Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study.

BACKGROUND: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. METHODS: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. RESULTS: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. CONCLUSION: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.

Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study.

BACKGROUND: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. METHODS: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. RESULTS: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. CONCLUSIONS: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6.

Validating the PROMIS cognitive function short form in cancer survivors.

PURPOSE: The Patient-Reported Outcome Measurement Information System Cognitive Function Short Form 8a  (PROMIS Cog) could provide a shorter, useful alternative to the often used Functional Assessment of Cancer Therapy - Cognition (FACT-Cog) in research and clinical care. This study aimed to determine the convergent validity and internal reliability of the PROMIS Cog in 3 separate samples of breast cancer survivors and to explore clinical cut points. METHODS: Data from three samples of breast cancer survivors were used for this secondary analysis. Convergent validity was determined by evaluating correlation strength among the derived PROMIS Cog and measures of depression, anxiety, stress, fatigue, sleep, loneliness, the FACT-Cog . Clinical cut-points for the PROMIS Cog were determined by plotting the receiver operating characteristic curves. RESULTS: 3 samples of breast cancer survivors (N = 471, N = 132, N = 90) were included. Absolute values of correlations demonstrating convergent validity ranged from 0.21 to 0.82, p's < 0.001, and were comparable to correlations with the full FACT-Cog 18 item perceived cognitive impairments (PCI) scale. ROC curve plots indicated a clinical cut off < 34 for the combined sample. CONCLUSION: The 8-item PROMIS Cog demonstrated good convergent validity and internal reliability in breast cancer survivors, comparable to the 18-item FACT-Cog PCI. The PROMIS Cog 8a is a brief self-report measure that can be easily incorporated into cancer-related cognitive impairment research designs or used in clinical settings.

Multimodal MRI examination of structural and functional brain changes in older women with breast cancer in the first year of antiestrogen hormonal therapy.

PURPOSE: Cancer patients are concerned about treatment-related cognitive problems. We examined effects of antiestrogen hormonal therapy on brain imaging metrics in older women with breast cancer. METHODS: Women aged 60 + treated with hormonal therapy only and matched non-cancer controls (n = 29/group) completed MRI and objective and self-reported cognitive assessment at pre-treatment/enrollment and 12 months later. Gray matter was examined using voxel-based morphometry (VBM), FreeSurfer, and brain age calculations. Functional MRI (fMRI) assessed working memory-related activation. Analyses examined cross-sectional and longitudinal differences and tested associations between brain metrics, cognition, and days on hormonal therapy. RESULTS: The cancer group showed regional reductions over 12 months in frontal, temporal, and parietal gray matter on VBM, reduced FreeSurfer cortical thickness in prefrontal, parietal, and insular regions, and increased working memory-related fMRI activation in frontal, cingulate, and visual association cortex. Controls showed only reductions in fusiform gyrus on VBM and FreeSurfer temporal and parietal cortex thickness. Women with breast cancer showed higher estimated brain age and lower regional gray matter volume than controls at both time points. The cancer group showed a trend toward lower performance in attention, processing speed, and executive function at follow-up. There were no significant associations between brain imaging metrics and cognition or days on hormonal therapy. CONCLUSION: Older women with breast cancer showed brain changes in the first year of hormonal therapy. Increased brain activation during working memory processing may be a sign of functional compensation for treatment-related structural changes. This hypothesis should be tested in larger samples over longer time periods. GOV IDENTIFIER: NCT03451383.

Impact of taxane-based chemotherapy among older women with breast cancer on cognition and quality of life: a longitudinal pooled analysis.

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 were 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 were 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.

Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study.

PURPOSE: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant therapy and tumor aggressivity in older breast cancer patients. METHODS: Women diagnosed with non-metastatic breast cancer (n = 705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score < 54 or having 2 tests < 1.5 SD or 1 test < 2 SD from the mean APE or LM domain score). RESULTS: HER2 positivity and the hormone receptor negative/HER2 + molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values < .05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM. CONCLUSIONS: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.

