Cognitive Dysfunction in MS: Bridging the Gap Between Neurocognitive Deficits, Neuropsychological Batteries and MRI

Erica Grazioli; Ann E Yeh; Ralph HB Benedict; Joy Parrish; Bianca Weinstock-Guttman


Future Neurology. 2008;3(1):49-59. 

In This Article

Genetics & Cognitive Dysfunction in MS

Several studies have suggested a link between specific genetic polymorphisms, including the APOE ε4 allele and the Met allele of the rs6265, and cognitive dysfunction in MS. The APOE ε4 allele has been reported to be strongly associated with degenerative diseases of the CNS, particularly Alzheimer's disease. It is thought to have a major effect on neuronal repair and remyelination. The APOE ε4 allele is thought to have a detrimental effect on neurite outgrowth.[74] Reports of the relationship between the APOE ε4 allele and physical dysfunction in MS have been conflicting.[75,76,77,78] However, the link between this polymorphism and severe cognitive disability may be clearer. Although Olivieri et al.[79] found no association between the polymorphism and NP function in their analysis of 98 patients with MS, more recently, two larger case series have suggested a link between this polymorphism and cognitive dysfunction. In 2007, Parmenter et al. evaluated 263 patients with MS. Twice as many patients with severe cognitive impairment carried the e4 allele than those without.[80] Similarly, Shi et al. found a significant association between the e4 allele and cognitive dysfunction, with a specific association between learning and memory.[81] In their study, half of the younger patients (31-40 years old) with cognitive deficits were positive for APOE ε4.

The Met allele of the rs6265 (Val66Met) single nucleotide polymorphism (SNP) is a sequence variation of the brain-derived neurotrophic factor gene (BDNF). BDNF is a homodimeric neurotrophic factor that can promote neuronal growth and repair. This SNP has been described in association with neurologic and psychiatric disease, including schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's disease.[82,83,84] It has been reported that reduced hippocampal and gray matter volumes have been associated with this polymorphism in healthy subjects.[85] In a study of 209 MS patients, Zivadinov et al. suggested an association between preservation of gray matter volume and this SNP.[86] A subset of patients (n = 108) received neurocognitive testing. There was no association between the presence of this SNP and neurocognitive measures, although a trend towards better performance on the PASAT and the presence of the SNP was observed. These studies suggest that the Val66Met promoter gene may have a protective effect in MS patients. Research studies such as this by Zivadinov et al., help to bridge the current understanding of the relationships among MRI measures, cognitive testing outcomes and genetic variation in MS. Future studies are necessary to develop newer and better outcomes of cognitive rehabilitation strategies based on these variables.


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