Brenna McDonald - Academia.edu (original) (raw)

Papers by Brenna McDonald

Cancers, May 23, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Understanding the interrelationships of clinical manifestations of Alzheimer's disease (AD) and f... more Understanding the interrelationships of clinical manifestations of Alzheimer's disease (AD) and functional connectivity (FC) as the disease progresses is necessary for use of FC as a potential neuroimaging biomarker. Degradation of resting-state networks in AD has been observed when FC is estimated over the entire scan, however, the temporal dynamics of these networks are less studied. We implemented a novel approach to investigate the modular structure of static (sFC) and time-varying (tvFC) connectivity along the AD spectrum in a two-sample Discovery/Validation design (n=80 and 81, respectively). Cortical FC networks were estimated across 4 diagnostic groups (cognitively normal, subjective cognitive decline, mild cognitive impairment, and AD) for whole scan (sFC) and with sliding window correlation (tvFC). Modularity quality (across a range of spatial scales) did not differ in either sFC or tvFC. For tvFC, group differences in temporal stability within and between multiple resting state networks were observed; however, these differences were not consistent between samples. Correlation analyses identified a relationship between global cognition and temporal stability of the ventral attention network, which was reproduced in both samples. While the ventral attention system has been predominantly studied in task-evoked designs, the relationship between its intrinsic dynamics at-rest and general cognition along the AD spectrum highlights its relevance regarding clinical manifestation of the disease.

Springer eBooks, Oct 19, 2014

ABSTRACT Since the inception of functional magnetic resonance imaging (fMRI) in the early 1990s, ... more ABSTRACT Since the inception of functional magnetic resonance imaging (fMRI) in the early 1990s, clinicians and researchers have been interested in the potential utility of this technology for replacement of the intracarotid amobarbital test (IAT). The IAT, or Wada test, is an invasive angiographic procedure, with some potential risks, that currently serves as the conventional standard for lateralization of language, memory, and other functions. The IAT is used primarily in patients under consideration for neurosurgery to treat epilepsy, but also in other neurosurgical populations (e.g., motor cortex tumor, arteriovenous malformation in language association cortex, etc.). If a valid assessment paradigm could be created, the advantages of fMRI assessment of memory and language functions over the IAT would be obvious. Functional MRI is a repeatable, noninvasive procedure with no significant known health risks for most individuals. It is also very flexible and can be readily modified to assess the clinical questions at issue for a particular patient. In addition, a recent cost analysis demonstrated considerable savings of total direct costs for fMRI over IAT.1

$Research paper thumbnail of Methylphenidate and \u3ci\u3eMemory and Attention Adaptation Training\u3c/i\u3e for persistent cognitive symptoms after traumatic brain injury: a randomized, placebo-controlled trial$

The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluat... more The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluate and compare the efficacy of two cognitive rehabilitation interventions (Memory and Attention Adaptation Training (MAAT) and Attention Builders Training (ABT)), with and without pharmacologic enhancement (i.e., with methylphenidate (MPH) or placebo), for treating persistent cognitive problems after traumatic brain injury (TBI). Adults with a history of TBI at least four months prior to study enrollment with either objective cognitive deficits or subjective cognitive complaints were randomized to receive MPH or placebo and MAAT or ABT, yielding four treatment combinations: MAAT/MPH (N=17), ABT/MPH (N=19), MAAT/placebo (N=17), and ABT/placebo (N=18). Assessments were conducted pre-treatment (baseline) and after six weeks of treatment (post-treatment). Outcome measures included scores on neuropsychological measures and subjective rating scales. Statistical analyses used linear regression m...

Cancer, Dec 20, 2019

BACKGROUND: Little is known about longitudinal symptom burden, its consequences for well-being, a... more BACKGROUND: Little is known about longitudinal symptom burden, its consequences for well-being, and whether lifestyle moderates the burden in older survivors. METHODS: The authors report on 36-month data from survivors aged ≥60 years with newly diagnosed, nonmetastatic breast cancer and noncancer controls recruited from August 2010 through June 2016. Symptom burden was measured as the sum of self-reported symptoms/diseases as follows: pain (yes or no), fatigue (on the Functional Assessment of Cancer Therapy [FACT]-Fatigue scale), cognitive (on the FACT-Cognitive scale), sleep problems (yes or no), depression (on the Center for Epidemiologic Studies Depression scale), anxiety (on the State-Trait Anxiety Inventory), and cardiac problems and neuropathy (yes or no). Well-being was measured using the FACT-General scale, with scores from 0 to 100. Lifestyle included smoking, alcohol use, body mass index, physical activity, and leisure activities. Mixed models assessed relations between treatment group (chemotherapy with or without hormone therapy, hormone therapy only, and controls) and symptom burden, lifestyle, and covariates. Separate models tested the effects of fluctuations in symptom burden and lifestyle on function. RESULTS: All groups reported high baseline symptoms, and levels remained high over time; differences between survivors and controls were most notable for cognitive and sleep problems, anxiety, and neuropathy. The adjusted burden score was highest among chemotherapy-exposed survivors, followed by hormone therapy-exposed survivors versus controls (P < .001). The burden score was related to physical, emotional, and functional well-being (eg, survivors with lower vs higher burden scores had 12.4-point higher physical well-being scores). The composite lifestyle score was not related to symptom burden or well-being, but physical activity was significantly associated with each outcome (P < .005). CONCLUSIONS: Cancer and its treatments are associated with a higher level of actionable symptoms and greater loss of well-being over time in older breast cancer survivors than in comparable noncancer populations, suggesting the need for surveillance and opportunities for intervention.

