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      BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke

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          Abstract

          Background

          Persistent motor impairment is common but highly heterogeneous poststroke. Genetic polymorphisms, including those identified on the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness.

          Objective

          To determine whether BDNF and APOE genotypes influence motor improvement facilitated by poststroke upper-limb rehabilitation.

          Methods

          BDNF-Val66Met and APOE isoform genotypes were determined using leukocyte DNA for 55 community-dwelling patients 2–123 months poststroke. All patients completed a dose-matched upper-limb rehabilitation program of either Wii-based Movement Therapy or Constraint-induced Movement Therapy. Upper-limb motor function was assessed pre- and post-therapy using a suite of functional measures.

          Results

          Motor function improved for all patients post-therapy, with no difference between therapy groups. In the pooled data, there was no significant effect of BDNF or APOE genotype on motor function at baseline, or following the intervention. However, a significant interaction between the level of residual motor function and BDNF genotype was identified ( p = 0.029), whereby post-therapy improvement was significantly less for Met allele carriers with moderate and high, but not low motor function. There was no significant association between APOE genotype and therapy outcomes.

          Conclusion

          This study identified a novel interaction between the BDNF-Val66Met polymorphism, motor-function status, and the magnitude of improvement with rehabilitation in chronic stroke. This polymorphism does not preclude, but may reduce, the magnitude of motor improvement with therapy, particularly for patients with higher, but not lower residual motor function. BDNF genotype should be considered in the design and interpretation of clinical trials.

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          Most cited references58

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          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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            Modulation of brain plasticity in stroke: a novel model for neurorehabilitation.

            Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model--which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies--is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance-recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.
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              Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.

              Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF(Met)), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNF(Met) is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF(Met) and wild-type BDNF (BDNF(Val)) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNF(Met) on BDNF(Val) intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF(Met) occurred only in neuronal and neurosecretory cells and that BDNF(Met) could alter the intracellular distribution and activity-dependent secretion of BDNF(Val). We determined that, when coexpressed in the same cell, approximately 70% of the variant BDNF forms BDNF(Val).BDNF(Met) heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNF(Met) or the BDNF(Val).BDNF(Met) heterodimer compared with BDNF(Val). Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/329961
                URI : http://frontiersin.org/people/u/329988
                URI : http://frontiersin.org/people/u/114809
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                17 May 2016
                2016
                : 7
                : 69
                Affiliations
                [1] 1Neuroscience Research Australia , Sydney, NSW, Australia
                [2] 2School of Medical Sciences, University of New South Wales , Sydney, NSW, Australia
                Author notes

                Edited by: Jean-Claude Baron, University of Cambridge, UK

                Reviewed by: Giovanni Di Pino, Campus Bio Medico University of Rome, Italy; Alana B. McCambridgem, University of Technology Sydney, Australia

                *Correspondence: Penelope A. McNulty, p.mcnulty@ 123456neura.edu.au

                Specialty section: This article was submitted to Stroke, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2016.00069
                4868962
                27242654
                938d3bbf-3314-44be-b48a-c2b4df31e6c5
                Copyright © 2016 Shiner, Pierce, Thompson-Butel, Trinh, Schofield and McNulty.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 March 2016
                : 25 April 2016
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 73, Pages: 10, Words: 7844
                Funding
                Funded by: National Stroke Foundation 10.13039/501100000930
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Award ID: 630440
                Categories
                Neuroscience
                Original Research

                Neurology
                motor rehabilitation,upper limb,stroke genetics,apolipoprotein e,brain-derived neurotrophic factor

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