykin, Andrew J.; McAllister, Thomas W.; Rhodes, C. Harker; Psychiatry, School of MedicineProblems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation.Item Alterations in brain structure related to breast cancer and its treatment: Chemotherapy and other considerations(Springer US, 2013-12) McDonald, Brenna C.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, School of MedicineCognitive effects of cancer and its treatment have been a topic of increasing investigation over the past ∼30 years. Recent studies have focused on better understanding the neural correlates of these effects, with an emphasis on post-chemotherapy effects in breast cancer patients. Structural MRI studies have utilized both automated and manual approaches to quantify gray and white matter characteristics (e.g., regional volume and density) in breast cancer patients treated with chemotherapy relative to patients who did not receive chemotherapy and/or healthy controls. While most work to date has been retrospective, a small number of baseline (pre-systemic therapy) and prospective longitudinal studies have been conducted. Data have consistently shown lower gray and white matter volume and density in patients treated with chemotherapy, particularly in frontal and temporal brain regions. Host factors and/or the cancer disease process and other therapies (e.g., antiestrogen treatment) also seem likely to contribute to the observed differences, though the relative contributions of these effects have not yet been investigated in detail. These structural abnormalities have been shown to relate to subjective and objective cognitive functioning, as well as to biological factors that may help to elucidate the underlying mechanism(s). This review examines the currently available published observations and discusses the major themes and promising directions for future studies.Item Analysis of the Inverse Association between Cancer and Alzheimer’s Disease: Results from the Alzheimer’s Disease Neuroimaging Initiative Cohort(Office of the Vice Chancellor for Research, 2014-04-11) Nudelman, Kelly N. H.; Risacher, Shannon L.; West, John D.; Nho, Kwangsik; Ramanan, Vijay K.; McDonald, Brenna C.; Shen, Li; Foroud, Tatiana M.; Schneider, Bryan P.; Saykin, Andrew J.Although a number of studies support a reciprocal inverse association between diagnoses of cancer and Alzheimer’s disease (AD), to date there has not been any systemic investigation of the neurobiological impact of or genetic risk factors underlying this effect. To facilitate this goal, this study aimed to replicate the inverse association of cancer and AD using data from the NIA Alzheimer’s Disease Neuroimaging Initiative, which includes age-matched cases and controls with information on cancer history, AD progression, neuroimaging, and genomic data. Subjects included individuals with AD (n=234), mild cognitive impairment (MCI, n=542), and healthy controls (HC, n=293). After controlling for sex, education, race/ethnicity, smoking, and apolipoprotein E (APOE) e2/3/4 allele groups, cancer history was protective against baseline AD diagnosis (p=0.042), and was associated with later age of AD onset (p=0.001). Cancer history appears to result in a cumulative protective effect; individuals with more than one cancer had a later age of AD onset compared to those with only one cancer (p=0.001). Finally, a protective effect of AD was also observed in individuals who developed incident cancer after enrolling (post-baseline visit); 20 individuals with MCI and 9 HC developed cancer, while no AD patients had subsequent cancer diagnoses (p=0.013). This supports previous research on the inverse association of cancer and AD, and importantly provides novel evidence that this effect appears to be independent of APOE, the major known genetic risk factor for AD. Future analyses will investigate the neurobiological and genetic basis of this effect.Item Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults(American Medical Association, 2016-06-01) Risacher, Shannon Leigh; McDonald, Brenna C.; Tallman, Eileen F.; West, John D.; Farlow, Martin R.; Unverzagt, Fredrick W.; Gao, Sujuan; Boustani, Malaz; Crane, Paul K.; Petersen, Ronald C.; Jack, Clifford R.; Jagust, William J.; Aisen, Paul S.; Weiner, Michael W.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, School of MedicineIMPORTANCE: The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications. OBJECTIVE: To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS). DESIGN, SETTING, AND PARTICIPANTS: The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015. MAIN OUTCOMES AND MEASURES: Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression. RESULTS: The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants. CONCLUSIONS AND RELEVANCE: The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.Item Association of cancer history with Alzheimer's disease onset and structural brain changes(2014-10) Nudelman, Kelly N. H.; Risacher, Shannon L.; West, John D.; McDonald, Brenna C.; Gao, Sujuan; Saykin, Andrew J.; Department of Medical and Molecular Genetics, IU School of MedicineEpidemiological studies show a reciprocal inverse association between cancer and Alzheimer's 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 Alzheimer's 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.Item Biological Hallmarks of Cancer in Alzheimer’s Disease(Elsevier, 2019-04-16) Nudelman, Kelly N. H.; McDonald, Brenna C.; Lahiri, Debomoy K.; Saykin, Andrew J.; Medical and Molecular