Paweł Szewczyk

Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury.

Numerous studies in animals have shown the unique property of olfactory ensheathing cells to stimulate regeneration of lesioned axons in the spinal cord. In a Phase I clinical trial, we assessed the safety and feasibility of transplantation of autologous mucosal olfactory ensheathing cells and olfactory nerve fibroblasts in patients with complete spinal cord injury. Six patients with chronic thoracic paraplegia (American Spinal Injury Association class A-ASIA A) were enrolled for the study. Three patients were operated, and three served as a control group. The trial protocol consisted of pre- and postoperative neurorehabilitation, olfactory mucosal biopsy, culture of olfactory ensheathing cells, and intraspinal cell grafting. Patients clinical state was evaluated by clinical, neurophysiological, and radiological tests. There were no adverse findings related to olfactory mucosa biopsy or transplantation of olfactory ensheathing cells at 1 year after surgery. There was no evidence of neurological deterioration, neuropathic pain, neuroinfection, or tumorigenesis. In one cell-grafted patient, an asymptomatic syringomyelia was observed. Neurological improvement was observed only in transplant recipients. The first two operated patients improved from ASIA A to ASIA C and ASIA B. Diffusion tensor imaging showed restitution of continuity of some white matter tracts throughout the focus of spinal cord injury in these patients. The third operated patient, although remaining ASIA A, showed improved motor and sensory function of the first spinal cords segments below the level of injury. Neurophysiological examinations showed improvement in spinal cord transmission and activity of lower extremity muscles in surgically treated patients but not in patients receiving only neurorehabilitation. Observations at 1 year indicate that the obtaining, culture, and intraspinal transplantation of autologous olfactory ensheathing cells were safe and feasible. The significance of the neurological improvement in the transplant recipients and the extent to which the cell transplants contributed to it will require larger numbers of patients.

Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging.

Treatment of patients sustaining a complete spinal cord injury remains an unsolved clinical problem because of the lack of spontaneous regeneration of injured central axons. A 38-year-old man sustained traumatic transection of the thoracic spinal cord at upper vertebral level Th9. At 21 months after injury, the patient presented symptoms of a clinically complete spinal cord injury (American Spinal Injury Association class A-ASIA A). One of the patients olfactory bulbs was removed and used to derive a culture containing olfactory ensheathing cells and olfactory nerve fibroblasts. Following resection of the glial scar, the cultured cells were transplanted into the spinal cord stumps above and below the injury and the 8-mm gap bridged by four strips of autologous sural nerve. The patient underwent an intense pre- and postoperative neurorehabilitation program. No adverse effects were seen at 19 months postoperatively, and unexpectedly, the removal of the olfactory bulb did not lead to persistent unilateral anosmia. The patient improved from ASIA A to ASIA C. There was improved trunk stability, partial recovery of the voluntary movements of the lower extremities, and an increase of the muscle mass in the left thigh, as well as partial recovery of superficial and deep sensation. There was also some indication of improved visceral sensation and improved vascular autoregulation in the left lower limb. The pattern of recovery suggests functional regeneration of both efferent and afferent long-distance fibers. Imaging confirmed that the grafts had bridged the left side of the spinal cord, where the majority of the nerve grafts were implanted, and neurophysiological examinations confirmed the restitution of the integrity of the corticospinal tracts and the voluntary character of recorded muscle contractions. To our knowledge, this is the first clinical indication of the beneficial effects of transplanted autologous bulbar cells.

Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study.