Alzheimers & Dementia, Dec 1, 2021

BackgroundThe relationship between amyloid and tau deposition and episodic memory‐related brain a... more BackgroundThe relationship between amyloid and tau deposition and episodic memory‐related brain activity is understudied. Our goal was to determine the association between brain activation on fMRI during encoding of complex scenes and amyloid and tau deposition on PET.Methods91 individuals from the Indiana Memory and Aging Study (36 cognitively normal (CN), 27 subjective cognitive decline (SCD), 28 mild cognitive impairment (MCI)) underwent amyloid ([18F]florbetapir or [18F]florbetaben) and [18F]flortaucipir PET, structural and functional MRI, and clinical and cognitive testing. The fMRI task was a scene encoding paradigm in which the participant is asked to try to remember a set of complex scenes relative to viewing a scrambled control image. Amyloid Centiloid (CL) and tau SUVR images were generated using standard methods. Amyloid positivity was defined as global cortical CL≥21. Areas activated during the task (“main effect” (ME)) across all participants were determined (Figure 1A). Mean BOLD signals from ME regions, the entorhinal cortex (EC), and the inferior parietal lobule (IPL) were extracted. Mean cortical amyloid CL and tau SUVR from the bilateral EC, IPL, and lateral temporal lobe (LTL) were also extracted. Tau and amyloid were non‐normally distributed, so Spearman correlation models were used to evaluate the relationship of scene encoding activation and PET. Age, diagnosis, and sex were evaluated as covariates but did not change the observed pattern of results.ResultsSignificant association between tau and scene encoding activation was observed (Figure 1B). When limited to amyloid‐positive individuals only (n=28), the observed associations were considerably stronger between scene encoding activation and both amyloid CL level and tau deposition (Figure 1C‐E). Similar results were observed when limiting to the CN and SCD groups.ConclusionAmyloid and tau deposition are associated with reduced brain activity during episodic memory encoding in older adults at risk for AD. These findings suggest that brain function is another important biomarker to consider in both the temporal sequencing of biomarkers (Jack et al. 2013) and the A/T/N framework. Future studies in larger samples are warranted. Reference: Jack et al. (2013) Lancet Neurology.

medRxiv (Cold Spring Harbor Laboratory), May 14, 2023

Understanding the interrelationships of brain function as measured by resting-state magnetic reso... more Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Breast Cancer Research and Treatment, Nov 24, 2021

Purpose:Older cancer patients are susceptible to long-term effects of chemotherapy, including can... more Purpose:Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and subjective measures of cognitive performance and well-being differ among older breast cancer survivors as a function of taxane-based chemotherapy treatment regimens.Methods:Individual-level data was pooled and harmonized from two large prospective studies of older (greater than 60 years) breast cancer survivors. Assessments were conducted prior to systemic therapy and up to 36-months after. Cognitive performance was assessed with objective (working memory, processing speed and executive functions) and subjective tests and physical, emotional and functional well-being was also assessed.Results:One hundred and sixty-seven (M age = 67.3 years) women, with 116 receiving chemotherapy with taxanes and 51 without taxanes contributed data. Declines in subjective cognition for both groups were significant between pre-treatment and 12-month follow-up. Significant improvements were seen on a measure of objective cognition (working memory) from 12 to 36-months. Measures of well-being improved from prior to systemic therapy to 12-months. Longitudinal changes across all measures did not vary as a function of receipt of taxane-based treatment.Conclusion:Older women who received treatment with taxanes did not have greater declines in cognitive performance or well-being than women receiving other chemotherapy regimens. Despite older cancer survivors being at greater risk for negative outcomes, treatment with taxane-based chemotherapies does not appear to exacerbate these health consequences.

