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 Altered Cerebral Blood Flow One Month after Systemic Chemotherapy for Breast Cancer: A Prospective Study Using Pulsed Arterial Spin Labeling MRI Perfusion(Public Library of Science, 2014-05-09) Nudelman, Kelly N. H.; Wang, Yang; McDonald, Brenna C.; Conroy, Susan K.; Smith, Dori J.; West, John D.; O’Neill, Darren P.; Schneider, Bryan P.; Saykin, Andrew J.; Medical and Molecular Genetics, School of MedicineCerebral 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.Item Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease(Elsevier, 2023) Swinford, Cecily G.; Risacher, Shannon L.; Vosmeier, Aaron; Deardorff, Rachael; Chumin, Evgeny J.; Dzemidzic, Mario; Wu, Yu-Chien; Gao, Sujuan; McDonald, Brenna C.; Yoder, Karmen K.; Unverzagt, Frederick W.; Wang, Sophia; Farlow, Martin R.; Brosch, Jared R.; Clark, David G.; Apostolova, Liana G.; Sims, Justin; Wang, Danny J.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineIdentification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.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 Associating Persistent Self-Reported Cognitive Decline with Neurocognitive Decline in Older Breast Cancer Survivors Using Machine Learning: The Thinking and Living with Cancer Study(Elsevier, 2022) Van Dyk, Kathleen; Ahn, Jaeil; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma A.; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Mandelblatt, Jeanne S.; Root, James C.; Radiology and Imaging Sciences, School of MedicineIntroduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors. Materials and methods: We enrolled breast cancer survivors with non-metastatic disease (n = 435) and age- and education-matched non-cancer controls (n = 441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline. Results: The sample of survivors and controls ranged in age from were ages 60-89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n = 60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC = 0.736) and survivors without decline (n = 147; AUC = 0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures. Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention.Item Associating persistent self-reported cognitive decline with neurocognitive decline in older breast cancer survivors using machine learning: The Thinking and Living with Cancer study(Elsevier, 2022-11) Van Dyk, Kathleen; Ahn, Jaeil; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma A.; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Mandelblatt, Jeanne S.; Root, James C.; Radiology and Imaging Sciences, School of MedicineIntroduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors. Materials and Methods: We enrolled breast cancer survivors with non-metastatic disease (n=435) and age- and education-matched non-cancer controls (n=441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline. Results: The sample of survivors and controls ranged in age from were ages 60–89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n=60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC=0.736) and survivors without decline (n=147; AUC=0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures. Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention.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 Alzheimer’s disease polygenic risk score with concussion severity and recovery metrics(Wiley, 2025-01-09) Dybing, Kaitlyn M.; McAllister, Thomas W.; Wu, Yu-Chien; McDonald, Brenna C.; McCrea, Michael A.; Broglio, Steven P.; Pasquina, Paul F.; Brooks, M. Alison; Mihalik, Jason P.; Guskiewicz, Kevin M.; Giza, Christopher C.; Goldman, Joshua; Duma, Stefan; Rowson, Steve; Svoboda, Steven; Cameron, Kenneth L.; Houston, Megan N.; Campbell, Darren E.; McGinty, Gerald; Jackson, Jonathan; Risacher, Shannon L.; Saykin, Andrew J.; Nudelman, Kelly N.; Radiology and Imaging Sciences, School of MedicineBackground: Shared genetic risk between Alzheimer’s disease (AD) and concussion may help explain the association between concussion and elevated risk for dementia. However, there has been little investigation into whether AD risk genes also associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate associations between AD genetic risk and concussion severity/recovery in the NCAA‐DoD Grand Alliance CARE Consortium (CARE) dataset. Method: There were 1,917 injuries in the dataset upon project initiation. After removing repeated injuries, related participants, and those without genetic/outcome data, we had 931 participants. Outcomes were number of days to return to play (RTP) as a recovery measure, and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated PRS using a published score (de Rojas et al., 2021) and performed a linear regression (MLR) of RTP by PRS in normal (<24 days) and long (>24 days) RTP subgroups. We then compared severity measures by PRS using MLR. Next, we used t‐tests to examine outcomes by APOE genotype in military and civilian subgroups. We also performed chi‐squared tests of RTP category (normal vs. long) by APOE genotype. Finally, we analyzed outcomes by PRS in European or African genetic ancestry subgroups using MLR. Result: Higher PRS was associated with longer injury to RTP interval in the normal RTP (<24 days) subgroup (estimate = 0.0412, SE = 0.182, p = 0.0237). 1 SD increase in PRS resulted in a 0.412 day (9.89 hours) increase to the interval. This may be clinically meaningful in the collegiate athlete environment. We did not identify any other significant differences. Conclusion: Our preliminary results provide limited evidence for an impact of AD PRS on concussion recovery, though the pattern was inconsistent and its clinical significance is uncertain. Future studies should attempt to replicate these findings in larger samples with longer follow‐up using PRS calculated from multiple/diverse populations, which will be especially relevant for diverse datasets like CARE.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.