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Item Association between Cardiovascular Disease and Cognitive Dysfunction in Breast Cancer Survivors(Wolters Kluwer, 2023) Von Ah, Diane; Crouch, Adele; Arthur, Elizabeth; Yang, Yesol; Nolan, Timiya; School of NursingBackground: Breast cancer survivors (BCS) may have a greater risk for cardiovascular disease [congestive heart failure (CHF) and hypertension (HTN)], which in turn, can affect cognitive dysfunction, a frequent, bothersome, and potentially debilitating symptom. Objective: The purpose of this study was to examine the relationship of cardiovascular disease on cognitive function in BCS. Methods: Baseline data from a double-blind RCT for cognitive training of BCS were examined. Early stage BCS (Stage I-IIIA) who were ≥21 years of age, completed adjuvant therapy (≥ 6 months), and reported cognitive concerns completed questionnaires and a brief neuropsychological assessment, including tests of memory, attention and working memory, speed of processing, and verbal fluency. Descriptive statistics, Pearson’s correlation coefficient and separate linear regression models for each cognitive domain were conducted. Results: 47 BCS, who were on average 57.3 (SD=8.1) years old, 58% White and had some college education (75%), completed the study. 44.7% of the BCS had cardiovascular disease (CHF or HTN). In linear regression models, cardiovascular disease was significantly related to immediate and delayed memory and attention and working memory (p<0.01–0.05). Conclusions: BCS who have cardiovascular disease may also be at a greater risk for cognitive dysfunction post-treatment. Results from this study inform both clinical practice and future research, specifically by examining the intersect between cancer, cardiovascular disease (cardiotoxicity), and cognition. Implications for Practice: Nurses should be aware that BCS with co-occurring cardiovascular disease are at higher risk for cognitive dysfunction, and work within the multidisciplinary team to optimize BCS health and function.Item Association of peripheral blood DNA methylation level with Alzheimer’s disease progression(BMC, 2021-10-15) Li, Qingqin S.; Vasanthakumar, Aparna; Davis, Justin W.; Idler, Kenneth B.; Nho, Kwangsik; Waring, Jeffrey F.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineBackground: Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Results: The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10-8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10-24), which was associated with both the slope of CDR-SB and the MCI conversion status. Conclusion: Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.Item Blood biomarkers for Alzheimer’s disease in clinical practice and trials(Springer Nature, 2023) Hansson, Oskar; Blennow, Kaj; Zetterberg, Henrik; Dage, Jeffrey; Neurology, School of MedicineBlood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also predict future development of AD dementia in patients with mild cognitive complaints. The use of such high-performing plasma p-tau assays in the clinical practice of specialist memory clinics would reduce the need for more costly investigations involving cerebrospinal fluid samples or positron emission tomography. Indeed, blood-based biomarkers already facilitate identification of individuals with pre-symptomatic AD in the context of clinical trials. Longitudinal measurements of such biomarkers will also improve the detection of relevant disease-modifying effects of new drugs or lifestyle interventions.Item Brain Activation Patterns during Visual Scene Encoding and Recognition fMRI Tasks in Early Phase Psychosis(Office of the Vice Chancellor for Research, 2015-04-17) Ayoubi, Nawead Z.; Mehdiyoun, Nicole F.; Yung, Matthew G.; Hummer, Tom; Francis, Michael M.; Breier, AlanSchizophrenia is a chronic and disabling illness that is associated with significant impairments in areas such as independent living, social functioning, and vocational functioning. Cognitive dysfunction is a core facet of schizophrenia with deficits occurring in areas of abstraction, attention, language, and memory. Episodic memory (EM) is a cognitive domain that has been shown to be impaired in schizophrenia. EM combines event-specific autobiographical experiences and information regarding the context in which events took place. Patients with schizophrenia may exhibit broad impairments in EM, with deficits occurring during encoding and retrieval with both visual and verbal tasks. There are a number of inconsistencies in the EM fMRI literature and indicating a need for first episode psychosis (FEP) versus chronic phase schizophrenia research. FEP have fewer and less severe medical comorbidities, shorter durations of antipsychotic treatment exposure, and lower severity of illness, all of which can impact data interpretation. In this study, brain activation patterns were assessed during performance of visual scene encoding and recognition fMRI tasks in FEP patients and healthy control subjects. It is hypothesized that FEP patients would demonstrate decreased activation during encoding and recognition in the main areas that mediate EM function, namely the hippocampus, prefrontal, and parietal cortices. Within the FEP group correlations