Brenna C. McDonald

Baseline MRI Predictors of Conversion from MCI to Probable AD in the ADNI Cohort

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a multi-center study assessing neuroimaging in diagnosis and longitudinal monitoring. Amnestic Mild Cognitive Impairment (MCI) often represents a prodromal form of dementia, conferring a 10-15% annual risk of converting to probable AD. We analyzed baseline 1.5T MRI scans in 693 participants from the ADNI cohort divided into four groups by baseline diagnosis and one year MCI to probable AD conversion status to identify neuroimaging phenotypes associated with MCI and AD and potential predictive markers of imminent conversion. MP-RAGE scans were analyzed using publicly available voxel-based morphometry (VBM) and automated parcellation methods. Measures included global and hippocampal grey matter (GM) density, hippocampal and amygdalar volumes, and cortical thickness values from entorhinal cortex and other temporal and parietal lobe regions. The overall pattern of structural MRI changes in MCI (n=339) and AD (n=148) compared to healthy controls (HC, n=206) was similar to prior findings in smaller samples. MCI-Converters (n=62) demonstrated a very similar pattern of atrophic changes to the AD group up to a year before meeting clinical criteria for AD. Finally, a comparison of effect sizes for contrasts between the MCI-Converters and MCI-Stable (n=277) groups on MRI metrics indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust. Validation of imaging biomarkers is important as they can help enrich clinical trials of disease modifying agents by identifying individuals at highest risk for progression to AD.

Longitudinal Assessment of Cognitive Changes Associated With Adjuvant Treatment for Breast Cancer: Impact of Age and Cognitive Reserve

PURPOSE To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. PATIENTS AND METHODS Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. RESULTS Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. CONCLUSION These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.

Brain Structure and Function Differences in Monozygotic Twins: Possible Effects of Breast Cancer Chemotherapy

PURPOSE Adjuvant chemotherapy has been associated with mild cognitive decline among a subset of breast cancer survivors. Late cognitive effects after chemotherapy can have a deleterious impact on survivor quality of life and functional health; however, the etiology of chemotherapy-related cognitive dysfunction remains unknown. PATIENTS AND METHODS We present a case of monozygotic twins who are discordant for breast cancer and chemotherapy exposure (ie, one twin contracted breast cancer and underwent chemotherapy, and the other had no breast cancer). As part of a larger study, each was evaluated with standardized, self-report measures of cognitive function, standard neuropsychological tests, and structural and functional magnetic resonance imaging (MRI). RESULTS Results indicated small differences in neuropsychological test performance but striking contrasts in self-reported cognitive complaints and structural and functional MRI images. Specifically, the twin who underwent chemotherapy had substantially more subjective cognitive complaints, more white matter hyperintensities on MRI, and an expanded spatial extent of brain activation during working memory processing than her nonaffected twin. CONCLUSION This case illustrates possible physiologic mechanisms that could produce long-term cognitive complaints among chemotherapy recipients and help formulate hypotheses for further empirical study in the area of chemotherapy-associated cognitive dysfunction.

Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort.

Atrophic changes in early Alzheimers disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimers Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration.

Regional brain atrophy in cognitively intact adults with a single APOE ε4 allele

Objective: To determine whether cognitively intact adults with the APOE ε3/ε4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the ε3 allele. Methods: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the ε3/ε3 genotype and 27 had the ε3/ε4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. Results: The ε3/ε4 participants showed lower gray matter density than the ε3/ε3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which ε3/ε4 participants showed higher gray matter density than ε3/ε3 participants. Conclusions: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE ε4 allele.

In-Home Virtual Reality Videogame Telerehabilitation in Adolescents With Hemiplegic Cerebral Palsy

UNLABELLED Golomb MR, McDonald BC, Warden SJ, Yonkman J, Saykin AJ, Shirley B, Huber M, Rabin B, AbdelBaky M, Nwosu ME, Barkat-Masih M, Burdea GC. In-home virtual reality videogame telerehabilitation in adolescents with hemiplegic cerebral palsy. OBJECTIVE To investigate whether in-home remotely monitored virtual reality videogame-based telerehabilitation in adolescents with hemiplegic cerebral palsy can improve hand function and forearm bone health, and demonstrate alterations in motor circuitry activation. DESIGN A 3-month proof-of-concept pilot study. SETTING Virtual reality videogame-based rehabilitation systems were installed in the homes of 3 participants and networked via secure Internet connections to the collaborating engineering school and childrens hospital. PARTICIPANTS Adolescents (N=3) with severe hemiplegic cerebral palsy. INTERVENTION Participants were asked to exercise the plegic hand 30 minutes a day, 5 days a week using a sensor glove fitted to the plegic hand and attached to a remotely monitored videogame console installed in their home. Games were custom developed, focused on finger movement, and included a screen avatar of the hand. MAIN OUTCOME MEASURES Standardized occupational therapy assessments, remote assessment of finger range of motion (ROM) based on sensor glove readings, assessment of plegic forearm bone health with dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), and functional magnetic resonance imaging (fMRI) of hand grip task. RESULTS All 3 adolescents showed improved function of the plegic hand on occupational therapy testing, including increased ability to lift objects, and improved finger ROM based on remote measurements. The 2 adolescents who were most compliant showed improvements in radial bone mineral content and area in the plegic arm. For all 3 adolescents, fMRI during grip task contrasting the plegic and nonplegic hand showed expanded spatial extent of activation at posttreatment relative to baseline in brain motor circuitry (eg, primary motor cortex and cerebellum). CONCLUSIONS Use of remotely monitored virtual reality videogame telerehabilitation appears to produce improved hand function and forearm bone health (as measured by DXA and pQCT) in adolescents with chronic disability who practice regularly. Improved hand function appears to be reflected in functional brain changes.

Alterations in Brain Activation During Working Memory Processing Associated With Breast Cancer and Treatment: A Prospective Functional Magnetic Resonance Imaging Study

PURPOSE To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging. PATIENTS AND METHODS Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001. RESULTS At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally. CONCLUSION Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.

Structural and functional magnetic resonance imaging of autism spectrum disorders

The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.

Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial

Objective: To evaluate the efficacy of a brief cognitive‐behavioral therapy (CBT) that is being developed for management of cognitive dysfunction following chemotherapy among breast cancer survivors. Memory and Attention Adaptation Training (MAAT) is a brief CBT designed to improve the quality of life and function among cancer survivors with post‐chemotherapy cognitive complaints.

Brain activation patterns associated with working memory in relapsing-remitting MS.

Background: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. Objective: To determine whether brain activation patterns associated with working memory are affected by MS. Methods: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). Results: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. Conclusions: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.