The BDNF Val66Met Polymorphism Has Opposite Effects on Memory Circuits of Multiple Sclerosis Patients and Controls

et al. (2013) The BDNF Val66Met Polymorphism Has Opposite Effects on Memory Circuits of Multiple Sclerosis Patients and Controls. PLoS ONE 8(4): e61063. doi:10.1371/journal.pone.0061063 66 The BDNF Val Met Polymorphism Has Opposite Effects on Memory Circuits of Multiple Sclerosis Patients and Controls Francesco Fera 0 Luca Passamonti 0 Antonio Cerasa 0 Maria Cecilia Gioia 0 Maria Liguori 0 Ida Manna 0 Paola Valentino 0 Aldo Quattrone 0 Jean-Claude Baron, University of Cambridge, United Kingdom 0 1 Universita` degli Studi ''Magna Graecia'', Dipartimento di Scienze Mediche e Chirurgiche, Catanzaro, Italia, 2 Consiglio Nazionale delle Ricerche, Unita` di Ricerca Neuroimmagini, Catanzaro, Italia, 3 Consiglio Nazionale delle Ricerche, Istituto di Scienze Neurologiche , Mangone (CS) , Italia Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val66Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val66Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val66 allele, relative to Met66 carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met66 carriers relative to Val66 homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val66Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis. - Funding: This research was founded by the Fondazione Italiana Sclerosi Multipla (FISM) (grant number #2003/R/24). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Episodic memory deficits represent one of the most frequent cognitive symptoms in Relapsing-Remitting Multiple Sclerosis (RR-MS) and have a devastating impact on patients ability to maintain independent living and working skills [12]. A number of previous studies have attempted to identify factors that predict the decline on episodic memory tasks in RR-MS patients [35]. Diffuse demyelination of the white-matter and the progressive degeneration across the neocortex are important causes of memory deficits in RR-MS because they tend to disrupt the communications between large scale brain networks [3]. At the same time, however, MS pathological changes stimulate neuronal plasticity that represents a fundamental adapting mechanism for maintaining a relatively normal cognitive function in spite of brain damage [612]. For example, two recent functional magnetic resonance imaging (fMRI) studies identified compensatory hyperactivations within the hippocampal system as a mechanism for preserving episodic memory in MS [1314]. Previous research has also demonstrated that common variations in the DNA sequence regulate memory function at the brain and behavioural level [1519]; hence, genetic factors are likely to influence the expression of cognitive symptoms in RR-MS. The Brain Derived Neurotrophic Factor (BDNF) is critically involved in neuronal survival and is considered as the most important neuromodulator of episodic memory [2024]. The nonconservative amino-acid substitution at codon 66 (Valine to Methionine, Val66Met) of the BDNF gene is a common polymorphism known to interfere with intracellular trafficking of the peptide and synaptic plasticity in the hippocampus [20,24]. The relevance of BDNF in MS has also been highlighted by studies reporting that, in active MS lesions, immune cells release several neurotrophic factors including BDNF [2528]. This suggests that even in the context of inflammation BDNF promotes plastic capacities of the brain [2526,28]. Enhancing our knowledge of the contribution of the BDNF polymorphism on brain activity of RR-MS patients would help defining the neurophysiological correlates underlying episodic memory in RR-MS. To this aim, neuroimaging has a unique potential for characterizing how the BDNF Val66Met polymorphism influences memory systems in RR-MS patients [2931]. Previous fMRI studies in healthy controls have shown that the BDNF Val66Met polymorphism significantly alters the hippocampal activity during episodic memory tasks [22,32]. An effect of the BDNF polymorphism has also been reported on the hippocampal volume of healthy controls and patients with psychiatric disorders [3337], although a recent genome wide meta-analysis has not confirmed this finding [38]. To date, the attempts to investigate the effect of the BDNF Val66Met polymorphism on the brain of MS patients have produced mixed results. A first study found that RR-MS patients with at least one copy of the Met66 allele display reduced total grey-matter volume relative to RR-MS Val66 homozygous and healthy controls (HC) carrying the Met66 allele or homozygous for the Val66 allele [27]. In contrast, later studies found the opposite result (i.e., the RR-MS Met66 carriers had greater grey-matter volumes relative to RR-MS Val66 homozygous) and suggested that the Met allele may be a protecting factor for grey-matter preservation in MS [2931]. Another fMRI study reported a differential effect of the BDNF polymorphism on the prefrontal-parietal activations and hippocampal disengagement in RR-MS patients and HC during a working-memory task [39]. However, this experiment did not specifically assess the contribution of the BDNF genotype on the hippocampal activity related to episodic memory. The present study aimed at investigatin (...truncated)