Monica Bucci

Neural Stem Cell Engraftment and Myelination in the Human Brain

Neural stem cell transplantation study suggests myelin formation in children with a severe hypomyelination disorder. Bringing Insulation Up to Code Faulty insulation around household wiring is an electric shock and fire hazard; likewise, defects in the insulation around nerve fibers—the myelin sheath—can have destructive effects. Because of myelin’s crucial roles in promoting the rapid transmission of nerve impulses and in axon integrity, mutations that affect myelin formation in the central nervous system cause severe neurological decline. Uchida et al. and Gupta et al. now investigate the use of neural stem cells—which can differentiate into myelin-producing oligodendrocytes—as a potential treatment for such disorders. Previous work showed that transplantation of human oligodendrocyte progenitors into newborn shiverer (Shi) mice, a hypomyelination model, could prolong survival. In the new work, Uchida et al. transplanted human neural stem cells, which had been expanded and banked, into the brains of newborn and juvenile Shi mice. Whereas the newborn mice were asymptomatic, the juvenile mice were already symptomatic and displayed advanced dysmyelination. These transplanted cells preferentially differentiated into oligodendrocytes that generated myelin, which ensheathed axons and improved nerve conduction in both categories of mice. In an open-label phase 1 study, Gupta et al. then tested the safety and efficacy of such cells in four young boys with a severe, fatal form of Pelizaeus-Merzbacher disease (PMD), a rare X-linked condition in which oligodendrocytes cannot myelinate axons. Human neural stem cells were transplanted directly into the brain; the procedure and transplantation were well tolerated. Magnetic resonance imaging techniques, performed before transplant and five times in the following year, were used to assess myelination. The imaging results were consistent with donor cell–derived myelination in the transplantation region in three of the four patients. These results support further study of potential clinical benefits of neural stem cell transplantation in PMD and other dysmyelination disorders. Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.

Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.

We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast‐enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS).

Spinal Cord Gray Matter Atrophy Correlates with Multiple Sclerosis Disability

In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase‐sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type.

Spinal cord gray matter atrophy correlates with multiple sclerosis disability - eScholarship

In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase‐sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type.

Resting state alpha-band functional connectivity and recovery after stroke

After cerebral ischemia, disruption and subsequent reorganization of functional connections occur both locally and remote to the lesion. However, the unpredictable timing and extent of sensorimotor recovery reflects a gap in understanding of these underlying neural mechanisms. We aimed to identify the plasticity of alpha-band functional neural connections within the perilesional area and the predictive value of functional connectivity with respect to motor recovery of the upper extremity after stroke. Our results show improvements in upper extremity motor recovery in relation to distributed changes in MEG-based alpha band functional connectivity, both in the perilesional area and contralesional cortex. Motor recovery was found to be predicted by increased connectivity at baseline in the ipsilesional somatosensory area, supplementary motor area, and cerebellum, contrasted with reduced connectivity of contralesional motor regions, after controlling for age, stroke onset-time and lesion size. These findings support plasticity within a widely distributed neural network and define brain regions in which the extent of network participation predicts post-stroke recovery potential.

Quantifying diffusion MRI tractography of the corticospinal tract in brain tumors with deterministic and probabilistic methods

Introduction Diffusion MRI tractography has been increasingly used to delineate white matter pathways in vivo for which the leading clinical application is presurgical mapping of eloquent regions. However, there is rare opportunity to quantify the accuracy or sensitivity of these approaches to delineate white matter fiber pathways in vivo due to the lack of a gold standard. Intraoperative electrical stimulation (IES) provides a gold standard for the location and existence of functional motor pathways that can be used to determine the accuracy and sensitivity of fiber tracking algorithms. In this study we used intraoperative stimulation from brain tumor patients as a gold standard to estimate the sensitivity and accuracy of diffusion tensor MRI (DTI) and q-ball models of diffusion with deterministic and probabilistic fiber tracking algorithms for delineation of motor pathways. Methods We used preoperative high angular resolution diffusion MRI (HARDI) data (55 directions, b = 2000 s/mm2) acquired in a clinically feasible time frame from 12 patients who underwent a craniotomy for resection of a cerebral glioma. The corticospinal fiber tracts were delineated with DTI and q-ball models using deterministic and probabilistic algorithms. We used cortical and white matter IES sites as a gold standard for the presence and location of functional motor pathways. Sensitivity was defined as the true positive rate of delineating fiber pathways based on cortical IES stimulation sites. For accuracy and precision of the course of the fiber tracts, we measured the distance between the subcortical stimulation sites and the tractography result. Positive predictive rate of the delineated tracts was assessed by comparison of subcortical IES motor function (upper extremity, lower extremity, face) with the connection of the tractography pathway in the motor cortex. Results We obtained 21 cortical and 8 subcortical IES sites from intraoperative mapping of motor pathways. Probabilistic q-ball had the best sensitivity (79%) as determined from cortical IES compared to deterministic q-ball (50%), probabilistic DTI (36%), and deterministic DTI (10%). The sensitivity using the q-ball algorithm (65%) was significantly higher than using DTI (23%) (p < 0.001) and the probabilistic algorithms (58%) were more sensitive than deterministic approaches (30%) (p = 0.003). Probabilistic q-ball fiber tracks had the smallest offset to the subcortical stimulation sites. The offsets between diffusion fiber tracks and subcortical IES sites were increased significantly for those cases where the diffusion fiber tracks were visibly thinner than expected. There was perfect concordance between the subcortical IES function (e.g. hand stimulation) and the cortical connection of the nearest diffusion fiber track (e.g. upper extremity cortex). Discussion This study highlights the tremendous utility of intraoperative stimulation sites to provide a gold standard from which to evaluate diffusion MRI fiber tracking methods and has provided an object standard for evaluation of different diffusion models and approaches to fiber tracking. The probabilistic q-ball fiber tractography was significantly better than DTI methods in terms of sensitivity and accuracy of the course through the white matter. The commonly used DTI fiber tracking approach was shown to have very poor sensitivity (as low as 10% for deterministic DTI fiber tracking) for delineation of the lateral aspects of the corticospinal tract in our study. Effects of the tumor/edema resulted in significantly larger offsets between the subcortical IES and the preoperative fiber tracks. The provided data show that probabilistic HARDI tractography is the most objective and reproducible analysis but given the small sample and number of stimulation points a generalization about our results should be given with caution. Indeed our results inform the capabilities of preoperative diffusion fiber tracking and indicate that such data should be used carefully when making pre-surgical and intra-operative management decisions.

