Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial.

Patients with schizophrenia have exceedingly high rates of metabolic comorbidity including type 2 diabetes and lose 15-20 years of life due to cardiovascular diseases, with early accrual of cardiometabolic disease. In this study, thirty overweight or obese (Body Mass Index (BMI) > 25) participants under 40 years old with schizophrenia spectrum disorders and early comorbid prediabetes or type 2 diabetes receiving antipsychotic medications were randomized, in a double-blind fashion, to metformin 1500 mg/day or placebo (2:1 ratio; n = 21 metformin and n = 9 placebo) for 4 months. The primary outcome measures were improvements in glucose homeostasis (HbA1c, fasting glucose) and insulin resistance (Matsuda index-derived from oral glucose tolerance tests and homeostatic model of insulin resistance (HOMA-IR)). Secondary outcome measures included changes in weight, MRI measures of fat mass and distribution, symptom severity, cognition, and hippocampal volume. Twenty-two patients (n = 14 metformin; n = 8 placebo) completed the trial. The metformin group had a significant decrease over time in the HOMA-IR (p = 0.043) and fasting blood glucose (p = 0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index, HbA1c, which could suggest liver-specific effects of metformin. There were no between group differences in other secondary outcome measures, while weight loss in the metformin arm correlated significantly with decreases in subcutaneous, but not visceral or hepatic adipose tissue. Our results show that metformin improved dysglycemia and insulin sensitivity, independent of weight loss, in a young population with prediabetes/diabetes and psychosis spectrum illness, that is at extremely high risk of early cardiovascular mortality. Trial Registration: This protocol was registered with clinicaltrials.gov (NCT02167620).

Reduced Flow in Delayed Graft Function as Assessed by IVIM Is Associated With Time to Recovery Following Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF), defined as the need for dialysis in the first week after kidney transplantation, frequently complicates posttransplantation care. The most common cause of DGF is ischemia-reperfusion injury (IRI). To date, no clinical tools can accurately estimate its severity, nor the time required for recovery of kidney function. PURPOSE: To investigate if parameters related to directed flow and diffusion of water, as determined by intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), could be used to differentiate DGF from normal graft function posttransplantation, predict time to recovery from DGF, and hence serve as a surrogate measure of IRI severity. STUDY TYPE: Prospective, cross-sectional cohort study. POPULATION: Fifty consecutive kidney transplant recipients within 3-10 days posttransplantation at our hospital. FIELD STRENGTH/SEQUENCE: 3.0T/IVIM-DWI. ASSESSMENT: The following IVIM-DWI parameters were studied: flow-fraction (f), apparent diffusion coefficient (ADC), and total-ADC (ADCT ). Mean intrarenal resistive index (R.I.) from Doppler ultrasound was also included for a comparison of IVIM-DWI with the clinical standard of care. STATISTICAL TESTS: Welch's t-test, Spearman's correlation, and linear regression. RESULTS: f was significantly reduced in DGF compared to non-DGF patients in the cortex, medulla, and whole renal parenchyma (P < 0.05). Time to recovery with respect to MRI correlated negatively with f (P < 0.05; rho = -0.52 (cortex), and -0.65 [parenchyma]), ADC (P < 0.05; rho = -0.59 [cortex], 0.59 [medulla], and -0.59 [parenchyma]) and ADCT (P < 0.05; rho = -0.54 [cortex], and -0.52 [medulla]). Whole renal parenchymal f predicted time to recovery relative to MRI (P < 0.05, adjusted r-squared = 0.36). R.I. was significantly different between the groups but did not correlate with time to recovery with respect to MRI (rho = 0.43, P = 0.096). DATA CONCLUSION: Quantification of renal flow using IVIM-DWI has the potential to serve as a surrogate measure of IRI severity to estimate the degree of and recovery from DGF. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Magnetic Resonance Elastography to Assess Fibrosis in Kidney Allografts.