Loneliness and mental health during the COVID-19 pandemic in older breast cancer survivors and noncancer controls.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had wide-ranging health effects and increased isolation. Older with cancer patients might be especially vulnerable to loneliness and poor mental health during the pandemic. METHODS: The authors included active participants enrolled in the longitudinal Thinking and Living With Cancer study of nonmetastatic breast cancer survivors aged 60 to 89 years (n = 262) and matched controls (n = 165) from 5 US regions. Participants completed questionnaires at parent study enrollment and then annually, including a web-based or telephone COVID-19 survey, between May 27 and September 11, 2020. Mixed-effects models were used to examine changes in loneliness (a single item on the Center for Epidemiologic Studies-Depression [CES-D] scale) from before to during the pandemic in survivors versus controls and to test survivor-control differences in the associations between changes in loneliness and changes in mental health, including depression (CES-D, excluding the loneliness item), anxiety (the State-Trait Anxiety Inventory), and perceived stress (the Perceived Stress Scale). Models were adjusted for age, race, county COVID-19 death rates, and time between assessments. RESULTS: Loneliness increased from before to during the pandemic (0.211; P = .001), with no survivor-control differences. Increased loneliness was associated with worsening depression (3.958; P < .001) and anxiety (3.242; P < .001) symptoms and higher stress (1.172; P < .001) during the pandemic, also with no survivor-control differences. CONCLUSIONS: Cancer survivors reported changes in loneliness and mental health similar to those reported by women without cancer. However, both groups reported increased loneliness from before to during the pandemic that was related to worsening mental health, suggesting that screening for loneliness during medical care interactions will be important for identifying all older women at risk for adverse mental health effects of the pandemic.

Executive Functioning and Depressive Symptoms After Cancer: The Mediating Role of Coping.

OBJECTIVE: Cognitive difficulties are a common complaint among patients with breast cancer and may adversely affect psychological well-being. In particular, problems with executive functioning (EF) may interfere with coping, which is known to influence depressive symptoms. The current study was designed to examine correlations between EF, coping, and depressive symptoms in breast cancer survivors and to longitudinally test the hypothesis that coping mediates the relationship between EF and depressive symptoms. METHODS: Participants included 171 women with early-stage breast cancer assessed at the end of primary treatment with surgery, radiation, and/or chemotherapy and at 6 months, 1 year, and 2 years after treatment follow-ups as part of the Mind-Body Study. Participants completed questionnaires to assess subjective EF, approach and avoidant coping, and depressive symptoms, and neuropsychological testing was conducted to assess objective EF. Bivariate correlations were used to examine associations between EF, coping, and depressive symptoms. Mediation analyses were conducted using a bootstrapping approach (PROCESS). RESULTS: At 1 year after treatment, objective and subjective EFs were correlated with avoidant coping (r = -0.172 [p = .024] and r = 0.297 [p < .001], respectively). In longitudinal analyses, use of the avoidant strategy behavioral disengagement at 1 year mediated the association between objective (95% bootstrap confidence interval = -0.282 to -0.042) and subjective (95% bootstrap confidence interval = 0.020 to 0.254) EFs at 6 months and depressive symptoms at 2 years. CONCLUSIONS: This study highlights how problems with EF during survivorship are associated with avoidant coping and depressive symptoms. Thus, these findings identify potential cognitive and affective targets for depression intervention in this population.

The cognitive effects of endocrine therapy in survivors of breast cancer: A prospective longitudinal study up to 6 years after treatment.

BACKGROUND: After treatment of primary breast cancer, endocrine therapy (ET) is prescribed for patients with hormone receptor-positive cancers. Despite ET recommendations of 5 to 10 years of treatment, to the authors' knowledge there is little prospective study of its impact on cognitive function over an extended period of time. ET has known pharmacologic effects on the brain. Cognitive side effects are a concern for many women, with mixed findings reported in various studies. The current prospective longitudinal study examined the neuropsychological effects of ET over time, up to 6 years after treatment. METHODS: A total of 189 survivors of early-stage breast cancer enrolled in the study prior to initiating ET if prescribed, and were followed at 6 months (175 patients), 12 months (173 patients), and for 3 to 6 years (102 patients) with self-report and neuropsychological assessments. Using linear mixed models, the authors examined whether neuropsychological performance or impairment rates differed over time based on whether or not ET was received. RESULTS: The authors did not find any effect of ET on neuropsychological performance or impairment at any time point among survivors who received it compared with women who did not. However, those who participated in the 3-year to 6-year year visit demonstrated better executive function at baseline. CONCLUSIONS: In the current observational cohort study, no detrimental effect of ET on cognitive function was identified in survivors of early-stage breast cancer receiving treatment with ET compared with those who were not.

Cognitive performance in survivors of breast cancer and markers of biological aging.

BACKGROUND: Biological aging pathways accelerated by cancer treatments may be a mechanism for cognitive impairment in cancer survivors. The goal of the current study was to examine whether indicators of biological aging, namely elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter peripheral blood mononuclear cell (PBMC) telomere length (TL) would be related to cognitive function in a cohort of survivors of breast cancer. METHODS: The authors evaluated a cross-sectional sample of 94 women aged 36 to 69 years who were treated for early-stage breast cancer 3 to 6 years previously. Leukocyte DNA damage, PBMC telomerase enzymatic activity, PBMC TL, and the inflammatory marker soluble tumor necrosis factor receptor II (sTNF-RII) were determined from blood samples. Cognitive function was assessed using a neuropsychological test battery and self-report. Linear regression models examined the relationship between biological aging predictors and cognitive outcomes. RESULTS: Both higher DNA damage and lower telomerase were found to be statistically significantly related to lower executive function scores adjusting for age, body mass index, race, years from treatment, and intelligence score (standardized coefficients [B], -0.23 and 0.30; all P values <.05). In addition, lower telomerase activity was associated with worse attention and motor speed scores (B values, 0.30 and 0.24; P <.05). sTNF-RII and TL were found to be unrelated to any of the neurocognitive domains. CONCLUSIONS: The results of the current study suggest a significant association between measures of biological aging and objective measures of cognitive performance in survivors of breast cancer. Future prospective studies are needed to confirm a causal role of biological aging as a driver of declines in cognitive function after cancer treatment.

Evaluating cognitive complaints in breast cancer survivors with the FACT-Cog and quantitative electroencephalography.

PURPOSE: Targeted methods for evaluating cognitive dysfunction in breast cancer survivors are needed to effectively address this important survivorship issue. To address this need, we examined the validity of a self-report instrument (The functional assessment of cancer therapy: cognitive function; FACT-Cog) regarding correspondence with neuropsychological performance versus depression and evaluated neurophysiological biomarkers of cognition and depressed mood in a sample of breast cancer survivors several years from diagnosis. METHODS: This is a cross-sectional study sample from the prospective observational Mind Body Study. Recruited participants were breast cancer survivors at least 3 years from cancer diagnosis who were part of a longitudinal cohort, and were without current psychiatric disorder or history of a neurological or cognitive disorder at baseline (after completion of primary cancer treatment). Exploratory analysis of the FACT-Cog and quantitative electroencephalography (qEEG) were conducted, with respect to their association with neuropsychological domain scores and depressive symptoms as measured by the Beck Depression Inventory, 2nd edition (BDI-II). RESULTS: Self-reported cognitive abilities and the impact of cognitive dysfunction on quality of life were associated with memory function in addition to depressive symptoms in our sample of breast cancer survivors. qEEG measures exhibit differential patterns of association with neuropsychological performance and mood. CONCLUSIONS: Our findings indicate that perceived cognitive abilities and the impact of cognitive difficulties on quality of life are valid indicators of objective cognitive function, independent of depressive symptoms. Neurophysiological correlates of cognitive function and depressive symptoms represent promising biomarkers of these behavioral difficulties in survivorship.

Inflammation and attentional bias in breast cancer survivors.

Evidence suggests an association between inflammation and depression, although findings are mixed. Focusing on core processes in depression may clarify associated biological underpinnings. Negative cognitive bias is a key component of depression, but has not been examined in relation to inflammation. Thus, we tested the hypothesis that elevated inflammatory markers would be associated with negative attentional bias in a sample of 91 breast cancer survivors. Participants were drawn from a larger study and provided blood samples for assessment of peripheral markers of inflammation and completed questionnaires and neuropsychological testing. Attentional bias towards emotional stimuli was assessed with a dot-probe computer task using emotional (sad, happy, angry) and neutral faces. Circulating concentrations of C-reactive protein (CRP) were positively correlated with negative attentional bias (p=.03), such that women with higher CRP allocated greater attention towards sad faces. This association held when controlling for attention function and current depressive symptoms. While cross-sectional, results are consistent with research showing that inflammation heightens the salience of negative emotional stimuli, and identify a novel pathway through which inflammation may lead to depression.

A randomized controlled trial of Kundalini yoga in mild cognitive impairment.

