BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke

And just when the hell is somebody going to write up a fucking stroke protocol on the use of BDNF for stroke recovery? Or is everyone in stroke a chickenshit? Not willing to publicly write up anything for survivors? This is why the complete stroke medical establishment needs to be destroyed.
http://journal.frontiersin.org/article/10.3389/fneur.2016.00069/full?utm_source=newsletter&

Christine T. Shiner^1,2, Kerrie D. Pierce¹, Angelica G. Thompson-Butel^1,2, Terry Trinh^1,2, Peter R. Schofield^1,2 and Penelope A. McNulty^1,2*

• ¹Neuroscience Research Australia, Sydney, NSW, Australia
• ²School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

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.

Introduction

Motor impairment is a common, disabling, and inherently heterogeneous outcome of stroke (1, 2). Patients typically present across a broad clinical continuum and undergo variable and often incomplete recovery of motor function over time and in response to targeted rehabilitation (3). Predicting poststroke prognosis and recovery potential has gained a prominent research focus, with the most common predictive factors being measures of lesion size (4, 5), location (6, 7), corticospinal tract integrity (8, 9), and initial impairment severity (10, 11). While more extensive corticospinal tract damage and more severe baseline impairment are generally associated with poorer prognosis poststroke (10–12), these factors alone cannot fully explain the degree of variability in poststroke motor outcomes and patients’ response to motor therapies (3, 13). In order to optimize rehabilitation and thus maximize poststroke recovery, a deeper understanding of the factors that mediate this residual variability is necessary.

Genetic variation may account for some of the unexplained variance in stroke recovery. In particular, single-nucleotide polymorphisms (SNPs) in genes related to cortical plasticity and neural repair could influence an individual’s capacity for use-dependent plasticity, and hence their responsiveness to poststroke rehabilitation [for review, see Ref. (14)]. Numerous genes of interest continue to emerge in the growing field of stroke genetics (14, 15). Here, we have adopted a candidate gene approach based on two genetic factors with the strongest evidence in subacute stroke and extended this investigation into the chronic setting. The candidate genes are the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes (16).

The BDNF gene encodes for the neurotrophin most abundantly expressed in the brain and involved in neuronal differentiation, survival, and synaptic plasticity (17–19). Approximately 30% of the Caucasian population and a higher percentage of the Asian population possess an SNP (rs6265) in the BDNF gene, resulting in a valine to methionine substitution at codon 66, the Val66Met polymorphism (20). This polymorphism alters the intracellular trafficking and activity-dependent release of BDNF (21, 22), and in healthy cohorts has been associated with a reduced capacity for use-dependent plasticity in the motor cortex (23–26) and impaired motor learning (26).

The BDNF-66Met allele may be detrimental to recovery following stroke (14), but the evidence to date remains contentious (27). Studies have primarily focused on subacute outcomes following spontaneous recovery, where both a significant negative association between Val66Met and stroke outcome (28–31) and a modest or negligible effect have been reported (16, 32–34). There is scant evidence of whether the Val66Met polymorphism influences long-term stroke recovery or responsiveness to targeted therapies. There is some suggestion that it may alter patient responsiveness to non-invasive brain stimulation (35, 36), but to date, no significant effect of this genotype on motor therapy has been identified (13).

Single-nucleotide polymorphisms within the APOE gene are less prevalent but potentially stronger genetic mediators of poststroke recovery (16). This gene encodes for a glycoprotein primarily involved in lipid transport and metabolism, but it also plays an important role in neuronal repair and synaptic remodeling (37, 38). Two SNPs (rs429358 and rs7412) in the APOE gene give rise to three distinct APOE isoforms, ε2 (Cys¹¹²/Arg¹⁵⁸Cys), ε3 (Cys¹¹²/Arg¹⁵⁸), and ε4 (Cys¹¹²Arg/Arg¹⁵⁸) (39). The ε4 isoform is present in only 10–20% of the population (40) but has been strongly implicated in the risk for Alzheimer’s disease (41, 42) and cardiovascular pathology (40, 43). Studies of APOE ε4 in stroke have mainly focused on stroke incidence rather than outcome (43), although emerging evidence suggests that the ε4 allele may have a detrimental effect on poststroke recovery (16, 44–46). Like BDNF, it remains uncertain whether APOE genotype can influence motor function and rehabilitation outcomes more chronically poststroke (13).

Here, we investigated whether BDNF and APOE genotype influence how stroke patients with stable motor function respond to a targeted protocol of upper-limb motor therapy poststroke. Data were collected from a pooled cohort of patients who received a dose-matched protocol of either Constraint-induced Movement Therapy, the current gold standard in upper-limb stroke rehabilitation, or Wii-based Movement Therapy, recently shown to be an engaging and equally efficacious therapy alternative (47). Given that no differences were demonstrated in any measure of upper-limb motor function between these two therapies (47), we did not expect to see differences according to therapy type, but rather according to genotype. We hypothesized that all patients would make some degree of motor improvement post-therapy, although those who possessed the BDNF-66Met or APOE-ε4 alleles would have less improvement with a standardized dose of therapy.

More at link