Thalamus pathology in multiple sclerosis: from biology to clinical application

Abstract

There is a broad consensus that MS represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, i.e. damage to axons, synapses and nerve cell bodies. While the clinician is equipped with appropriate tools to dampen peripheral cell recruitment and, thus, is able to prevent immune-cell driven relapses, effective therapeutic options to prevent the simultaneously progressing neurodegeneration are still missing. Furthermore, while several sophisticated paraclinical methods exist to monitor the inflammatory-driven aspects of the disease, techniques to monitor progression of early neurodegeneration are still in their infancy and have not been convincingly validated. In this review article, we aim to elaborate why the thalamus with its multiple reciprocal connections is sensitive to pathological processes occurring in different brain regions, thus acting as a "barometer" for diffuse brain parenchymal damage in MS. The thalamus might be, thus, an ideal region of interest to test the effectiveness of new neuroprotective MS drugs. Especially, we will address underlying pathological mechanisms operant during thalamus degeneration in MS, such as trans-neuronal or Wallerian degeneration. Furthermore, we aim at giving an overview about different paraclinical methods used to estimate the extent of thalamic pathology in MS patients, and we discuss their limitations. Finally, thalamus involvement in different MS animal models will be described, and their relevance for the design of preclinical trials elaborated.

The Effect of Dimethyl Fumarate on Cerebral Gray Matter Atrophy in Multiple Sclerosis

“…Considering these will help us understand how DMF may exert its therapeutic effect. First, the DGM is highly interconnected with the rest of the brain [63–65], and thus is quite vulnerable to the “dying back” (Wallerian degeneration) effects of neuronal loss following MS-related WM demyelination and axonal transection [65–68]. This would be consistent with the present findings, showing a significant inverse correlation between T2LV and total DGM volume.…”

Lesion Expansion in Experimental Demyelination Animal Models and Multiple Sclerosis Lesions

“…**P<0.01; ***P<0.001, tested by unpaired t test difficulties with the visualization of gray matter lesions using standard histochemical techniques, such as LFB/PAS stains, distracted the MS community into the more striking white matter pathology research. Gray matter pathology is now well-approved in MS patients and involves both cortical [2,45,46] and subcortical gray matter areas [1,[46][47][48]. Since there is no reliable way to detect or measure the entire cortical lesion load in living MS patients [49], the knowledge about the dynamics and distribution of cortical demyelination is sparse.…”

“…Multiple sclerosis (MS) was classically considered a typical white matter disease, but recent histopathology and imaging studies have convincingly shown that a substantial part of the cortical as well as subcortical gray matter is involved in the pathological process [1][2][3]. Although a number of early pathological studies [4] acknowledged the existence of such cortical and deep gray matter lesions in the central nervous system (CNS) of MS patients, only in the last 15 years, have we begun to understand the intensity and frequency of gray matter disease, the techniques required for assessing, and its important clinical implications in relation to disability and cognitive impairment.…”

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis

“…First, the caudate and other DGM nuclei are highly metabolically active structures [42] owing to their reciprocal connectivity and core processing role involving nearly all regions of the brain and, in turn, sub-serving a wide range of functions (e.g., cognition, sensation, motor control, visual function, behavior) [43][44][45]. Thus, given the diffuse and widespread damage, including axonal loss, of WM both in lesions and areas free of overt lesions (normal-appearing WM) in patients with MS [46], the DGM are vulnerable to diaschisis and Wallerian degeneration from damage in the brain and spinal cord [22,47]. Second, emerging histologic and ultra-high field MRI studies have shown a propensity for the disease process, particularly in PMS, to directly affect the DGM by the presence of lesions [48].…”