Jerrel Rutlin

White Matter Microstructural Integrity in Youth With Type 1 Diabetes

Decreased white and gray matter volumes have been reported in youth with type 1 diabetes mellitus (T1DM), but the effects of hyperglycemia on white matter integrity have not been quantitatively assessed during brain development. We performed diffusion tensor imaging, using two complimentary approaches—region-of-interest and voxelwise tract-based spatial statistics—to quantify white matter integrity in a large retrospective study of T1DM youth and control participants. Exposure to chronic hyperglycemia, severe hyperglycemic episodes, and severe hypoglycemia, as defined in the Diabetes Control and Complications Trial (DCCT), were estimated through medical records review, HbA1c levels, and interview of parents and youth. We found lower fractional anisotropy in the superior parietal lobule and reduced mean diffusivity in the thalamus in the T1DM group. A history of three or more severe hyperglycemic episodes was associated with reduced anisotropy and increased diffusivity in the superior parietal lobule and increased diffusivity in the hippocampus. These results add microstructural integrity of white matter to the range of structural brain alterations seen in T1DM youth and suggest vulnerability of the superior parietal lobule, hippocampus, and thalamus to glycemic extremes during brain development. Longitudinal analyses will be necessary to determine how these alterations change with age or additional glycemic exposure.

Early Brain Vulnerability in Wolfram Syndrome

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

White matter integrity and executive abilities in individuals with phenylketonuria

Previous studies have revealed white matter abnormalities in the brains of individuals with phenylketonuria (PKU), but the microstructural nature of these abnormalities and their relationship to phenylalanine (Phe) levels and cognitive outcomes are poorly understood. In the current study, the microstructural integrity of white matter in 29 individuals with early-treated PKU and 12 healthy controls was examined using two complementary diffusion tensor imaging (DTI) approaches: region-of-interest (ROI) based analysis and voxel-wise tract based spatial statistics (TBSS) analysis. Relationships among DTI, executive abilities, and Phe level findings were explored. DTI revealed widespread lowering of mean diffusivity (MD) in the white matter of the PKU group in comparison with the control group. Executive abilities were also poorer for individuals with PKU than controls. Within the PKU group, lower MD was associated with higher Phe level and poorer executive abilities. These findings are the first to demonstrate the interplay among microstructural white matter integrity, executive abilities, and Phe control in individuals with PKU.

White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria.

Tetrahydrobiopterin (BH(4)) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH(4) responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH(4). Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH(4) treatment within a single study.

Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria.

In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (N=36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.

Brain aerobic glycolysis and motor adaptation learning

Significance A substantial fraction of glucose used by the brain does not enter the oxidative phosphorylation pathway despite the presence of adequate oxygen, a phenomenon known as aerobic glycolysis. Among its several functions, aerobic glycolysis makes substantial contributions to biosynthesis, thus becoming a marker of synaptic plasticity. Combining PET and MRI brain-imaging techniques, we characterized the role of aerobic glycolysis in plasticity during the performance of a motor adaptation learning task. Our findings support a link between aerobic glycolysis and learning as well as providing unexpected evidence of a potential role of microglia in long-term depression and synaptic pruning. Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learning-dependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual–motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity.

Thalamic Activation During Slightly Subphysiological Glycemia in Humans

OBJECTIVE The central nervous system mechanisms of defenses against falling plasma glucose concentrations, and how they go awry and result in iatrogenic hypoglycemia in diabetes, are not known. Hypoglycemic plasma glucose concentrations of 55 mg/dL (3.0 mmol/L) cause symptoms, activate glucose counterregulatory systems, and increase synaptic activity in a network of brain regions including the dorsal midline thalamus in humans. We tested the hypothesis that slightly subphysiological plasma glucose concentrations of 65 mg/dL (3.6 mmol/L), which do not cause symptoms but do activate glucose counterregulatory systems, also activate brain synaptic activities. RESEARCH DESIGN AND METHODS We measured relative regional cerebral blood flow (rCBF), an index of synaptic activity, in predefined brain regions with [15O]water positron emission tomography, symptoms, and plasma epinephrine and glucagon concentrations during a 2-h euglycemic (90 mg/dL) to hypoglycemic (55 mg/dL) clamp (n = 20) or a 2-h euglycemic to slight subphysiological (65 mg/dL) clamp (n = 9) in healthy humans. RESULTS Clamped plasma glucose concentrations of 65 mg/dL did not cause hypoglycemic symptoms, but raised plasma epinephrine and glucagon concentrations and increased rCBF (P = 0.007) only in the dorsal midline thalamus. CONCLUSIONS Slightly subphysiological plasma glucose concentrations increase synaptic activity in the dorsal midline thalamus in humans.

Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.

Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.

Tract-based analysis of white matter integrity in psychotic and nonpsychotic bipolar disorder

BACKGROUND At least 50% of individuals with bipolar disorder (BD) present with psychosis during their lifetime. Psychotic symptoms have sometimes been linked to specific genetic and phenotypic markers. This study aims to explore potential differences between bipolar disorder subtypes by measuring white matter integrity of the brain and relationships with clinical measures. METHODS Diffusion tensor imaging and clinical measures were acquired from 102 participants, grouped as psychotic bipolar disorder (PBD) (n=48), non-psychotic bipolar disorder (NBD) (n=24), and healthy controls (n=30). We utilized a powerful, automated tool (TRACULA: Tracts Constrained by Underlying Anatomy) to analyze the fractional anisotropy (FA) and mean diffusivity (MD) of 18 white matter tracts. RESULTS Decreased FA in numerous tracts was observed in bipolar disorder groups compared to healthy controls: bilateral cingulum-cingulate gyrus bundles, corticospinal tracts, and superior longitudinal fasciculi as well as the right hemisphere cingulum-angular bundle. Only left uncinate fasciculus FA differed between PBD and NPBD groups. We found no group differences in MD. Positive symptoms correlated with FA in the superior (inversely) and inferior (directly) longitudinal fasciculi. Negative symptoms directly correlated with mean FA of the corticospinal tract and cingulum-angular bundle. LIMITATIONS Neurotropic, mood-stabilizing medication prescribed for individuals with BD may interact with measures of white matter integrity in our BD participants. CONCLUSION Our results indicate decreased white matter coherence in BD. Minimal differences in white matter FA between PBD and NPBD participants suggest related underlying neurobiology.

Resting-state Functional Magnetic Resonance Imaging in Presurgical Functional Mapping: Sensorimotor Localization

This article compares resting-state functional magnetic resonance (fMR) imaging with task fMR imaging for presurgical functional mapping of the sensorimotor (SM) region. Before tumor resection, 38 patients were scanned using both methods. The SM area was anatomically defined using 2 different software tools. Overlap of anatomic regions of interest with task activation maps and resting-state networks was measured in the SM region. A paired t-test showed higher overlap between resting-state maps and anatomic references compared with task activation when using a maximal overlap criterion. Resting state-derived maps are more comprehensive than those derived from task fMR imaging.