Hypertension is associated with cognitive decline in elderly persons. We studied asymptomatic hypertensive subjects using brain magnetic resonance (MR) spectroscopy to evaluate metabolite impairments ...before the appearance of symptoms in patients with different treatment outcomes. In all, 14 healthy controls and 37 asymptomatic hypertensive patients (17 controlled and 20 resistant) underwent brain structural MR and MR spectroscopy of the posterior paralimbic (PPL) area and left frontal white matter. Ischemic burden (IB), global cortical atrophy and microbleeds were analyzed with visual scales. Metabolite ratios involving N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myoinositol (mI) were computed. Ultrasound measurements, including intima-media thickness, plaques and hemodynamic ratios, were obtained. Intergroup differences in IB, atrophy and metabolite ratios, and the atrophy and IB relationship were assessed with parametric and nonparametric statistical tests. In addition, the impacts of demographic, analytic and clinical factors, ischemia and atrophy, and ultrasound measurements on metabolite ratios were assessed. The significance level was set at P<or=0.05. Higher atrophy scores presented with higher total or frontal IB (P<0.05). However, there was no intergroup difference in atrophy and IB. PPL mI/Cr was increased in resistant hypertension (P<0.021), whereas frontal NAA/Cr (P<0.007) showed opposite trends between controlled (increased ratios) and resistant (decreased ratios) hypertension. Unlike PPL mI/Cr, frontal NAA/Cr showed significant correlations with the lipid profile and ultrasound measurements. PPL mI/Cr increases in resistant hypertension, and frontal NAA/Cr diverges between controlled and resistant hypertension before physical and neuropsychological symptoms appear.
Abstract Purpose To demonstrate drop in brain ADC measurements from low to high b values; to evaluate the structural information provided based on those changes; and to discuss the anatomical reasons ...for ADC differences. Methods Four cerebral ROI (precuneus-PRC, hippocampus-HIP, and the genu-GCC and splenium-SCC of the corpus callosum-CC) were drawn for ADC measurements with low (1000) and high (3000) b -value DWI in 50 normal subjects. ANOVA and Bonferroni correction tested ADC differences between areas, between both hemispheres, between GCC and SCC, and between b -value related ADC drop within areas. Pearson test evaluated dependence of interhemispheric and intercallosum ADC measurements obtained with the same b -value, dependence between areas of intrazonal drop, and the interhemispheric and intercallosum dependence of intrazonal drop. Results ADCs differed between areas ( P <.0001). Interhemispheric ADC only differed in PRC with low b -value ( P <.027). No HIP asymmetries occurred regardless the b -value. ADC drop within PRC and HIP was similar but differed ( P <.0001) from ADC drop within both CC ROI. ADC drop was also different between GCC and SCC ( P <.0001). In PRC and HIP, ADC showed a significant interhemispheric and intrazonal dependence ( P <.0001). There was no GCC to SCC ADC dependence. Intrazonal dependence in the CC was only significant in the SCC ( P <.001). Interhemispheric dependence of intrazonal drop was significant (PRC P =.007; HIP P <.0001) but failed to reach significance in the CC. Conclusion Low and high b -value measurements show different diffusion behaviours within different tissues, especially in a highly anisotropic structure as the corpus callosum. This fact can provide valuable information about brain structure and different diffusion compartments in clinical DWI.
Abstract Objective To report MRI spinal changes after surgical infusion of bone marrow stem cells (BMSc) in ALS patients and assess their correlation with clinical events and functional performance. ...Methods BMSc were surgically injected in the thoracic spinal cord of 11 ALS patients (6/5 male/female; median age 46 years). We performed first-week and third, sixth, ninth and twelfth post-surgical months spinal MRIs. The spinal changes in the postsurgical week and follow-up MRIs, as well as clinical events, functional scales and respiratory and electromyography data, were longitudinally monitored. Correlations between the imaging and clinical data were evaluated with the Spearman's test. Results Transient extradural fluid collections (100%), transient spinal cord T2 hyperintensity (81.8%), and chronic spinal cord deformities (63.6%) were the dominating MRI changes. Spinal cord hemorrhages (27.3%) and cystic myelomalacia (1/11 patients) were important although unusual findings. During the follow-up, minor adverse events of mild to moderate intensity eventually improved. Initial and follow-up imaging scores showed a strongly positive correlation ( r 0.879, P < 0.001). The initial and delayed clinical scores did not correlate. There was no significant correlation between any of the imaging scores and clinical data. Conclusions Infusion of BMSc produces a variety of spinal changes apparently unrelated with clinical events and disease worsening.
