Thalamic neurodegeneration in multiple sclerosis

Abstract

Multiple sclerosis is still regarded primarily as a disease of the white matter. However, recent evidence suggests that there may be significant involvement of gray matter. Here, we have used magnetic resonance imaging and magnetic resonance spectroscopy in vivo and histopathology postmortem to estimate thalamic neuronal loss in patients with multiple sclerosis. Our results show that neuronal loss in multiple sclerosis can be substantial (30-35% reduction). We conclude that a neurodegenerative pathology may make a major contribution to the genesis of symptoms in multiple sclerosis.

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

“…38 It is reduced by ϳ20% in thalamic gray matter in secondary progressive MS and in a postmortem study the decrease in NAA (accompanied by atrophy) was associated with decreased numbers of neurones. 7 In primary progressive MS, reduction of NAA and atrophy appear to be relatively independent of T2 lesion load. 85 Two approaches have been used to measure NAA: 1) an absolute measure of concentration using and external standard reference of known concentration, and 2) a ratio of NAA/Cr which assumes that Cr (creatine/phosphocreatine) remains stable in pathological situations.…”

“…4,5 In NAGM, careful examination has revealed an abundance of demyelinated lesions that typically exhibit less inflammation than those seen in white matter but that may exhibit neuronal and axonal loss. 6,7 Given the widespread nature of pathological changes in NAWM and NAGM, it seems likely that they contribute to clinical progression; how they relate to focal inflammatory demyelinating white matter lesions and to the overall pathogenesis of the disease is unclear.…”

Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications

“…and such studies will be complicated by the lack of sensitivity of current imaging techniques in detecting the majority of cortical plaques [86]. In addition to the cortical rim, deep gray matter structures are also impacted in MS, with the thalamus showing early and significant atrophy associated with axonal and neuronal loss [87,88]. Thalamic atrophy has been linked with fatigue and cognitive impairment [89,90], but the effect of DMAs on thalamic volume or function has not been assessed.…”

Imaging of multiple sclerosis: Role in neurotherapeutics

“…Neuronal and axonal loss occurs on a large scale in MS and affects both white matter 160 and gray matter. 161 As recently reviewed, the rate of atrophy in MS varies over time 157 and can be detected in the earliest stages of disease (i.e., in patients with CIS who later develop clinically definite MS). 162 CNS atrophy is a progressive phenomenon that worsens with increasing disease duration and worsening disease course (FIG.…”

“…208 There are two possible explanations for how iron deposition might relate to the pathophysiology of the disease, each with its own therapeutic implications. First, iron accumulation may purely represent an epiphenomenon resulting from neurodegeneration that occurs in gray matter in MS. 113,161 If so, T2 hypointensity may serve as a method for monitoring therapeutic effects on the neurodegenerative component of the disease. Second, iron may participate directly in the pathogenesis of MS by promoting the generation of free radicals, oxidative stress, lipid peroxidation, and neurotoxicity.…”