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.

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.

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 is 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.

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, learningdependent 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.T he resting brain's energy needs are supported almost entirely by the metabolism of glucose to carbon dioxide and water (1). The first step of this process, glycolysis, requires no oxygen whereas the second step, oxidative phosphorylation, does. In the normal adult human brain, 10-15% of the glucose never reaches the second step-it is shunted away from oxidative phosphorylation despite the presence of adequate oxygen (2-5). This process is commonly referred to as aerobic glycolysis (AG).Several roles for AG have been identified, including biosynthesis (for recent reviews, see refs. 6-8), the regulation of cellular redox states (9, 10), the regulation of apoptosis (11), the provision of ATP for membrane pumps (12)(13)(14), and the regulation of cell excitability (15, 16). More recently, similar functions of AG have been observed in the posttranscriptional control of T-cell effector function (17, 18), an observation now extended to the microglia (19), where it is associated with an activated state related to inflammation as well as synaptic pruning.In the developing human brain, at a time when synaptic growth rates are highest (approximately age 10), total glucose consumption is twice that of the adult, and 30% of that glucose consumption is AG (a recent summary of this early literature is contained in ref. 20), suggesting an important role in brain development. Another remarkable feature of AG in the adult human brain is that it varies regionally (21): nearly 25% of resting glucose consumption in the medial prefrontal cortex is AG whereas AG constitutes as little as 2% glucose consumption in the cerebellum and medial temporal lobes. Correlation of these regional data with regional gene expression in the adult human brain revealed increased gene expression typical of infancy (i.e., neotony) that is related to synapse formation and growth (20).Further supporting the link between AG and plasticity are findings demonstrating that lactate, released by astrocytes and taken up by neurons, is critical for memory formation. Neuronal uptake of lactate ch...

Objective Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown. Design We used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection. Methods Antiretroviral-naive PHI (defined as <1 year after infection, n = 62), chronic HIV infection (CHI, n = 16), and HIV-uninfected (n = 19) participants had DTI, laboratory, and neuropsychometric performance assessments. DTI metrics were examined using region of interest and whole brain voxelwise analyses. Linear mixed-effects models assessed correlations between DTI measures and laboratory and neuropsychometric performance values. Results PHI participants were assessed at a median 4.1 months after estimated infection, and had median CD4+ cell count of 573 cells/µl, and HIV-1 RNA viral load of 4.5 log10 copies/ml in plasma and 2.6 log10 copies/ml in cerebrospinal fluid (CSF). DTI metrics in PHI individuals were similar to HIV— participants and correlated with disruptions in the blood-brain barrier (indicated by CSF/plasma albumin ratio and CSF protein). CHI participants had significant loss of white matter integrity that correlated with biomarkers of infection and inflammation (blood viral load, CD4+ T-cell count, and neopterin, and CSF white blood cell). Within the PHI group, DTI metrics inversely correlated with increasing days since infection. Conclusion In individuals assessed during PHI, group DTI measures suggested relative preservation of white matter microstructural integrity, but were associated with disruption of the blood-brain barrier and estimated duration of infection.

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.

Synopsis The goal of this article is to compare resting state fMRI with task fMRI as a tool for presurgical functional mapping of the sensorimotor (SM) region. Prior to tumor resection, 38 patients were scanned using both methods. The SM area was anatomically defined using two different software tools. Overlap of anatomical 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 anatomical references as compared to task activation when using a maximal overlap criterion. Resting state derived maps are more comprehensive than those derived from task fMRI.

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