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Intraspinal AAV Injections Immediately Rostral to a Thoracic Spinal Cord Injury Site Efficiently Transduces Neurons in Spinal Cord and Brain.

ABSTRACT: In the vast majority of studies utilizing adeno-associated virus (AAV) in central nervous system applications, including those published with spinal cord injury (SCI) models, AAV has been administered at the level of the cell body of neurons targeted for genetic modification, resulting in transduction of neurons in the vicinity of the injection site. However, as SCI interrupts many axon tracts, it may be more beneficial to transduce a diverse pool of supraspinal neurons. We determined if descending axons severed by SCI are capable of retrogradely transporting AAV to remotely transduce a variety of brain regions. Different AAV serotypes encoding the reporter green fluorescent protein (GFP) were injected into gray and white matter immediately rostral to a spinal transection site. This resulted in the transduction of thousands of neurons within the spinal cord and in multiple regions within the brainstem that project to spinal cord. In addition, we established that different serotypes had disparate regional specificity and that AAV5 transduced the most brain and spinal cord neurons. This is the first demonstration that retrograde transport of AAV by axons severed by SCI is an effective means to transduce a collection of supraspinal neurons. Thus, we identify a novel, minimally invasive means to transduce a variety of neuronal populations within both the spinal cord and the brain following SCI. This paradigm to broadly distribute viral vectors has the potential to be an important component of a combinatorial strategy to promote functional axonal regeneration.Molecular Therapy-Nucleic Acids (2013) 2, e108; doi:10.1038/mtna.2013.34; published online 23 July 2013.

SUBMITTER: Klaw MC

PROVIDER: S-EPMC3731889 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Project description:Background/objectivesWe recently developed techniques to monitor intraspinal pressure (ISP) and spinal cord perfusion pressure (SCPP) from the injury site to compute the optimum SCPP (SCPPopt) in patients with acute traumatic spinal cord injury (TSCI). We hypothesized that ISP and SCPPopt can be predicted using clinical factors instead of ISP monitoring.MethodsSixty-four TSCI patients, grades A-C (American spinal injuries association Impairment Scale, AIS), were analyzed. For 24 h after surgery, we monitored ISP and SCPP and computed SCPPopt (SCPP that optimizes pressure reactivity). We studied how well 28 factors correlate with mean ISP or SCPPopt including 7 patient-related, 3 injury-related, 6 management-related, and 12 preoperative MRI-related factors.ResultsAll patients underwent surgery to restore normal spinal alignment within 72 h of injury. Fifty-one percentage had U-shaped sPRx versus SCPP curves, thus allowing SCPPopt to be computed. Thirteen percentage, all AIS grade A or B, had no U-shaped sPRx versus SCPP curves. Thirty-six percentage (22/64) had U-shaped sPRx versus SCPP curves, but the SCPP did not reach the minimum of the curve, and thus, an exact SCPPopt could not be calculated. In total 5/28 factors were associated with lower ISP: older age, excess alcohol consumption, nonconus medullaris injury, expansion duroplasty, and less intraoperative bleeding. In a multivariate logistic regression model, these 5 factors predicted ISP as normal or high with 73% accuracy. Only 2/28 factors correlated with lower SCPPopt: higher mean ISP and conus medullaris injury. In an ordinal multivariate logistic regression model, these 2 factors predicted SCPPopt as low, medium-low, medium-high, or high with only 42% accuracy. No MRI factors correlated with ISP or SCPPopt.ConclusionsElevated ISP can be predicted by clinical factors. Modifiable factors that may lower ISP are: reducing surgical bleeding and performing expansion duroplasty. No factors accurately predict SCPPopt; thus, invasive monitoring remains the only way to estimate SCPPopt.