BACKGROUND: Global population aging will result in increasing rates of cognitive decline and dementia. Thus, effective, low-cost, and low side-effect interventions for the treatment and prevention of cognitive decline are urgently needed. Our study is the first to investigate the effects of Kundalini yoga (KY) training on mild cognitive impairment (MCI). METHODS: Older participants (≥55 years of age) with MCI were randomized to either a 12-week KY intervention or memory enhancement training (MET; gold-standard, active control). Cognitive (i.e. memory and executive functioning) and mood (i.e. depression, apathy, and resilience) assessments were administered at baseline, 12 weeks and 24 weeks. RESULTS: At baseline, 81 participants had no significant baseline group differences in clinical or demographic characteristics. At 12 weeks and 24 weeks, both KY and MET groups showed significant improvement in memory; however, only KY showed significant improvement in executive functioning. Only the KY group showed significant improvement in depressive symptoms and resilience at week 12. CONCLUSION: KY group showed short- and long-term improvements in executive functioning as compared to MET, and broader effects on depressed mood and resilience. This observation should be confirmed in future clinical trials of yoga intervention for treatment and prevention of cognitive decline (NCT01983930).

Neural correlates of apathy in late-life depression: a pilot [18 F]FDDNP positron emission tomography study.

BACKGROUND: Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late-life depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross-sectional pilot study, we performed positron emission tomography scans after injection of 2-(1-{6-[(2-[18 F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([18 F]FDDNP), an in vivo amyloid and tau neuroimaging study, in patients with LLD to explore neural correlates of apathy. METHODS: Sixteen depressed elderly volunteers received clinical assessments and [18 F]FDDNP positron emission tomography scans. The cross-sectional relationship of [18 F]FDDNP binding levels with depression (Hamilton Depression Rating Scale) and apathy (Apathy Evaluation Scale) were studied using Spearman's correlation analyses because of the relatively small sample size. Age, sex, and years of education were partialed out. Significance levels were set at P ≤ 0.05. RESULTS: [18 F]FDDNP binding in the anterior cingulate cortex was negatively associated with the Apathy Evaluation Scale total (r = -0.62, P = 0.02; where low Apathy Evaluation Scale score equals greater severity of apathy). This suggests that apathy in LLD is associated with higher amyloid and/or tau levels in the anterior cingulate cortex. None of the regional [18 F]FDDNP binding levels was significantly associated with the Hamilton Depression Rating Scale total. CONCLUSION: This pilot study suggests that increased apathy in subjects with LLD may be associated with greater amyloid and/or tau burden in certain brain regions. Future studies in larger samples would elucidate the generalizability of these results, which eventually could lead to improved diagnostic and treatment methods in LLD.

Comparing the unmatched count technique and direct self-report for sensitive health-risk behaviors in HIV+ adults.

Researchers often rely on self-report measures to assess sensitive health-risk behaviors in HIV+ individuals, yet the accuracy of self-report has been questioned, particularly when inquiring about behaviors that may be embarrassing, risky, and/or taboo. We compared an anonymous reporting method - the unmatched count technique (UCT) - to direct self-report (DSR) in order to assess reporting differences for several health-risk behaviors related to medication adherence and sexual risk. Contrary to hypotheses, the UCT only produced a significantly higher estimated base rate for one sensitive behavior: reporting medication adherence to one's physician, which may have been contextually primed by our study design. Our results suggest that anonymous reporting methods may not increase disclosure compared to DSR when assessing several health-risk behaviors in HIV+ research volunteers. However, our results also suggest that contextual factors should be considered and investigated further, as they may influence perception of sensitive behavior.

Measuring cognitive complaints in breast cancer survivors: psychometric properties of the patient's assessment of own functioning inventory.

