Multiple Sclerosis Fatigue: A Longitudinal Structural MRI and Diffusion Tensor Imaging Study.

BACKGROUND AND PURPOSE: Previous cross-sectional studies have reported the involvement of thalamus, pallidum, superior cerebellar peduncle, temporal cortex, and fronto-parietal white matter in multiple sclerosis (MS)-related fatigue. However, the longitudinal imaging correlates of fatigue severity variation in MS remain unclear. METHODS: Structural and diffusion tensor imaging (DTI) data were collected from 43 relapsing remitting MS (RRMS) patients with fatigue (Fatigue Severity Scale [FSS] range: 1-7). Subcortical nuclei volume using FreeSurfer and cortical diffusion indices using a cross-modality technique were measured at baseline and year 1. RESULTS: The pallidal volume had significantly decreased (P = .002) by year 1, although the fatigue score variation was not significant. At year 1, the pallidal volume (P = .023) and fractional anisotropy (FA, P = .013) of right temporal cortex (RTC) correlated significantly with FSS. CONCLUSIONS: The pallidal volume and the FA-RTC may be used to evaluate longitudinal fatigue severity variation. Our study proposes new biomarkers to monitor fatigue severity in MS patients.

Enhancement of hippocampal neurogenesis by lithium.

Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2's antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.

Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects?

BACKGROUND: Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo. METHODS: Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner). RESULTS: A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes. CONCLUSIONS: This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.

Evidence for coupling between glucose metabolism and glutamate cycling using FDG PET and 1H magnetic resonance spectroscopy in patients with epilepsy.

The purpose of this study was to examine the relation between glucose metabolism and glutamate concentration in the human brain, in both the normal and diseased state. Regional values of glucose metabolism measured with 2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography (FDG PET) studies and single-voxel proton magnetic resonance spectroscopy (1H MRS) measurements of the glutamate/ glutamine/gamma-aminobutyric acid (Glx) tissue concentration were determined in multiple brain regions in 11 patients (5 girls and 6 boys, mean age 7.5 years) with medically intractable partial epilepsy. FDG PET and 1H MRS studies were performed in the interictal state in seven patients and in the ictal/periictal state in four patients. Regions of interest were identified in epileptic cortex (determined by intracranial and/or scalp electroencephalography) and in contralateral normal brain regions. Lower glucose metabolism and lower Glx concentrations were found in the epileptic focus than in the contralateral normal cortex in all seven patients examined in the interictal state, whereas higher glucose metabolism and higher Glx concentrations were observed in the epileptic focus in the four patients who had ictal/periictal studies. Significant correlations were found between the values of cerebral glucose utilization and Glx concentration in epileptic brain region, in nonepileptic brain regions, and in epileptic and nonepileptic regions combined. These results demonstrate a significant relation between glucose metabolism and glutamate/glutamine concentration in normal and epileptic cerebral cortex. This relation is maintained in both the interictal and ictal states.