Journal of Clinical Oncology, Jun 1, 2022

Background: Cancer-related cognitive impairment (CRCI) can include persistent memory symptoms, an... more Background: Cancer-related cognitive impairment (CRCI) can include persistent memory symptoms, and affects many cancer survivors. Memory and Attention Adaptation Training (MAAT) is an evidencebased cognitive behavioral therapy (CBT) that improves CRCI with demonstrated efficacy in telehealth delivery. MAAT consists of 8 weekly (45-minute) video visits. The aims of this study are to confirm MAAT telehealth efficacy in a phase III RCT (MAAT versus Supportive Therapy; ST) across large catchment areas of two comprehensive cancer centers. A secondary aim is to evaluate treatment-induced brain activation as assessed by functional MRI (fMRI) in a subset of participants. We present remote treatment and data capture methods of this open NCI-sponsored (R01CA244673) randomized clinical trial (NCT 04586530). These methods have high success in participant accrual despite COVID-19 pandemic conditions, and can be readily adopted to other clinical trials to enhance rural/underserved enrollment. Methods: We are enrolling 200 adult, stage I-III breast cancer survivors 1-5 years post-chemotherapy with cognitive complaints. Individuals with CNS disease, previous brain injury, dementia or psychiatric disorder are excluded. All study procedures are completed from the participant's home (except fMRI). Eligibility screening is a semi-structured phone interview followed by detailed informed consent online (Research Electronic Data Capture: REDCap) with staff phone guidance. Consented participants complete baseline brief phone-based neurocognitive assessment and validated patient-reported outcome measures (PROs) of cognition and quality of life via REDCap. Participants are randomized to MAAT or ST and assigned treating clinicians at respective cancer centers. All 8 visits are completed through secure telehealth platforms, followed by repeat phone/online assessment posttreatment and again at 6 months. Enrollment began in 3/2021. As of 1/2022 (9 months), 56 participants are enrolled (28% of the planned sample), 47 randomized (MAAT 24; ST 23), with 24 completing post-treatment assessments. If all assessments and treatment visits were in person, travel burden per participant is 968 miles/20.5 hours driven, and 542(US2021Federalrate).Thus,studytravelsavingstodateare542 (US 2021 Federal rate). Thus, study travel savings to date are 542(US2021Federalrate).Thus,studytravelsavingstodateare30,352. Participant feedback indicates telehealth makes participation possible, similar to previous MAAT research. The current RCT demonstrates utility, efficiency and cost-savings of telehealth and remote data capture technology in the conduct of cancer control research. Elements of methods described can also be adopted for cancer therapeutic trials. Comprehensive cancer centers, where most clinical trials are based, can enhance participation of remote and/or underserved populations that have higher rates of cancer, more disease burden and less opportunity for trial participation. Clinical trial information: NCT04586530

Social Science Research Network, 2018

Alzheimer's disease is considered a disconnection syndrome, motivating the use of brain network m... more Alzheimer's disease is considered a disconnection syndrome, motivating the use of brain network measures to detect changes in whole-brain resting state functional connectivity (FC). We investigated changes in FC within and among resting state networks (RSN) across four different stages in the Alzheimer's disease continuum. FC changes were examined in two independent cohorts of individuals (84 and 58 individuals, respectively) each comprising control, subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia groups. For each participant, FC was computed as a matrix of Pearson correlations between pairs of time series from 278 gray matter brain regions. We determined significant differences in FC modular organization with two distinct approaches, network contingency analysis and multiresolution consensus clustering. Network contingency analysis identified RSN sub-blocks that differed significantly across clinical groups. Multiresolution consensus clustering identified differences in the stability of modules across multiple spatial scales. Significant modules were further tested for statistical association with memory and executive function cognitive domain scores. Across both analytic approaches and in both participant cohorts, the findings converged on a pattern of FC that varied systematically with diagnosis within the frontoparietal network (FP) and between the FP network and default mode network (DMN). Disturbances of modular organization were manifest as greater internal coherence of the FP network and stronger coupling between FP and DMN, resulting in less segregation of these two networks. Our findings suggest that the pattern of interactions within and between specific RSNs offers new insight into the functional disruption that occurs across the Alzheimer's disease spectrum.