PURPOSE: Cognitive complaints are a concern for breast cancer survivors. Among various published measures for cognitive complaints, the Patient's Assessment of Own Functioning Inventory (PAOFI) is one of the few assessing a spectrum of cognitive abilities, including those most commonly reported by breast cancer survivors. This study aimed to examine the psychometric properties of the PAOFI in breast cancer survivors. METHODS: An exploratory factor analysis was conducted with a sample of breast cancer survivors (n = 189) who had completed all primary cancer treatments. Construct validity was examined by correlating factor scores with valid measures of cognitive complaints, fatigue, and quality of life. Reliability was measured by internal consistency of the items in each factor within this sample, a separate sample of breast cancer survivors with high persistent cognitive complaints (n = 72), and healthy controls (n = 63). Factor scores were compared across the three samples. RESULTS: A five-factor structure similar to the PAOFI standardization study was found, with factors related to executive functioning (accounting for most of the variance), two aspects of memory functioning, language, and motor/sensory-perceptual abilities. Factor scores highly correlated with measures of cognitive complaints, fatigue, and quality of life. Executive functioning and memory-related factors achieved adequate reliability across samples. Scores were significantly different across the three samples as expected. CONCLUSIONS: The PAOFI is a reliable and valid tool for measuring cognitive complaints in breast cancer survivors.

The effects of age and physical health on processing speed in HIV.

The impact of age and physical health on processing speed was investigated in 42 non-demented HIV+ individuals ranging in age from 30 to 75. We used the Medical Outcomes Study-HIV Healthy Survey (MOS-HIV) to measure self-reported physical health, neuropsychological tests to measure psychomotor and cognitive processing speed (Delis-Kaplan Executive Function System Trail Making Test, Grooved Pegboard Test, letter and category fluency), and a test of the foreperiod effect to measure reaction time under increasing attentional load. Results indicated that aging and worse physical health each independently contributed to slowing on different processing speed measures, while the interaction between aging and physical health did not contribute to processing speed. These findings highlight the importance of considering physical health separately from age when measuring cognitive function in HIV+ adults.

Pseudo-Resting-State Functional MRI Derived from Dynamic Susceptibility Contrast Perfusion MRI Can Predict Cognitive Impairment in Glioma.

BACKGROUND AND PURPOSE: Resting-state functional MRI (rs-fMRI) can be used to estimate functional connectivity (FC) between different brain regions, which may be of value for identifying cognitive impairment in patients with brain tumors. Unfortunately, neither rs-fMRI nor neurocognitive assessments are routinely assessed clinically, mostly due to limitations in examination time and cost. Since DSC perfusion MRI is often used clinically to assess tumor vascularity and similarly uses a gradient-echo-EPI sequence for T2*-sensitivity, we theorized a "pseudo-rs-fMRI" signal could be derived from DSC perfusion to simultaneously quantify FC and perfusion metrics, and these metrics can be used to estimate cognitive impairment in patients with brain tumors. MATERIALS AND METHODS: Twenty-four consecutive patients with gliomas were enrolled in a prospective study that included DSC perfusion MRI, resting-sate functional MRI (rs-fMRI), and neurocognitive assessment. Voxelwise modeling of contrast bolus dynamics during DSC acquisition was performed and then subtracted from the original signal to generate a residual "pseudo-rs-fMRI" signal. Following the preprocessing of pseudo-rs-fMRI, full rs-fMRI, and a truncated version of the full rs-fMRI (first 100 timepoints) data, the default mode, motor, and language network maps were generated with atlas-based ROIs, Dice scores were calculated for the resting-state network maps from pseudo-rs-fMRI and truncated rs-fMRI using the full rs-fMRI maps as reference. Seed-to-voxel and ROI-to-ROI analyses were performed to assess FC differences between cognitively impaired and nonimpaired patients. RESULTS: Dice scores for the group-level and patient-level (mean±SD) default mode, motor, and language network maps using pseudo-rs-fMRI were 0.905/0.689 ± 0.118 (group/patient), 0.973/0.730 ± 0.124, and 0.935/0.665 ± 0.142, respectively. There was no significant difference in Dice scores between pseudo-rs-fMRI and the truncated rs-fMRI default mode (P = .97) or language networks (P = .30), but there was a difference in motor networks (P = .02). A multiple logistic regression classifier applied to ROI-to-ROI FC networks using pseudo-rs-fMRI could identify cognitively impaired patients (sensitivity = 84.6%, specificity = 63.6%, receiver operating characteristic area under the curve (AUC) = 0.7762 ± 0.0954 (standard error), P = .0221) and performance was not significantly different from full rs-fMRI predictions (AUC = 0.8881 ± 0.0733 (standard error), P = .0013, P = .29 compared with pseudo-rs-fMRI). CONCLUSIONS: DSC perfusion MRI-derived pseudo-rs-fMRI data can be used to perform typical rs-fMRI FC analyses that may identify cognitive decline in patients with brain tumors while still simultaneously performing perfusion analyses.