BACKGROUND AND OBJECTIVES: Fibrosis is a major cause of kidney allograft injury. Currently, the only means of assessing allograft fibrosis is by biopsy, an invasive procedure that samples <1% of the kidney. We examined whether magnetic resonance elastography, an imaging-based measure of organ stiffness, could noninvasively estimate allograft fibrosis and predict progression of allograft dysfunction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney allograft recipients >1 year post-transplant undergoing an allograft biopsy first underwent free-breathing, flow-compensated magnetic resonance elastography on a 3.0-T magnetic resonance imaging scanner. Each patient had serial eGFR measurements after the elastography scan for a follow-up period of up to 1 year. The mean stiffness value of the kidney allograft was compared with both the histopathologic Banff fibrosis score and the rate of eGFR change during the follow-up period. RESULTS: Sixteen patients who underwent magnetic resonance elastography and biopsy were studied (mean age: 54±9 years old). Whole-kidney mean stiffness ranged between 3.5 and 7.3 kPa. Whole-kidney stiffness correlated with biopsy-derived Banff fibrosis score (Spearman rho =0.67; P<0.01). Stiffness was heterogeneously distributed within each kidney, providing a possible explanation for the lack of a stronger stiffness-fibrosis correlation. We also found negative correlations between whole-kidney stiffness and both baseline eGFR (Spearman rho =-0.65; P<0.01) and eGFR change over time (Spearman rho =-0.70; P<0.01). Irrespective of the baseline eGFR, increased kidney stiffness was associated with a greater eGFR decline (regression r2=0.48; P=0.03). CONCLUSIONS: Given the limitations of allograft biopsy, our pilot study suggests the potential for magnetic resonance elastography as a novel noninvasive measure of whole-allograft fibrosis burden that may predict future changes in kidney function. Future studies exploring the utility and accuracy of magnetic resonance elastography are needed.

Investigating Microstructural Abnormalities and Neurocognition in Sub-Acute and Chronic Traumatic Brain Injury Patients with Normal-Appearing White Matter: A Preliminary Diffusion Tensor Imaging Study.

For a significant percentage of subjects, with chronic traumatic brain injury (TBI), who report persisting cognitive impairment and functional loss, the diagnosis is often impeded by the fact that routine neuroimaging often does not reveal any abnormalities. In this paper, we used diffusion tensor imaging (DTI) to investigate the apparently normal white matter (as assessed by routine magnetic resonance imaging) in the brains of 19 subjects with sub-acute (9) and chronic (10) TBI. We also assessed memory, executive function, and visual-motor coordination in these subjects. Using a voxel-wise approach, we investigated if parameters of diffusion were significantly different between TBI subjects and 17 healthy controls (HC), who were demographically matched to the TBI group. We also investigated if changes in DTI parameters were associated with neuropsychological performance in either group. Our results indicate significantly increased mean and axial diffusivity (MD and AD, respectively) values in widespread brain locations in TBI subjects, while controlling for age, sex, and time since injury. HC performed significantly better than the TBI subjects on tests of memory and executive function, indicating the persisting functional loss in chronic TBI. We found no correlation between diffusion parameters and performance on test of executive function in either group. We found negative correlation between FA and composite memory scores, and positive correlation between RD and visuomotor coordination test scores, in various tracts in both groups. Our study suggests that changes in MD and AD can indicate persisting micro-structure abnormalities in normal-appearing white matter in the brains of subjects with chronic TBI. Our results also suggest that FA in major white matter tracts is correlated with memory in health and in disease, alike; larger and longitudinal studies are needed to discern potential differences in these correlations in the two groups.

Diffusion Tensor Imaging Findings in Post-Concussion Syndrome Patients after Mild Traumatic Brain Injury: A Systematic Review.

OBJECTIVES: To review the evidence for the use of diffusion tensor imaging (DTI) parameters in the human brain as a diagnostic tool for and predictor of post-concussion syndrome (PCS) after a mild traumatic brain injury (mTBI). DESIGN: Systematic review. DATA SOURCES: All relevant studies in AMED, Embase, MEDLINE, Ovid, PubMed, Scopus, and Web of Science through 20 May, 2016. STUDY SELECTION: Studies that analyze traditional DTI measures [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)] and the severity of PCS symptoms or the development of PCS in humans after an mTBI. DATA EXTRACTION: Population studied, patient source, mTBI diagnosis method, PCS diagnosis method, DTI values measured, significant findings, and correlation between DTI findings and PCS. DATA SYNTHESIS: Ten studies investigated correlations between DTI values and PCS symptom severity or between DTI values and the development of PCS in mTBI patients. Decreased FA and increased MD and RD were associated with the development and severity of PCS. AD was not found to change significantly. Brain regions found to have significant changes in DTI parameters varied from study to study, although the corpus callosum was most frequently cited as having abnormal DTI parameters in PCS patients. CONCLUSION: DTI abnormalities correlate with PCS incidence and symptom severity, as well as indicate an increased risk of developing PCS after mTBI. Abnormal DTI findings should prompt investigation of the syndrome to ensure optimal symptom management at the earliest stages. Currently, there is no consensus in the literature about the use of one DTI parameter in a specific region of the brain as a biomarker for PCS because no definite trends for DTI parameters in PCS subjects have been identified. Further research is required to establish a standard biomarker for PCS.