can be determined by comparing brain activation patterns with cognition (Brief Assessment of Cognition in Schizophrenia [BACS]) and symptom (Positive and Negative Syndrome Scale [PANSS]) outcome measures. Results indicate that during the encoding task FEP exhibited significantly lower activation in the hippocampus and fusiform gyrus when compared to controls. During the recognition task FEP showed a significantly weaker cortical response in the posterior cingulate cortex, the precuneus, and the left middle temporal cortex when compared to controls. These results demonstrate a pattern of alteration in hippocampal, parietal, and temporal activity during EM processes in FEP. Altered hippocampal response in FEP may reflect dysfunctional binding mechanisms and less efficient encoding.Item Brain Imaging in Pediatric Cancer Survivors: Correlates of Cognitive Impairment(American Society of Clinical Oncology, 2021) Kesler, Shelli R.; Sleurs, Charlotte; McDonald, Brenna C.; Deprez, Sabine; van der Plas, Ellen; Nieman, Brian J.; Radiology and Imaging Sciences, School of MedicineItem Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-β 42/40 positivity(Springer Nature, 2024-02-10) Pyun, Jung-Min; Park, Young Ho; Youn, Young Chul; Kang, Min Ju; Shim, Kyu Hwan; Jang, Jae-Won; You, Jihwan; Nho, Kwangsik; Kim, SangYun; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineVarious plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aβ42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET-/plasma-, PET-/plasma+, PET+/plasma-, PET+/plasma+) using Alzheimer's Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET-/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET-/plasma+ showed intermediate changes between PET-/plasma- and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma- represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aβ42/40 than IA-Elc. IA-Elc showed more plasma Aβ42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET-/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.Item Cognitive Dysfunction in Older Breast Cancer Survivors: An Integrative Review(Wolters Kluwer, 2022) Crouch, Adele; Champion, Victoria; Von Ah, Diane; School of NursingBackground: Approximately 60% of the more than 3.8 million breast cancer survivors (BCSs) living in the United States are 60 years or older. Breast cancer survivors experience many symptoms including cognitive dysfunction; however, little is known regarding how age affects these symptoms. Objective: This integrative review was conducted to synthesize the literature on cognitive dysfunction in older BCSs. The purpose was to (1) describe the prevalence of objective and subjective cognitive dysfunctions and (2) examine factors associated with cognitive dysfunction in older BCSs. Methods: Whittemore and Knafl's integrative review methodology was used to examine cognitive dysfunction in BCSs 60 years or older. Results: Twelve quantitative studies were included. Up to 41% of older BCSs experienced cognitive dysfunction on neuropsychological examination, and up to 64% reported cognitive dysfunction on subjective measures pretreatment. Approximately half of older BCSs experienced cognitive decline from pretreatment to posttreatment regardless of cognitive measure. The domains most impacted were memory, executive functioning, and processing speed. Objective and subjective cognitive dysfunctions were associated with age, comorbidities, chemotherapy receipt, sleep, neuropsychological symptom cluster, frailty, and quality of life. Conclusions: Cognitive dysfunction among older BCSs was common both prior to and following treatment. Cognitive dysfunction was associated with multiple factors that are compounded in the aging population and could be detrimental to quality of life and independent living. Implications to practice: Early assessment and intervention by healthcare providers, including nurses, for cognitive dysfunction in older BCSs are essential. Future research should focus on evidence-based interventions for cognitive dysfunction incorporating the unique needs of older BCSs.Item Cognitive Dysfunction Prevalence and Associated Factors in Older Breast Cancer Survivors(Elsevier, 2022) Crouch, Adele; Champion, Victoria L.; Unverzagt, Frederick W.; Pressler, Susan J.; Huber, Lesa; Moser, Lyndsi R.; Cella, David; Von Ah, Diane; School of NursingObjectives: The purpose of this study was to examine the prevalence and factors associated with objective and subjective cognitive dysfunction in older breast cancer survivors (BCS). Materials and methods: This cross-sectional descriptive study leveraged previously collected data from older BCS (n = 335). Separate linear regression models were used to determine relationships between demographic factors (age, education), medical factors (comorbidities), disease factors (time since diagnosis, cancer stage), cancer-related symptoms (depressive symptoms, anxiety, fatigue, sleep disturbance) and cognitive dysfunction measures, including objective learning, delayed recall, attention, executive function-working memory, verbal fluency and subjective attentional function. Results: Cognitive dysfunction was prevalent with up to 18.6% of older BCS experiencing mild-moderate dysfunction (1.5 standard deviations