Project description:Background/objectiveWe have recently developed monitoring from the injury site in patients with acute, severe traumatic spinal cord injuries to facilitate their management in the intensive care unit. This is analogous to monitoring from the brain in patients with traumatic brain injuries. This study aims to determine whether, after traumatic spinal cord injury, fluctuations in the monitored physiological, and metabolic parameters at the injury site are causally linked to changes in limb power.MethodsThis is an observational study of a cohort of adult patients with motor-incomplete spinal cord injuries, i.e., grade C American spinal injuries association Impairment Scale. A pressure probe and a microdialysis catheter were placed intradurally at the injury site. For up to a week after surgery, we monitored limb power, intraspinal pressure, spinal cord perfusion pressure, and tissue lactate-to-pyruvate ratio. We established correlations between these variables and performed Granger causality analysis.ResultsNineteen patients, aged 22-70 years, were recruited. Motor score versus intraspinal pressure had exponential decay relation (intraspinal pressure rise to 20 mmHg was associated with drop of 11 motor points, but little drop in motor points as intraspinal pressure rose further, R2 = 0.98). Motor score versus spinal cord perfusion pressure (up to 110 mmHg) had linear relation (1.4 motor point rise/10 mmHg rise in spinal cord perfusion pressure, R2 = 0.96). Motor score versus lactate-to-pyruvate ratio (greater than 20) also had linear relation (0.8 motor score drop/10-point rise in lactate-to-pyruvate ratio, R2 = 0.92). Increased intraspinal pressure Granger-caused increase in lactate-to-pyruvate ratio, decrease in spinal cord perfusion, and decrease in motor score. Increased spinal cord perfusion Granger-caused decrease in lactate-to-pyruvate ratio and increase in motor score. Increased lactate-to-pyruvate ratio Granger-caused increase in intraspinal pressure, decrease in spinal cord perfusion, and decrease in motor score. Causality analysis also revealed multiple vicious cycles that amplify insults to the cord thus exacerbating cord damage.ConclusionMonitoring intraspinal pressure, spinal cord perfusion pressure, lactate-to-pyruvate ratio, and intervening to normalize these parameters are likely to improve limb power.

Project description:The injured spinal cord is a complex system influenced by many local and systemic factors that interact over many timescales. To help guide clinical management, we developed a technique that monitors intraspinal pressure from the injury site in patients with acute, severe traumatic spinal cord injuries. Here, we hypothesize that spinal cord injury alters the complex dynamics of the intraspinal pressure signal quantified by computing hourly the detrended fluctuation exponent alpha, multiscale entropy, and maximal Lyapunov exponent lambda. 49 patients with severe traumatic spinal cord injuries were monitored within 72 h of injury for 5 days on average to produce 5,941 h of intraspinal pressure data. We computed the spinal cord perfusion pressure as mean arterial pressure minus intraspinal pressure and the vascular pressure reactivity index as the running correlation coefficient between intraspinal pressure and arterial blood pressure. Mean patient follow-up was 17 months. We show that alpha values are greater than 0.5, which indicates that the intraspinal pressure signal is fractal. As alpha increases, intraspinal pressure decreases and spinal cord perfusion pressure increases with negative correlation between the vascular pressure reactivity index vs. alpha. Thus, secondary insults to the injured cord disrupt intraspinal pressure fractality. Our analysis shows that high intraspinal pressure, low spinal cord perfusion pressure, and impaired pressure reactivity strongly correlate with reduced multi-scale entropy, supporting the notion that secondary insults to the injured cord cause de-complexification of the intraspinal pressure signal, which may render the cord less adaptable to external changes. Healthy physiological systems are characterized by edge of chaos dynamics. We found negative correlations between the percentage of hours with edge of chaos dynamics (-0.01 ≤ lambda ≤ 0.01) vs. high intraspinal pressure and vs. low spinal cord perfusion pressure; these findings suggest that secondary insults render the intraspinal pressure more regular or chaotic. In a multivariate logistic regression model, better neurological status on admission, higher intraspinal pressure multi-scale entropy and more frequent edge of chaos intraspinal pressure dynamics predict long-term functional improvement. We conclude that spinal cord injury is associated with marked changes in non-linear intraspinal pressure metrics that carry prognostic information.

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Intraspinal AAV Injections Immediately Rostral to a Thoracic Spinal Cord Injury Site Efficiently Transduces Neurons in Spinal Cord and Brain.

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