Assessing intracortical myelin in the living human brain using myelinated cortical thickness.

Alterations in the myelination of the cerebral cortex may underlie abnormal cortical function in a variety of brain diseases. Here, we describe a technique for investigating changes in intracortical myelin in clinical populations on the basis of cortical thickness measurements with magnetic resonance imaging (MRI) at 3 Tesla. For this, we separately compute the thickness of the shallower, lightly myelinated portion of the cortex and its deeper, heavily myelinated portion (referred to herein as unmyelinated and myelinated cortex, respectively). Our expectation is that the thickness of the myelinated cortex will be a specific biomarker for disruptions in myeloarchitecture. We show representative atlases of total cortical thickness, T, unmyelinated cortical thickness, G, and myelinated cortical thickness, M, for a healthy group of 20 female subjects. We further demonstrate myelinated cortical thickness measurements in a preliminary clinical study of 10 bipolar disorder type-I subjects and 10 healthy controls, and report significant decreases in the middle frontal gyrus in T, G, and M in the disorder, with the largest percentage change occurring in M. This study highlights the potential of myelinated cortical thickness measurements for investigating intracortical myelin involvement in brain disease at clinically relevant field strengths and resolutions.

Patterns of myeloarchitecture in lower limb amputees: an MRI study.

Functional studies of cortical plasticity in humans suggest that the motor cortex reorganizes when the descending motor output pathway is disrupted as a result of limb amputation. The question thus arises if the underlying anatomical organization of the motor cortex is also altered in limb amputation. Owing to challenges involved in imaging the thin cerebral cortex in vivo, there is limited data available on the anatomical or morphological plasticity of the motor cortex in amputation. In this paper, we study the morphology of the primary motor cortex in four lower limb amputees with 37 or more years of amputation and four age and gender-matched controls using 0.7 mm isotropic, T1-weighted MRI optimized to produce enhanced intracortical contrast based on myelin content. We segment the cortex into myelinated and unmyelinated gray matter. We determine the myelinated thickness which is the thickness of the well-myelinated tissue in the deeper layers of the cortex. We compare the bilateral differences in the myelinated thickness between amputees and controls. We also compare bilateral differences in cortical thickness between the two groups. Our measurements show no statistically significant difference between the amputees and controls in the myelinated thickness and in cortical thickness, in the region of the primary motor cortex representing the lower leg.

Optimizing T1-weighted imaging of cortical myelin content at 3.0 T.

With increases in the sensitivity and resolution of anatomical MRI for the brain, methods for mapping the organization of the cerebral cortex by imaging its myelin content have emerged. This identifies major sensory and motor regions and could be used in studies of cortical organization, particularly if patterns of myelination can be visualized over the cortical surface robustly in individual subjects. The imaging problem is difficult, however, because of the relative thinness of the cerebral cortex and the low intracortical tissue contrast. In this paper, we optimize the contrast of T(1)-weighted MRI to help better visualize patterns of myelination. We measure a small but statistically significant difference in T(1) of 171 ± 40 ms between cortical regions with low and high myelin contents in the human cortex at 3T, and then perform simulations to choose parameters for an inversion-recovery pulse sequence that utilizes this T(1) difference to increase contrast within the cortex. We show that lengthening the delay between signal acquisition and the next inversion pulse in the sequence increases intracortical contrast more effectively than does image averaging. Using the optimized sequence, we show that major myelinated regions that are relatively thick, such as the primary motor and auditory regions, can be visualized well in individuals at 3T using whole-cortex 3D images made at 1mm isotropic resolution, while thinner regions, such as the primary visual cortex, can be visualized using targeted 3D images made at 0.5mm isotropic resolution. Our findings demonstrate that patterns of myelination can be better visualized in individual subjects when the imaging is optimized to highlight intracortical contrast and can help to pave the way for the creation of matched maps of microanatomy and function in the cortex of living individual humans.

Visualizing myeloarchitecture with magnetic resonance imaging in primates.

The pattern of myelination over the cerebral cortex, termed myeloarchitecture, is an established and often-used feature to visualize cortical organization with histology in a variety of primate species. In this paper, we use in vivo magnetic resonance imaging (MRI) and advanced image processing using surface rendering to visualize and characterize myeloarchitecture in a small nonhuman primate, the common marmoset (Callithrix jacchus). Through images made in four female adult marmosets, we produce a representative 3D map of marmoset myeloarchitecture and flatten and annotate this map to show the location and extent of a variety of major areas of the cortex, including the primary visual, auditory, and somatosensory areas. By treating our MRI data as a surface, we can measure the surface area of cortical areas, and we present these measurements here to summarize cortical organization in the marmoset.