Long-term evolution of multiple sclerosis disability in the treatment era.

To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long‐term prognostic value.

Quantifying accuracy and precision of diffusion MR tractography of the corticospinal tract in brain tumors

OBJECT The aim of this paper was to validate the diffusion tensor imaging (DTI) model for delineation of the corticospinal tract using cortical and subcortical white matter electrical stimulation for the location of functional motor pathways. METHODS The authors compare probabilistic versus deterministic DTI fiber tracking by reconstructing the pyramidal fiber tracts on preoperatively acquired DTI in patients with brain tumors. They determined the accuracy and precision of these 2 methods using subcortical stimulation points and the sensitivity using cortical stimulation points. The authors further explored the reliability of these methods by estimation of the potential that the found connections were due to a random chance using a novel neighborhood permutation method. RESULTS The probabilistic tracking method delineated tracts that were significantly closer to the stimulation points and was more sensitive than deterministic DTI fiber tracking to define the tracts directed to the motor sites. However, both techniques demonstrated poor sensitivity to finding lateral motor regions. CONCLUSIONS This study highlights the importance of the validation and quantification of preoperative fiber tracking with the aid of electrophysiological data during the surgery. The poor sensitivity of DTI to delineate lateral motor pathways reported herein suggests that DTI fiber tracking must be used with caution and only as adjunctive data to established methods for motor mapping.

Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis

IMPORTANCE In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques. OBJECTIVES To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels. DESIGN, SETTING, AND PARTICIPANTS Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital. MAIN OUTCOMES AND MEASURES Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates. RESULTS Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume. CONCLUSIONS AND RELEVANCE Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Spinal Arterial Anatomy and Risk Factors for Lower Extremity Weakness following Endovascular Thoracoabdominal Aortic Aneurysm Repair with Branched Stent-Grafts

Purpose: To evaluate spinal arterial anatomy and identify risk factors for lower extremity weakness (LEW) following endovascular thoracoabdominal aortic aneurysm (TAAA) repair. Methods: A retrospective review was conducted of 37 patients (27 men; mean age 74.8±7.1 years, range 58–86) undergoing endovascular TAAA repair with branched stent-grafts at a single academic institution from July 2005 to December 2007. Data were collected on preoperative comorbidities, duration of operation, blood loss, type of anesthesia, extent of aortic coverage, blood pressure, cerebrospinal fluid (CSF) pressure and drainage, and postoperative development of LEW. Pre- and postoperative contrast-enhanced computed tomographic angiograms (CTA) in a 26-patient subset were analyzed to evaluate the number of patent intercostal and lumbar arteries before and after repair. Results: All patients were neurologically intact at the end of the operation. Seven (19%) patients developed LEW postoperatively: 6 perioperatively and 1 after discharge. LEW was associated with postoperative hypotension, internal iliac artery (IIA) occlusion, and fewer patent segmental arteries on preoperative CTA. Lowest mean systolic blood pressure was <90 mmHg in all 6 (100%) patients who developed LEW in hospital compared to 12 (44%) of the 27 patients who did not develop LEW (p=0.02). Complete resolution of LEW (n=4) followed prompt measures to raise blood pressure and lower CSF pressure. Persistent LEW (n=3) was associated with sustained hypotension from sepsis, postoperative bleeding, and hemodialysis, respectively. Two (29%) of 7 patients with LEW either lost prograde flow to an IIA during repair or had bilaterally occluded IIAs preoperatively compared to 2 (7%) of 30 patients without LEW (p=0.16). Comparison of pre- and postoperative CTAs showed no reduction in the mean number of patent segmental arteries in patients with or without LEW. Conclusion: Endovascular TAAA repair inevitably occludes direct inflow to lumbar and intercostal arteries. The distal segments of these arteries to the spine, however, are seen to remain patent through collaterals. Measures to preserve collateral pathways and increase perfusion pressure may help prevent or treat LEW.