The Influence of Spatial Registration on Detection of Cerebral Asymmetries Using Voxel-Based Statistics of Fractional Anisotropy Images and TBSS

The sensitivity of diffusion tensor imaging (DTI) for detecting microstructural white matter alterations has motivated the application of voxel-based statistics (VBS) to fractional anisotropy (FA) images (FA-VBS). However, detected group differences may depend on the spatial registration method used. The objective of this study was to investigate the influence of spatial registration on detecting cerebral asymmetries in FA-VBS analyses with reference to data obtained using Tract-Based Spatial Statistics (TBSS). In the first part of this study we performed FA-VBS analyses using three single-contrast and one multi-contrast registration: (i) whole-brain registration based on T2 contrast, (ii) whole-brain registration based on FA contrast, (iii) individual-hemisphere registration based on FA contrast, and (iv) a combination of (i) and (iii). We then compared the FA-VBS results with those obtained from TBSS. We found that the FA-VBS results depended strongly on the employed registration approach, with the best correspondence between FA-VBS and TBSS results when approach (iv), the “multi-contrast individual-hemisphere” method was employed. In the second part of the study, we investigated the spatial distribution of residual misregistration for each registration approach and the effect on FA-VBS results. For the FA-VBS analyses using the three single-contrast registration methods, we identified FA asymmetries that were (a) located in regions prone to misregistrations, (b) not detected by TBSS, and (c) specific to the applied registration approach. These asymmetries were considered candidates for apparent FA asymmetries due to systematic misregistrations associated with the FA-VBS approach. Finally, we demonstrated that the “multi-contrast individual-hemisphere” approach showed the least residual spatial misregistrations and thus might be most appropriate for cerebral FA-VBS analyses

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited

White matter hyperintensities in relation to cognition in HIV-infected men with sustained suppressed viral load on cART

OBJECTIVES: The objective of this study was to assess whether HIV-infected patients on long-term successful combination antiretroviral therapy (cART) have more extensive white matter hyperintensities (WMH) of presumed vascular origin compared with uninfected controls and whether these intensities are associated with cognitive impairment. Furthermore, we explored potential determinants of increased WMH loadin long-term suppressed HIV infection. DESIGN: A cross-sectional comparison of WMH in an observational cohort. METHODS: Clinical, cognitive and magnetic resonance imagingdata were collected from 103middle-aged, aviremic HIV-infected menon cART and 70 HIV-uninfected, otherwise similar controls. In the MRI data, WMH load was quantified by automated approaches and qualitatively reviewed by an experienced neuroradiologist using the Fazekas scale. RESULTS: HIV-infected men hadan increased WMHload. Among HIV-infected patients, increased WMH load was independently associated witholder age, higher diastolic blood pressure and D-dimer levels,and longer time spent with a CD4 count below 500 cells/mm. HIV-associated cognitive deficits were associated with increased WMHload. CONCLUSIONS: WMHare more extensive and associated with cognitive deficitsin middle-aged,aviremic cART-treated HIV-infected men. The extent of WMH load wasassociated with both cardiovascular risk factors and past immune deficiency. Since cognitive impairment in these same patients is also associated with these risk factors, this may suggest that in the setting of HIV, WMH and cognitive deficits share a common etiology. This supports the importance of optimizing cardiovascular risk management, and early, effective treatment of HIVinfection

Is heart rate variability associated with frequency and intensity of vasomotor symptoms among healthy perimenopausal and postmenopausal women?

ObjectiveResearch has suggested that the autonomic nervous system (ANS) is involved in the experience of vasomotor symptoms (VMS) during menopause. We examined the relationship of VMS intensity and heart rate variability (HRV), a measure of ANS function.MethodsWomen (n = 282) were recruited from three American states for a clinical trial of yoga, exercise, and omega-3 fatty acid supplements for VMS. To be eligible, women had to report at least 14 VMS per week, with some being moderate to severe. Sitting electrocardiograms were recorded for 15 min using Holter monitors at both baseline and 12-week follow-up. Time and frequency domain HRV measures were calculated. Women completed daily diary measures of VMS frequency and intensity for 2 weeks at baseline and for 1 week at the follow-up assessment 12 weeks later. Multivariable linear regression was used to assess the relationship between VMS and baseline HRV measures and to compare change in HRV with change in VMS over the 12 weeks.ResultsBaseline HRV was not associated with either VMS frequency or intensity at baseline. Change in HRV was not associated with change in VMS frequency or intensity across the follow-up.InterpretationHeart rate variability (HRV) was not associated with basal VMS frequency or intensity in perimenopausal and postmenopausal women experiencing high levels of VMS. Autonomic function may be associated with the onset or presence of VMS, but not with the number or intensity of these symptoms

Increased brain-predicted aging in treated HIV disease

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters. Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45-82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machinelearning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18- 90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD 5 brain-predicted brain age 2 chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out. Results: HIV-positive individuals had greater brain-PAD score (mean \ub1 SD 2.15 \ub1 7.79 years) compared to HIV-negative individuals (20.87 \ub1 8.40 years; b = 3.48, p < 0.01). Increased brainPAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures. Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging