Justin M. Brown, Bob S. Carter, Keith E. Tansey, and Ross Zafonte
Amy K. Wagner, Dianxu Ren, Yvette P. Conley, Xiecheng Ma, Mary E. Kerr, Ross D. Zafonte, Ava M. Puccio, Donald W. Marion, and C. Edward Dixon
Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3′ variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI.
Sixty-three patients with severe TBI (Glasgow Coma Scale score ≤ 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury.
Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002).
In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.
Douglas Kondziolka, Gary K. Steinberg, Lawrence Wechsler, Carolyn C. Meltzer, Elaine Elder, James Gebel, Sharon DeCesare, Tudor Jovin, Ross Zafonte, Jonathan Lebowitz, John C. Flickinger, David Tong, Michael P. Marks, Catriona Jamieson, Desiree Luu, Teresa Bell-Stephens, and Jeffrey Teraoka
No definitive treatment exists to restore lost brain function following a stroke. Transplantation of cultured neuronal cells has been shown to be safe and effective in animal models of stroke and safe in a Phase 1 human trial. In the present study the authors tested the usefulness of human neuron transplantation followed by participation in a 2-month stroke rehabilitation program compared with rehabilitation alone in patients with substantial fixed motor deficits associated with a basal ganglia stroke.
Human neuronal cells (LBS-Neurons; Layton BioScience, Inc.) were delivered frozen and then thawed and formulated on the morning of surgery. The entry criteria in this randomized, observer-blinded trial of 18 patients included age between 18 and 75 years, completed stroke duration of 1 to 6 years, presence of a fixed motor deficit that was stable for at least 2 months, and no contraindications to stereotactic surgery. Patients were randomized at two centers to receive either 5 or 10 million implanted cells in 25 sites (seven patients per group) followed by participation in a stroke rehabilitation program, or to serve as a nonsurgical control group (rehabilitation only; four patients). The surgical techniques used were the same at both centers. All patients underwent extensive pre- and postoperative motor testing and imaging. Patients received cyclosporine A for 1 week before and 6 months after surgery. The primary efficacy measure was a change in the European Stroke Scale (ESS) motor score at 6 months. Secondary outcomes included Fugl-Meyer, Action Research Arm Test, and Stroke Impact Scale scores, as well as the results of other motor tests. Nine strokes were ischemic in origin and nine were hemorrhagic.
All 14 patients who underwent surgery (ages 40–70 years) underwent uncomplicated surgeries. Serial evaluations (maximum duration 24 months) demonstrated no cell-related adverse serological or imaging-defined effects. One patient suffered a single seizure, another had a syncopal event, and in another there was burr-hole drainage of an asymptomatic chronic subdural hematoma. Four of seven patients who received 5 million cells (mean improvement 6.9 points) and two of seven who received 10 million cells had improved ESS scores at 6 months; however, there was no significant change in the ESS motor score in patients who received cell implants (p = 0.756) compared with control or baseline values (p = 0.06). Compared with baseline, wrist movement and hand movement scores recorded on the Fugl-Meyer Stroke Assessment instrument were not improved (p = 0.06). The Action Research Arm Test gross hand-movement scores improved compared with control (p = 0.017) and baseline (p = 0.001) values. On the Stroke Impact Scale, the 6-month daily activities score changed compared with baseline (p = 0.045) but not control (p = 0.056) scores, and the Everyday Memory test score improved in comparison with baseline (p = 0.004) values.
Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with motor deficits due to stroke. Although a measurable improvement was noted in some patients and this translated into improved activities of daily living in some patients as well, this study did not find evidence of a significant benefit in motor function as determined by the primary outcome measure. This experimental trial indicates the safety and feasibility of neuron transplantation for patients with motor stroke.