BACKGROUND & AIMS The aim of the study was to evaluate early metabolic perfusion, and microstructural cerebral changes in patients with the hepatitis C virus (HCV) infection and normal appearing brain on plain MR using advanced MR techniques, as well as to assess correlations of MR measurements with the liver histology activity index (HAI). METHODS Fifteen HCV-positive patients and 18 control subjects underwent single voxel MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI), using a 1.5T MR unit. MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr) were calculated. PWI values of relative cerebral blood volume (rCBV) were assessed from 8 areas including several cortical locations, basal ganglia, and fronto-parietal white matter. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. RESULTS Compared to controls, HCV-positive patients showed significantly (p < 0.05) lower NAA/Cr ratios within frontal and parietal white matters, lower rCBV values within frontal and temporo-parietal cortices, decreased FA values, as well as increased ADC values in several white matter tracts. We also found elevated rCBV values in basal ganglia regions. The increase in mI/Cr and Cho/Cr ratio was correlated with a higher HAI score. CONCLUSIONS The results of advanced MR techniques indicate neurotoxicity of HCV reflected by neuronal impairment within white matter, cortical hypoperfusion, and disintegrity within several white matter tracts. Hyperperfusion in basal ganglia may be an indicator of brain inflammation in HCV patients. Our findings may suggest a biologic link between HCV-related liver disease and cerebral dysfunction.

Evaluation of metabolic changes within the normal appearing gray and white matters in neurologically asymptomatic HIV-1-positive and HCV-positive patients: Magnetic resonance spectroscopy and immunologic correlation

OBJECTIVE The aim of the study was to evaluate early metabolic changes using proton MR spectroscopy (MRS) in asymptomatic HIV-1-positive and HCV-positive patients without abnormalities in the structural MR examination. METHODS Sixty-five asymptomatic patients: 21 HIV-1-positive naive, 20 HIV-1-positive with combination antiretroviral therapy (cART), 9 HIV-1/HCV-positive naive, 15 HCV-positive naive and 18 normal subjects were enrolled in the study. The MRS examinations were performed with a 1.5T MR scanner. Voxels were located in the following regions: posterior cingulate gyrus (PCG), anterior cingulate gyrus (ACG), parietal white matter (PWM), left basal ganglia (BG) and frontal white matter (FWM). The NAA/Cr, Cho/Cr, mI/Cr ratios and correlations of MRS measurements with the immunologic data were analyzed. RESULTS There was a significant decrease (p<0.05) of the NAA/Cr ratios in PCG, ACG and PWM regions in HIV-1-positive cART treated patients compared to the normal subjects. The significantly decreased NAA/Cr ratios in PWM and FWM were observed in HCV infected patients. The subjects with HIV-1/HCV co-infection revealed significantly lower NAA/Cr ratios in the ACG area. Other metabolite ratios in all analyzed regions, as well as the NAA/Cr ratios in BG showed no significant differences. The decrease of CD4n T cell count was associated with the decease of the NAA/Cr ratio in the PCG area and the increase of Cho/Cr ratio in the FWM region. CONCLUSIONS The metabolic changes - reduction of NAA/Cr ratios are most pronounced in HIV-1-positive patients using cART. The low CD4n T cell count is a risk factor for neurocognitive impairment in HIV-1-positive patients.

Application of diffusion tensor imaging (DTI) in pathological changes of the spinal cord

Summary We review the current knowledge concerning clinical applications of the advanced technique of magnetic resonance imaging (MRI): diffusion tensor imaging (DTI) of the spinal cord. Due to technical difficulties, DTI has rarely been used in spinal cord diseases. However, in our opinion it is potentially a very useful method in diagnosis of the different pathological processes of the spinal cord and spinal canal. We discuss the physical principles and technical aspects of DTI, as well as current and future applications. DTI seems to be a very promising method for assessment of spinal cord trauma, spinal canal tumors, degenerative myelopathy, as well as demyelinating and infectious diseases of the spinal cord. DTI enables both qualitative and quantitative (by measuring of the fractional anisotropy and apparent diffusion coefficient parameters) assessment of the spinal cord. The particular applications are illustrated by the examples provided in this article.

Multimodal imaging in diagnosis of Alzheimer's disease and amnestic mild cognitive impairment: value of magnetic resonance spectroscopy, perfusion, and diffusion tensor imaging of the posterior cingulate region.