below mean of non-cancer controls) in at least one cognitive domain. Poor to moderate subjective attentional function was reported by 26% of older BCS. More depressive symptoms were significantly related to poorer cognitive function including learning (p < .01), delayed recall (p < .05), verbal fluency (p < .001), and subjective attentional function (p < .001) but not attention and executive function-working memory. Age, education, anxiety, and fatigue were also negatively associated with cognitive function in some models (p < .05-0.001). Conclusion: Cognitive dysfunction is common among older BCS and depressive symptoms, anxiety, and fatigue are related factors. Importantly, depressive symptoms were not only related to self-report, but also to cognitive performance. Healthcare providers should be aware of and assess for related factors and cognitive dysfunction itself in older BCS even years after diagnosis and treatment thorough geriatric assessment. Future longitudinal research is needed to discern these relationships.Item Cohort study into the neural correlates of postoperative delirium: the role of connectivity and slow-wave activity(Elsevier, 2020-07) Tanabe, Sean; Mohanty, Rosaleena; Lindroth, Heidi; Casey, Cameron; Ballweg, Tyler; Farahbakhsh, Zahra; Krause, Bryan; Prabhakaran, Vivek; Banks, Matthew I.; Sanders, Robert D.; Medicine, School of MedicineBackground: Delirium frequently affects older patients, increasing morbidity and mortality; however, the pathogenesis is poorly understood. Herein, we tested the cognitive disintegration model, which proposes that a breakdown in frontoparietal connectivity, provoked by increased slow-wave activity (SWA), causes delirium. Methods: We recruited 70 surgical patients to have preoperative and postoperative cognitive testing, EEG, blood biomarkers, and preoperative MRI. To provide evidence for causality, any putative mechanism had to differentiate on the diagnosis of delirium; change proportionally to delirium severity; and correlate with a known precipitant for delirium, inflammation. Analyses were adjusted for multiple corrections (MCs) where appropriate. Results: In the preoperative period, subjects who subsequently incurred postoperative delirium had higher alpha power, increased alpha band connectivity (MC P<0.05), but impaired structural connectivity (increased radial diffusivity; MC P<0.05) on diffusion tensor imaging. These connectivity effects were correlated (r2=0.491; P=0.0012). Postoperatively, local SWA over frontal cortex was insufficient to cause delirium. Rather, delirium was associated with increased SWA involving occipitoparietal and frontal cortex, with an accompanying breakdown in functional connectivity. Changes in connectivity correlated with SWA (r2=0.257; P<0.0001), delirium severity rating (r2=0.195; P<0.001), interleukin 10 (r2=0.152; P=0.008), and monocyte chemoattractant protein 1 (r2=0.253; P<0.001). Conclusions: Whilst frontal SWA occurs in all postoperative patients, delirium results when SWA progresses to involve posterior brain regions, with an associated reduction in connectivity in most subjects. Modifying SWA and connectivity may offer a novel therapeutic approach for delirium.Item Comorbidity, cognitive dysfunction, physical functioning, and quality of life in older breast cancer survivors(Springer, 2022-01) Crouch, Adele; Champion, Victoria L.; Von Ah, Diane; School of NursingPurpose: Older breast cancer survivors (BCS) may be at greater risk for cognitive dysfunction and other comorbidities; both of which may be associated with physical and emotional well-being. This study will seek to understand these relationships by examining the association between objective and subjective cognitive dysfunction and physical functioning and quality of life (QoL) and moderated by comorbidities in older BCS. Methods: A secondary data analysis was conducted on data from 335 BCS (stages I-IIIA) who were ≥ 60 years of age, received chemotherapy, and were 3-8 years post-diagnosis. BCS completed a one-time questionnaire and neuropsychological tests of learning, delayed recall, attention, working memory, and verbal fluency. Descriptive statistics and separate linear regression analyses testing the relationship of each cognitive assessment on physical functioning and QoL controlling for comorbidities were conducted. Results: BCS were on average 69.79 (SD = 3.34) years old and 5.95 (SD = 1.48) years post-diagnosis. Most were stage II (67.7%) at diagnosis, White (93.4%), had at least some college education (51.6%), and reported on average 3 (SD = 1.81) comorbidities. All 6 physical functioning models were significant (p < .001), with more comorbidities and worse subjective attention identified as significantly related to decreased physical functioning. One model found worse subjective attention was related to poorer QoL (p < .001). Objective cognitive function measures were not significantly related to physical functioning or QoL. Conclusions: A greater number of comorbidities and poorer subjective attention were related to poorer outcomes and should be integrated into research seeking to determine predictors of physical functioning and QoL in breast cancer survivors.
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