Publisher, 2019

Introducion: With the increasing number of children exposed to HIV or antiretroviral therapy in u... more Introducion: With the increasing number of children exposed to HIV or antiretroviral therapy in utero, there are concerns that this population may have worse neurodevelopmental outcomes compared to those who are unexposed. The objective of this study was to systematically review the clinical and preclinical literature on the effects of in utero exposure to HIV and/or antiretroviral therapy (ART) on neurodevelopment. Methods: We systematically searched OVID Medline, PsycINFO and Embase, as well as the Cochrane Collaborative Database, Google Scholar and bibliographies of pertinent articles. Titles, abstracts, and full texts were assessed independently by two reviewers. Data from included studies were extracted. Results are summarized qualitatively. Results: The search yielded 3027 unique titles. Of the 255 critically reviewed full-text articles, 25 met inclusion criteria for the systematic review. Five articles studied human subjects and looked at brain structure and function. The remaining 20 articles were preclinical studies that mostly focused on behavioural assessments in animal models. The few clinical studies had mixed results. Some clinical studies found no difference in white matter while others noted higher fractional anisotropy and lower mean diffusivity in the brains of HIV-exposed uninfected children compared to HIV-unexposed uninfected children, correlating with abnormal neurobehavioral scores. Preclinical studies focused primarily on neurobehavioral changes resulting from monotherapy with either zidovudine or lamivudine. Various developmental and behavioural changes were noted in preclinical studies with ART exposure, including decreased grooming, decreased attention, memory deficits and fewer behaviours associated with appropriate social interaction. Conclusions: While the existing literature suggests that there may be some neurobehavioral differences associated with HIV and ART exposure, limited data are available to substantially support these claims. More research is needed comparing neurobiological factors between HIV-exposed uninfected and HIV-unexposed uninfected children and using exposures consistent with current clinical care.

PMC, Dec 1, 2014

Purpose-This study examined the association of post-treatment changes in cognitive performance, A... more Purpose-This study examined the association of post-treatment changes in cognitive performance, APOE and smoking in breast cancer patients treated with adjuvant therapy. Participants and Methods-Breast cancer patients treated with chemotherapy (N=55, age=51.9+/−7.1, education=15.7+/−2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N=68, age=56.8+/−8.3, education=14.8+/−2.2) and healthy controls (N=43, age=53.0+/−10.1, education=15.2+/−2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated. Results-The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, i.e., patients without a smoking history had significantly lower

Cancer Epidemiology, Biomarkers & Prevention, 2023

medRxiv (Cold Spring Harbor Laboratory), Sep 15, 2022

Background: There have been no published genome-wide studies of the genetics of cancerand treatme... more Background: There have been no published genome-wide studies of the genetics of cancerand 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 breast cancer 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 outcomes. CRCD was assessed using longitudinal domain scores on neurocognitive 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=1.624x10-8), and rs78786199 (chromosome 2, p=1.925x10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Genelevel analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusion: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, which play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may drive susceptibility to CRCD.

The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, Jun 1, 2011

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Alzheimers & Dementia, Jul 1, 2017

JNCI Cancer Spectrum, Jan 27, 2021

Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) ge... more Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene e4 polymorphisms. APOE e4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas e2 polymorphisms protect against AD. However, the effects of e2 polymorphisms on CRCD have not been evaluated. Methods: We evaluated nonmetastatic breast cancer survivors (n ¼ 427) and matched noncancer controls (n ¼ 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an e2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with e2/e4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any e4 positivity. Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta ¼ 0.32, 95% confidence interval ¼ 0.00 to 0.65); the chemotherapy group with an e2 allele had higher scores at baseline and maintained higher scores over time compared with those without an e2 allele, and this protective effect was not seen for other groups. There was no effect of e2 on learning and memory domain scores. Conclusions: APOE e2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.

Neurotherapeutics, Apr 1, 2021

Cancer- and treatment-related cognitive dysfunction (CRCD) is a common challenge faced by patient... more Cancer- and treatment-related cognitive dysfunction (CRCD) is a common challenge faced by patients diagnosed with non-central nervous system (CNS) cancer. It has become increasingly recognized that multiple factors likely play a role in these symptoms, including the cancer disease process, systemic treatments (e.g., chemotherapy and endocrine therapies), and risk factors that may predispose an individual to both cancer and cognitive dysfunction. As the field has evolved, advanced neuroimaging techniques have been applied to better understand the neural correlates of CRCD. This review focuses on structural neuroimaging findings related to CRCD in adult non-CNS cancer populations, including examination of gray matter volume/density and white matter integrity differences between cancer patients and comparison groups, as well as emerging findings regarding structural network abnormalities. Overall, this literature has demonstrated consistent findings of reduced gray matter volume/density and white matter integrity in cancer patients relative to comparison groups. These are most prominent in individuals treated with chemotherapy, though alterations have also been noted in those treated with anti-estrogen and androgen-deprivation therapies. Alterations in gray and white matter structural network connectivity have also been identified. These structural abnormalities have been observed most prominently in frontal and temporal brain regions, and have been shown to correlate with subjective and objective cognitive function, as well as with physiological and clinical variables, helping to inform understanding of CRCD mechanisms. To date, however, structural neuroimaging techniques have not been utilized in systematic studies of potential CRCD treatments, suggesting a potentially fruitful avenue for future research.