The purpose of this study was to assess metabolic, perfusion, and microstructural changes within the posterior cingulate area in patients with Alzheimers disease (AD) and amnestic mild cognitive impairment (aMCI) using advanced MR techniques such as: spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI). Thirty patients with AD (mean age 71.5 y, MMSE 18), 23 with aMCI (mean age 66 y, MMSE 27.4), and 15 age-matched normal controls (mean age 69 y, MMSE 29.5) underwent conventional MRI followed by MRS, PWI, and DTI on 1.5 Tesla MR unit. Several metabolite ratios (N-acetylaspartate [NAA]/creatine [Cr], choline [Ch]/Cr, myoinositol [mI]/Cr, mI/NAA, mI/Cho) as well as parameters of cerebral blood volume relative to cerebellum and fractional anisotropy were obtained in the posterior cingulate region. The above parameters were correlated with the results of neuropsychological tests. AD patients showed significant abnormalities in all evaluated parameters while subjects with aMCI showed only perfusion and diffusion changes in the posterior cingulate area. Only PWI and DTI measurements revealed significant differences among the three evaluated subject groups. DTI, PWI, and MRS results showed significant correlations with neuropsychological tests. DTI changes correlated with both PWI and MRS abnormalities. Of neuroimaging methods, DTI revealed the highest accuracy in diagnosis of AD and aMCI (0.95, 0.79) followed by PWI (0.87, 0.67) and MRS (0.82, 0.47), respectively. In conclusion, AD is a complex pathology regarding both grey and white matter. DTI seems to be the most useful imaging modality to distinguish between AD, aMCI, and control group, followed by PWI and MRS.

Value of Perfusion-Weighted MR Imaging in the Assessment of Early Cerebral Alterations in Neurologically Asymptomatic HIV-1-Positive and HCV-Positive Patients

Background and Purpose Asymptomatic central nervous system (CNS) involvement occurs in the early stage of the human immunodeficiency virus (HIV) infection. It has been documented that the hepatitis C virus (HCV) can replicate in the CNS. The aim of the study was to evaluate early disturbances in cerebral microcirculation using magnetic resonance (MR) perfusion-weighted imaging (PWI) in asymptomatic HIV-1-positive and HCV-positive patients, as well as to assess the correlation between PWI measurements and the clinical data. Materials and Methods Fifty-six patients: 17 HIV-1-positive non-treated, 18 HIV-1-positive treated with combination antiretroviral therapy (cART), 7 HIV-1/HCV-positive non-treated, 14 HCV-positive before antiviral therapy and 18 control subjects were enrolled in the study. PWI was performed with a 1.5T MR unit using dynamic susceptibility contrast (DSC) method. Cerebral blood volume (CBV) measurements relative to cerebellum (rCBV) were evaluated in the posterior cingulated region (PCG), basal ganglia (BG), temporoparietal (TPC) and frontal cortices (FC), as well as in white matter of frontoparietal areas. Correlations of rCBV values with immunologic data and liver histology activity index (HAI) were analyzed. Results Significantly lower rCBV values were found in the right TPC and left FC as well as in PCG in HIV-1-positive naïve (p = 0.009; p = 0.020; p = 0.012), HIV-1 cART treated (p = 0.007; p = 0.009; p = 0.033), HIV-1/HCV-positive (p = 0.007; p = 0.027; p = 0.045) and HCV-positive patients (p = 0.010; p = 0.005; p = 0.045) compared to controls. HIV-1-positive cART treated and HIV-1/HCV-positive patients demonstrated lower rCBV values in the right FC (p = 0.009; p = 0.032, respectively) and the left TPC (p = 0.036; p = 0.005, respectively), while HCV-positive subjects revealed lower rCBV values in the left TPC region (p = 0.003). We found significantly elevated rCBV values in BG in HCV-positive patients (p = 0.0002; p<0.0001) compared to controls as well as to all HIV-1-positive subjects. There were no significant correlations of rCBV values and CD4 T cell count or HAI score. Conclusions PWI examination enables the assessment of HIV-related as well as HCV-related early cerebral dysfunction in asymptomatic subjects. HCV-infected patients seem to reveal the most pronounced perfusion changes.