The objective of this article is to assess the safety of intraspinal infusion of autologous bone marrow mononuclear cells (BMNCs) and, ultimately, to look for histopathological signs of cellular ...neurotrophism in amyotrophic lateral sclerosis (ALS) patients. We conducted an open single arm phase I trial. After 6 months observation, autologous BMNCs were infused into the posterior spinal cord funiculus. Safety was the primary endpoint and was defined as the absence of serious transplant-related adverse events. In addition, forced vital capacity (FVC), ALS-functional rating scale (ALS-FRS), Medical Research Council scale for assessment of muscle power (MRC), and Norris scales were assessed 6 and 3 months prior to the transplant and quarterly afterward for 1 year. Pathological studies were performed in case of death. Eleven patients were included. We did not observe any severe transplant-related adverse event, but there were 43 nonsevere events. Twenty-two (51%) resolved in ≤2 weeks and only four were still present at the end of follow-up. All were common terminology criteria for adverse events grade ≤2. No acceleration in the rate of decline of FVC, ALS-FRS, Norris, or MRC scales was observed. Four patients died on days 359, 378, 808, and 1,058 post-transplant for reasons unrelated to the procedure. Spinal cord pathological analysis showed a greater number of motoneurons in the treated segments compared with the untreated segments (4.2 ± 0.8 motoneurons per section mns per sect and 0.9 ± 0.3 mns per sect, respectively). In the treated segments, motoneurons were surrounded by CD90+ cells and did not show degenerative ubiquitin deposits. This clinical trial confirms not only the safety of intraspinal infusion of autologous BMNC in ALS patients but also provides evidence strongly suggesting their neurotrophic activity.
Among brain tumours, those arising from the deep brain are rare. In many cases they are low-grade astrocytomas. But primitive neuroectodermal tumours, ganglion cell tumours, oligodendrogliomas, ...lymphomas, and germinal neoplasms can also grow up from the basal ganglia and thalamic region. In other occasions peripheral neoplasms developing in neighbouring structures like the cerebral lobes, the ventricular walls, choroidal plexus, pineal gland and the hypothalamic-chiasmatic-suprasellar region can spread to the deep brain.
Imaging cannot reliably indicate that a histological picture for a tumour of this kind should be suspected. Although the macro- and microscopical characteristics of brain tumours are often the basis of the imaging findings, these data usually overlap and are only useful as an approximation tool.
Nonetheless, whilst radiologists and clinicians must always be cautious when evaluating the macroscopic peculiarities of a brain tumour, the value of imaging cannot be overestimated when any sort of pathology is encountered. Moreover, besides the classic CT and MRI findings, new MRI-related techniques, such as magnetic resonance spectroscopy (MRS), are able to extract a different kind of information from cerebral neoplasms, and they could be important widespread diagnostic alternatives in the very near future.
Gene editing constitutes a novel approach for precisely correcting disease-causing gene mutations. Frameshift mutations in COL7A1 causing recessive dystrophic epidermolysis bullosa are amenable to ...open reading frame restoration by non-homologous end joining repair-based approaches. Efficient targeted deletion of faulty COL7A1 exons in polyclonal patient keratinocytes would enable the translation of this therapeutic strategy to the clinic. In this study, using a dual single-guide RNA (sgRNA)-guided Cas9 nuclease delivered as a ribonucleoprotein complex through electroporation, we have achieved very efficient targeted deletion of COL7A1 exon 80 in recessive dystrophic epidermolysis bullosa (RDEB) patient keratinocytes carrying a highly prevalent frameshift mutation. This ex vivo non-viral approach rendered a large proportion of corrected cells producing a functional collagen VII variant. The effective targeting of the epidermal stem cell population enabled long-term regeneration of a properly adhesive skin upon grafting onto immunodeficient mice. A safety assessment by next-generation sequencing (NGS) analysis of potential off-target sites did not reveal any unintended nuclease activity. Our strategy could potentially be extended to a large number of COL7A1 mutation-bearing exons within the long collagenous domain of this gene, opening the way to precision medicine for RDEB.
Highly efficient and safe approaches for precise correction of pathogenic mutations are required to realize the full potential of gene-editing protocols for clinical practice. Here we describe a single-step NHEJ-based CRISPR/Cas9 strategy of COL7A1 mutation-bearing exon deletion with unprecedented efficacy for ex vivo correction of recessive dystrophic epidermolysis bullosa.
The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive ...environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.
The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.
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