[Show abstract][Hide abstract] ABSTRACT: Cortical, thalamic and hippocampal gray matter atrophy in relapsing-remitting MS (RRMS) is associated cognitive deficits. However, the role of interconnecting white matter pathways including the fornix, cingulum, and uncinate fasciculus (UF) is less well studied.
To assess MS damage to a hippocampal-thalamic-prefrontal network and the relative contributions of its components to specific cognitive domains.
We calculated diffusion tensor fractional anisotropy (FA) in the fornix, cingulum and UF as well as thalamic and hippocampal volumes in 27 RRMS patients and 20 healthy controls. A neuropsychological battery was administered and 4 core tests known to be sensitive to MS changes were used to assess cognitive impairment. To determine the relationships between structure and cognition, all tests were grouped into 4 domains: attention/executive function, processing speed, verbal memory, and spatial memory. Univariate correlations with structural measures and depressive symptoms identified potential contributors to cognitive performance and subsequent linear regression determined their relative effects on performance in each domain. For significant predictors, we also explored the effects of laterality and axial versus radial diffusivity.
RRMS patients had worse performance on the Symbol Digit Modalities Test, but no significant impairment in the 4 cognitive domains. RRMS had reduced mean FA of all 3 pathways and reduced thalamic and hippocampal volumes compared to controls. In RRMS we found that thalamic volume and BDI predicted attention/executive function, UF FA predicted processing speed, thalamic volume predicted verbal memory, and UF FA and BDI predicted spatial memory.
Hippocampal-thalamic-prefrontal disruption affects cognitive performance in early RRMS with mild to minimal cognitive impairment, confirming both white and gray matter involvement in MS and demonstrating utility in assessing functional networks to monitor cognition.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. While current medication reduces relapses and inflammatory activity, it has only a modest effect on long-term disability and gray matter atrophy. Here, we have characterized the potential neuroprotective effects of testosterone on cerebral gray matter in a pilot clinical trial. Ten men with relapsing-remitting MS were included in this open-label phase II trial. Subjects were observed without treatment for 6 months, followed by testosterone treatment for another 12 months. Focal gray matter loss as a marker for neurodegeneration was assessed using voxel-based morphometry. During the non-treatment phase, significant voxel-wise gray matter decreases were widespread (p≤ 0.05 corrected). However, during testosterone treatment, gray matter loss was no longer evident. In fact, a significant gray matter increase in the right frontal cortex was observed (p≤ 0.05 corrected). These observations support the potential of testosterone treatment to stall (and perhaps even reverse) neurodegeneration associated with MS. Furthermore, they warrant the investigation of testosterone's neuroprotective effects in larger, placebo controlled MS trials as well as in other neurodegenerative diseases. This is the first report of gray matter increase as the result of treatment in MS.
[Show abstract][Hide abstract] ABSTRACT: Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.
[Show abstract][Hide abstract] ABSTRACT: Motor deficits in relapsing remitting multiple sclerosis (RRMS) patients are monitored using standard measures of disability that assess performance ranging from walking ability to hand function, thus reflecting involvement of a variety of motor pathways. We investigated the relative contributions of diffuse white matter damage and focal lesions using diffusion tensor imaging (DTI), in predicting future worsening of hand function in RRMS. The nine hole peg test (NHPT), a test of fine hand motor control, was used to measure baseline upper limb function in 16 controls and 25 RRMS patients, and then performed at follow-up on 22 of these patients at 6 and 12 months. Tract-based spatial statistics (TBSS) were used across the whole brain as a non-hypothesis driven method for localizing white matter changes associated with motor deficits. Subsequently, we used probabilistic fiber tractography in the corticospinal tracts (CST) and the transcallosal hand motor (TCHM) fibers to assess the predictive power of diffusion metrics and/or functionally relevant visible lesion volumes on the decline of hand motor function over the next 12 months. While fractional anisotropy (FA) and radial diffusivity (RD) of both pathways were strongly associated with NHPT performance at baseline, only RD of the TCHM fibers was predictive of NHPT decline over the next 12 months. Neither total visible lesion load nor pathway specific lesion loads were indicative of NHPT performance or progression. The TCHM fibers may play an important role in modifying the effects of MS pathology on fine motor control, and RD in these fibers may be a sensitive biomarker for future disability.
[Show abstract][Hide abstract] ABSTRACT: The hippocampus is likely involved in mood disorders, but in vivo evidence for the role of anatomically distinct hippocampal subregions is lacking. Multiple sclerosis, an inflammatory disease of the central nervous system, is linked to a high prevalence of depression as well as hippocampal damage and may thus provide important insight into the pathologic correlates of medical depression. We examined the role of subregional hippocampal volume for depression in relapsing-remitting multiple sclerosis.
Anatomically defined hippocampal subregional volumes (cornu ammonis 1-3 [CA1-CA3] and the dentate gyrus [CA23DG], subiculum, entorhinal cortex) were measured using a high-resolution T2-weighted magnetic resonance imaging sequence in 29 relapsing-remitting multiple sclerosis patients and 20 matched healthy control subjects. Diurnal salivary cortisol was assessed at awakening, 4 pm, and 9 pm on 2 consecutive days. Subjects also completed the Beck Depression Inventory.
Multiple sclerosis patients showed smaller hippocampal volumes compared with control subjects, particularly in the CA1 and subiculum subregions. In addition, multiple sclerosis patients with depressive symptoms (Beck Depression Inventory score >13) also showed smaller CA23DG volumes and higher cortisol levels. Within the multiple sclerosis group, CA23DG volume was correlated with depressive symptoms and cortisol levels. There were no associations with number of previous steroid treatments, global atrophy, or disease duration.
This report provides in vivo evidence for selective association of smaller CA23DG subregional volumes in the hippocampus with cortisol hypersecretion and depressive symptoms in multiple sclerosis.
[Show abstract][Hide abstract] ABSTRACT: Gray matter brain structures, including deep nuclei and the cerebral cortex, are affected significantly and early in the course of multiple sclerosis and these changes may not be directly related to demyelinating white matter lesions. The hippocampus is an archicortical structure that is critical for memory functions and is especially sensitive to multiple insults including inflammation. We used high-resolution MR imaging at 3.0 T to measure hippocampal volumes in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients and controls. We found that both groups of MS patients had hippocampal atrophy and that this volume loss was in excess of global brain atrophy. Subregional analysis revealed selective volume loss in the cornu ammonis (CA) 1 region of the hippocampus in RRMS with further worsening of CA1 loss and extension into other CA regions in SPMS. Hippocampal atrophy was not correlated with T2-lesion volumes, and right and left hippocampi were affected equally. Volume loss in the hippocampus and subregions was correlated with worsening performance on word-list learning, a task requiring memory encoding, but not with performance on the Paced Auditory Serial Addition Task (PASAT), a test of information processing speed. Our findings provide evidence for selective and progressive hippocampal atrophy in MS localized initially to the CA1 subregion that is associated with deficits in memory encoding and retrieval. The underlying histopathological substrate for this selective, symmetric and disproportionate regional hippocampal vulnerability remains speculative at this time. Further understanding of this process could provide targets for therapeutic interventions including neuroprotective treatments.