Faculty Bibliography

BACKGROUND: Data are sparse regarding the impacts of habitual physical activity (PA) and sedentary behavior on cardiovascular (CV) risk in older adults with mobility limitations. METHODS AND RESULTS: This study examined the baseline, cross-sectional association between CV risk and objectively measured PA among participants in the Lifestyle Interventions and Independence for Elders (LIFE) study. The relationship between accelerometry measures and predicted 10-year Hard Coronary Heart Disease (HCHD) risk was modeled by using linear regression, stratified according to CVD history. Participants (n=1170, 79+/-5 years) spent 642+/-111 min/day in sedentary behavior (ie, <100 accelerometry counts/min). They also spent 138+/-43 min/day engaging in PA registering 100 to 499 accelerometry counts/min and 54+/-37 min/day engaging in PA >/=500 counts/min. Each minute per day spent being sedentary was associated with increased HCHD risk among both those with (0.04%, 95% CI 0.02% to 0.05%) and those without (0.03%, 95% CI 0.02% to 0.03%) CVD. The time spent engaging in activities 100 to 499 as well as >/=500 counts/min was associated with decreased risk among both those with and without CVD (P<0.05). The mean number of counts per minute of daily PA was not significantly associated with HCHD risk in any model (P>0.05). However, a significant interaction was observed between sex and count frequency (P=0.036) for those without CVD, as counts per minute was related to HCHD risk in women (beta=-0.94, -1.48 to -0.41; P<0.001) but not in men (beta=-0.14, -0.59 to 0.88; P=0.704). CONCLUSIONS: Daily time spent being sedentary is positively associated with predicted 10-year HCHD risk among mobility-limited older adults. Duration, but not intensity (ie, mean counts/min), of daily PA is inversely associated with HCHD risk score in this population-although the association for intensity may be sex specific among persons without CVD. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov Unique identifier: NCT01072500.

OBJECTIVE: To assess relationships between spinal cord MRI (SC-MRI) and retinal measures, and to evaluate whether these measures independently relate to clinical disability in multiple sclerosis (MS). METHODS: One hundred two patients with MS and 11 healthy controls underwent 3-tesla brain and cervical SC-MRI, which included standard T1- and T2-based sequences and diffusion-tensor and magnetization-transfer imaging, and optical coherence tomography with automated segmentation. Clinical assessments included visual acuity (VA), Expanded Disability Status Scale, MS functional composite, vibration sensation threshold, and hip-flexion strength. Regions of interest circumscribing SC cross-sections at C3-4 were used to obtain cross-sectional area (CSA), fractional anisotropy (FA), perpendicular diffusivity (lambda perpendicular), and magnetization transfer ratio. Multivariable regression assessed group differences and SC, retinal, and clinical relationships. RESULTS: In MS, there were correlations between SC-CSA, SC-FA, SC-lambda perpendicular, and peripapillary retinal nerve fiber layer (pRNFL) (p = 0.01, p = 0.002, p = 0.001, respectively) after adjusting for age, sex, prior optic neuritis, and brain atrophy. In multivariable clinical models, when SC-CSA, pRNFL, and brain atrophy were included simultaneously, SC-CSA and pRNFL retained independent relationships with low-contrast VA (p = 0.04, p = 0.002, respectively), high-contrast VA (p = 0.06, p = 0.008), and vibration sensation threshold (p = 0.01, p = 0.05). SC-CSA alone retained independent relationships with Expanded Disability Status Scale (p = 0.001), hip-flexion strength (p = 0.001), and MS functional composite (p = 0.004). CONCLUSIONS: In this cross-sectional study of patients with MS, correlations exist between SC-MRI and retinal layers, and both exhibit independent relationships with clinical dysfunction. These findings suggest that the SC and optic nerve reflect ongoing global pathologic processes that supplement measures of whole-brain atrophy, highlighting the importance of combining measures from unique compartments to facilitate a thorough examination of regional and global disease processes that contribute to clinical disability in MS.

BACKGROUND:Shank3, a post-synaptic density protein involved in N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement, is implicated in the pathophysiology of bipolar disorder. We hypothesized that elevated baseline plasma Shank3 levels might predict antidepressant response to the NMDA receptor antagonist ketamine. METHODS:Twenty-nine subjects with bipolar depression received a double-blind, randomized, subanesthetic dose (.5 mg/kg) ketamine infusion. Of the patients for whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17 completed post-ketamine [(18)F]-FDG PET. RESULTS:Higher baseline Shank3 levels predicted antidepressant response at Days 1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009). Greater baseline Shank3 also predicted increased glucose metabolism in the hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02). LIMITATIONS/CONCLUSIONS:Limitations include the small sample size, inability to assess the source of peripheral Shank3, and the lack of a placebo group for baseline Shank3 levels and comparative structural/functional neuroimaging. CONCLUSIONS:Shank3 is a potential biomarker of antidepressant response to ketamine that correlates with baseline amygdala volume and increased glucose metabolism in the amygdala and hippocampus.

Objective: To determine whether African-American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian-American (CA) MS patients. Methods: 687 MS patients (81 AA) and 110 healthy control (HC) subjects (14 AA) were recruited at three academic hospitals between 2008 and 2012. Using mixed effects regression models, we compared high and low contrast visual acuity (HCVA and LCVA) and high-definition spectral-domain optical coherence tomography (Cirrus-OCT) measures of retinal architecture between MS patients of self-identified AA and CA ancestry. Results: In HC, baseline peripapillary retinal nerve fiber layer thickness (RNFL) was 6.1 mum greater in AA (p = 0.047), while ganglion cell / inner plexiform layer (GCIP) thickness did not differ by race. In MS patients, baseline RNFL did not differ by race, and GCIP was 3.98 microm thinner in AA (p = 0.004). AA had faster RNFL and GCIP thinning rates compared to CA (p = 0.004 and p= 0.046, respectively). AA MS patients had lower baseline HCVA (p = 0.02) and worse LCVA per year of disease duration (p= 0.039). Among patients with an acute optic neuritis (AON) history, AA had greater loss of HCVA than CA patients (p = 0.012). Interpretation: This multicenter investigation provides objective evidence that AA MS patients exhibit accelerated retinal damage compared to CA MS patients. Self-identified AA ancestry is associated with worse MS-related visual disability, particularly in the context of an AON history, suggesting a more aggressive inflammatory disease course among AA MS patients or a subpopulation therein. ANN NEUROL 2014. (c) 2014 American Neurological Association.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.