Genetics, School of MedicineAlthough Alzheimer’s disease (AD) is an international health research priority for our aging population, little therapeutic progress has been made. This lack of progress may be partially attributable to disease heterogeneity. Previous studies have identified an inverse association of cancer and AD, suggesting that cancer history may be one source of AD heterogeneity. These findings are particularly interesting in light of the number of common risk factors and two-hit models hypothesized to commonly drive both diseases. We reviewed the ten hallmark biological alterations of cancer cells to investigate overlap with the AD literature and identified overlap of all ten hallmarks in AD, including: 1) potentially common underlying risk factors, such as increased inflammation, deregulated cellular energetics, and genome instability, 2) inversely regulated mechanisms, including cell death and evading growth suppressors, and 3) functions with more complex, pleiotropic mechanisms, some of which may be stage-dependent in AD, such as cell adhesion/contact inhibition and angiogenesis. Additionally, we discuss the recent observation of a biological link between cancer and AD neuropathology. Finally, we address the therapeutic implications of this topic. The significant overlap of functional pathways and molecules between these diseases, some similarly and some oppositely regulated or functioning in each disease, supports the need for more research to elucidate cancer-related AD genetic and functional heterogeneity, with the aims of better understanding AD risk mediators, as well as further exploring the potential for some types of drug repurposing towards AD therapeutic development.Item Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study(ASCO, 2018-11) Mandelblatt, Jeanne S.; Small, Brent J.; Luta, Gheorghe; Hurria, Arti; Jim, Heather; McDonald, Brenna C.; Graham, Deena; Zhou, Xingtao; Clapp, Jonathan; Zhai, Wanting; Breen, Elizabeth; Carroll, Judith E.; Denduluri, Neelima; Dilawari, Asma; Extermann, Martine; Isaacs, Claudine; Jacobsen, Paul B.; Kobayashi, Lindsay C.; Holohan Nudelman, Kelly; Root, James; Stern, Robert A.; Tometich, Danielle; Turner, Raymond; VanMeter, John W.; Saykin, Andrew J.; Ahles, Tim; Radiology and Imaging Sciences, School of MedicinePurpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores (P = .05) and those initiating hormonal therapy having lower LM scores at 12 months (P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant (P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures (P < .001); frailty was associated with baseline APE and self-reported decline (P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning.Item Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy(American Society of Clinical Oncology, 2016-03-01) Nudelman, Kelly N.H.; McDonald, Brenna C.; Wang, Yang; Smith, Dori J.; West, John D.; O'Neill, Darren P.; Zanville, Noah R.; Champion, Victoria L.; Schneider, Bryan P.; Saykin, Andrew J.; IU School of NursingPURPOSE: To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment-related brain structural changes. METHODS: Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. RESULTS: Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). CONCLUSION: Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications.Item Chemotherapy, estrogen, and cognition : neuroimaging and genetic variation(2014-02-25) Conroy, Susan Kim; McDonald, Brenna C.; Saykin, Andrew J.; Chambers, R. Andrew; Miller, Kathy (Kathy D.); Yoder, Karmen K.The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.Item Chemotherapy-induced amenorrhea: a prospective study of brain activation changes and neurocognitive correlates(Springer US, 2013-12) Conroy, Susan K.; McDonald, Brenna C.; Ahles, Tim A.; West, John D.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, School of MedicineChemotherapy-induced amenorrhea (CIA) often occurs in pre- and peri-menopausal BC patients, and while cancer/chemotherapy and abrupt estrogen loss have separately been shown to affect cognition and brain function, studies of the cognitive effects of CIA are equivocal, and its effects on brain function are unknown. Functional MRI (fMRI) during a working memory task was used to prospectively assess the pattern of brain activation and deactivation prior to and one month after chemotherapy in BC patients who experienced CIA (n=9), post-menopausal BC patients undergoing chemotherapy (n=9), and pre- and post-menopausal healthy controls (n=6 each). Neurocognitive testing was also performed at both time points. Repeated measures general linear models were used to assess statistical significance, and age was a covariate in all analyses. We observed a group-by-time interaction in the combined magnitudes of brain activation and deactivation (p = 0.006): the CIA group increased in magnitude from baseline to post-treatment while other groups maintained similar levels over time. Further, the change in brain activity magnitude in CIA was strongly correlated with change in processing speed neurocognitive testing score (r=0.837 p=0.005), suggesting this increase in brain activity reflects effective cognitive compensation. Our results demonstrate prospectively that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Cognitive correlates add to the potential clinical significance of these findings. These findings have implications for risk appraisal and development of prevention or treatment strategies for cognitive changes in CIA.