Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis
ABSTRACT We previously reported selective decreases of neocortical volumes in patients with early relapsing-remitting (RR) multiple sclerosis (MS) with mild cognitive impairment, with a good correlation between cortical volumes and cognitive measures.
To assess the relevance of gray matter changes over time to changes in cognition in RRMS.
A longitudinal survey after 2.5 years. Each patient underwent a magnetic resonance imaging (MRI) protocol identical to that performed at baseline; cognitive performance was reassessed with the Rao Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis.
Two university MS clinics.
Of 41 patients with RRMS who participated in the original cross-sectional study, 28 were available for the follow-up evaluation (18 women; mean +/- SD age, 37.1 +/- 8.9 years; mean +/- SD MS duration, 7.3 +/- 2.9 years; mean +/- SD Expanded Disability Status Scale score, 1.8 +/- 1.5).
We measured the percentage of brain volume changes, normalized cortical volume (NCV) changes, and normalized deep gray matter volume changes on conventional T1-weighted MRIs and changes in lesion load on T2-weighted MRIs. The number of tests failed on the Rao Brief Repeatable Battery were used to classify the patients as cognitively deteriorating or stable or improving.
We identified 12 of 28 cognitively deteriorating and 16 of 28 stable or improving patients. These subgroups did not differ in the mean +/- SD percentage of brain volume changes (-2.1% +/- 1.2% vs -1.3% +/- 1.3%; P = .11), normalized deep gray matter volume changes (-2.1 +/- 2.8 mL vs -0.6 +/- 3.1 mL; P = .60), and changes in lesion load on T2-weighted MRIs (1.9 +/- 2.6 mL vs 1.6 +/- 2.3 mL; P = .73). However, NCV changes were significantly higher in deteriorating than in stable or improving patients (-43.0 +/- 18.9 mL vs -17.8 +/- 26.6 mL; P = .007). In deteriorating patients, NCV changes were correlated with performance in a verbal fluency test (r = 0.73; P < .001). In a regression model, only NCV changes were significantly associated with deteriorating cognitive performance (odds ratio, 0.8; 95% confidence interval, 0.7-0.9).
Progressive neocortical gray matter loss is relevant to MS-associated cognitive impairment and may represent a sensitive marker of deteriorating cognitive performance in RRMS.
- SourceAvailable from: Francesco Patti
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- "Several authors investigated the role of GM and its association with CI. In a group of RRMS patients, Amato et al.  found that cortical atrophy was correlated with a poor performance on NPS testing. In particular neocortical atrophy was associated with impairment in verbal memory, verbal fluency, and attention. "
ABSTRACT: Multiple sclerosis (MS) is an immune-mediated disease affecting central nervous system (CNS). Although MS is classically considered a white matter (WM) disease, the involvement of gray matter (GM) in the pathogenic process has been confirmed by pathology studies and MRI studies. Impairment of cognitive domains such as memory, mental processing speed, attention, and executive function can occur from the early stage of the disease and tends to worsen over time, despite stable physical symptoms. WM demyelination is moderately correlated with CI, suggesting that probably WM abnormalities alone cannot fully explain the extent of clinical symptoms in MS, including CI. Several MRI techniques have shown the involvement of GM in MS and the association between GM damage, physical disability, and CI. The aim of this review is to provide an overview of CI and GM damage assessed by structural brain MRI.01/2014; 2014:609694. DOI:10.1155/2014/609694
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- "MS-related cognitive impairment has been consistently associated with brain atrophy also in the earliest disease stages , , , and damage to several GM structures can be associated with impairment of specific cognitive functions . Here we have demonstrated that variants of CNR1 gene have a direct effect on executive functioning measured by WLG test, ST (inhibition of automatic response), D-KEFS Sorting test (verbal/nonverbal modality-specific problem-solving skills, ability to transfer sorting concepts into action and ability to inhibit previous description responses to engage in flexibility of thinking). "
ABSTRACT: Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.PLoS ONE 12/2013; 8(12):e82848. DOI:10.1371/journal.pone.0082848 · 3.23 Impact Factor
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- "CII is negatively correlated with grey matter volume , . However, in TT group of PP-MS patient, the CII and the frequency of CI subjects were not significantly higher respect to CT/CC group (p>0.1 for both comparisons; Fig. 5C,D), a front of a major extent of neuronal damage detected at OCT. PP-MS TT subjects had higher values at PASAT (51.37±9.5 versus 42.65±12.1, "
ABSTRACT: Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.PLoS ONE 06/2013; 8(6):e67357. DOI:10.1371/journal.pone.0067357 · 3.23 Impact Factor