Parry–Romberg syndrome: clinical, electrophysiological and neuroimaging correlations

Parry–Romberg syndrome (PRS) is a rare disorder, described in the nineteenth century by Caleb Parry and Moritz Romberg, characterized by acquired and slowly progressive atrophy of one side of the face. The pathogenesis of PRS is still unclear. Immune-mediated processes are thought to be a basic factor in PRS etiology, but autonomic nervous system might also be impaired. A case of PRS in a 26-year-old woman with coexisting disturbances in the lower left limb is presented. The multimodal electrophysiological studies were done, including electroencephalography, visual, brain auditory, somatosensory and trigeminal somatosensory evoked potentials, blink reflex, standard neurographic and electromyographic examinations, quantitative sensory tests and autonomic tests. Neuroimaging studies consisted of brain MR, single voxel proton MR spectroscopy, diffusion tensor imaging with fiber tractography. Based on multimodal electrophysiological and neuroimaging studies, it was concluded that the impairment in PRS is multisystemic, i.e., motor, sensory, and autonomic. A cortical origin of the symptoms is possible.

Quantitative MR evaluation of atrophy, as well as perfusion and diffusion alterations within hippocampi in patients with Alzheimer’s disease and mild cognitive impairment

Background The aim of this study was to evaluate atrophy rates, perfusion, and diffusion disturbances within the hippocampus, which is the site of characteristic changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Material/Methods Thirty patients with AD (mean age 71.2 yrs) – 34 with MCI (mean age 67.7 yrs) and 20 healthy controls (mean age 68.1 yrs) – underwent structural MR examination followed by perfusion and diffusion-weighted imaging on a 1.5 T scanner. Visual rating of hippocampal atrophy, planimetric measurements of hippocampal formation (HF) and perihippocampal fluid spaces (PFSs), and values of relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were assessed. The results were correlated with the MMSE scores. Results In AD we found decreased size of HF and increased diameters of PFSs and ADC values, compared to MCI and control group. Compared to normal controls, the MCI group showed decreased HF size and increased diameters of only medial PFS. There were no differences in rCBV values among all the subject groups. Planimetric measurements of hippocampal atrophy showed the highest accuracy in diagnosing AD and MCI. In all patients, the increased rates of hippocampal atrophy correlated with the increased ADC values. In MCI, MMSE scores correlated with the HF size and ADC values. Conclusions In AD and MCI, hippocampal atrophy is associated with decreased tissue integrity without coexisting perfusion disturbances. Of all evaluated hippocampal measurements, atrophy rates seem to be the most useful parameters in detecting changes among AD, MCI, and control subjects.

Evaluation of the Posterior Cingulate Region with FDG-PET and Advanced MR Techniques in Patients with Amnestic Mild Cognitive Impairment: Comparison of the Methods

BACKGROUND The posterior cingulate region is an area of the earliest pathological changes in amnestic mild cognitive impairment (aMCI). The utility of FDG-PET imaging in dementia is already well established. OBJECTIVES The aim of the study was to compare FDG-PET with advanced MR measurements: MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI) within the posterior cingulate region in patients with aMCI. METHODS Fifty-five patients diagnosed with aMCI (66.5 y) and 20 age-matched controls (69 y) underwent MR examination including MRS, PWI, and DTI followed by FDG-PET scanning. Values of MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr), PWI cerebral blood volume (rCBV), and DTI fractional anisotropy (FA) were compared to the FDG-PET rates of glucose metabolism. RESULTS Compared to controls, aMCI patients showed significant (p < 0.05) glucose hypometabolism, and lower rCBV and FA values. FDG-PET results correlated significantly with rCBV values. Compared to FDG-PET, PWI showed similar and DTI greater accuracy in distinguishing aMCI from controls. According to FDG-PET findings, two groups of aMCI patients were established: those with lower (PET-positive) and normal (PET-negative) glucose uptake. PET-positive aMCI subjects showed normal MRS findings, lower rCBV and FA values, while PET-negative patients revealed normal MRS and PWI results but significantly lower FA values. CONCLUSIONS Advanced MR techniques such as PWI and particularly DTI may be regarded as competitive techniques to FDG-PET. DTI was the only method to show alterations in aMCI patients with normal FDG-PET, PWI, and MRS findings. DTI seems to be a very sensitive biomarker of early degeneration in aMCI.