Attack-related damage of thalamic nuclei in neuromyelitis optica spectrum disorders.

OBJECTIVES: In neuromyelitis optica spectrum disorders (NMOSD) thalamic damage is controversial, but thalamic nuclei were never studied separately. We aimed at assessing volume loss of thalamic nuclei in NMOSD. We hypothesised that only specific nuclei are damaged, by attacks affecting structures from which they receive afferences: the lateral geniculate nucleus (LGN), due to optic neuritis (ON) and the ventral posterior nucleus (VPN), due to myelitis. METHODS: Thirty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 50.1±14.1 years, 36 women, 25 with prior ON, 36 with prior myelitis) and 37 healthy controls (age: 47.8 ± 12.5 years, 32 women) were included in this cross-sectional study. Thalamic nuclei were assessed in magnetic resonance images, using a multi-atlas-based approach of automated segmentation. Retinal optical coherence tomography was also performed. RESULTS: Patients with ON showed smaller LGN volumes (181.6±44.2 mm3) compared with controls (198.3±49.4 mm3; B=-16.97, p=0.004) and to patients without ON (206.1±50 mm3 ; B=-23.74, p=0.001). LGN volume was associated with number of ON episodes (Rho=-0.536, p<0.001), peripapillary retinal nerve fibre layer thickness (B=0.70, p<0.001) and visual function (B=-0.01, p=0.002). Although VPN was not smaller in patients with myelitis (674.3±67.5 mm3) than controls (679.7±68.33; B=-7.36, p=0.594), we found reduced volumes in five patients with combined myelitis and brainstem attacks (B=-76.18, p=0.017). Volumes of entire thalamus and other nuclei were not smaller in patients than controls. CONCLUSION: These findings suggest attack-related anterograde degeneration rather than diffuse thalamic damage in NMOSD. They also support a potential role of LGN volume as an imaging marker of structural brain damage in these patients.

Role of Combined Lipoic Acid and Vitamin D3 on Astrocytes as a Way to Prevent Brain Ageing by Induced Oxidative Stress and Iron Accumulation.

Brain ageing is a complex multifactorial process characterized by gradual and continuous loss of neuronal functions. It is hypothesized that at the basis of brain ageing as well as age-related diseases, there is an impairment of the antioxidant defense system leading to an increase of oxidative stress. In this study, two different biological aspects involved in brain ageing and neurodegeneration have been investigated: oxidative stress and iron accumulation damage. In primary mouse astrocytes, the stimulation with 50 µM lipoic acid (LA) and 100 nM vitamin D (vitD) was first investigated in a time-course study to determine the dosages to be used in combination and then in a permeability test using an in vitro blood-brain barrier. In a second set of experiments, the role of oxidative stress was investigated pretreating astrocytes with 200 µM H2O2 for 30 min. The ability of vitD and LA alone and combined together to prevent or repair the damage caused by oxidative stress was investigated after 24 h of stimulation by the MTT test, mitochondrial membrane potential measurement, and Western blot analysis. To induce neurodegeneration, cells were pretreated with 300 µM catalytic iron for 6 days and then treated with vitD and LA alone and combined for additional 6 days to investigate the protection exerted by combination, analyzing viability, ROS production, iron concentration, and activation of intracellular pathways. In our study, the combination of LA and vitD showed beneficial effects on viability of astrocytes, since the substances are able to cross the brain barrier. In addition, combined LA and vitD attenuated the H2O2-induced apoptosis through the mitochondrial-mediated pathway. The combination was also able to counteract the adverse conditions caused by iron, preventing its accumulation. All these data support the hypothesis of the synergistic and cooperative activity exerted by LA and vitD in astrocytes indicating a possible new strategy to slow down ageing.

Clinical associations of T2-weighted lesion load and lesion location in small vessel disease: Insights from a large prospective cohort study.

BACKGROUND: Subcortical T2-weighted (T2w) lesions are very common in older adults and have been associated with dementia. However, little is known about the strategic lesion distribution and how lesion patterns relate to vascular risk factors and cognitive impairment. AIM: The aim of this study was to analyze the association between T2w lesion load and location, vascular risk factors, and cognitive impairment in a large cohort of older adults. METHODS: 1017 patients participating in a large prospective cohort study (INtervention project on cerebroVAscular disease and Dementia in the district of Ebersberg, INVADE II) were analyzed. Cerebral T2w white matter and deep grey matter lesions, the so-called white matter hyperintensities (WMHs), were outlined semi-automatically on fluid attenuated inversion recovery images and normalized to standard stereotaxic space (MNI152) by non-linear registration. Patients were assigned to either a low-risk or a high-risk group. The risk assessment considered ankle brachial index, intima media thickness, carotid artery stenosis, atrial fibrillation, previous cerebro-/cardiovascular events and peripheral artery disease as well as a score based on cholesterol levels, blood pressure and smoking. Separate lesion distributions were obtained for the two risk groups and compared using voxel-based lesion-symptom mapping. Moreover, we assessed the relation between lesion location and cognitive impairment (demographically adjusted z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery Plus, CERAD-NAB Plus) using voxel-based statistics (α = 0.05). RESULTS: A total of 878 out of 1017 subjects (86%) had evaluable MRI data and were included in the analyses (mean age: 68.2 ±â€¯7.6 years, female: 515). Patients in the high-risk group were characterized by a significantly higher age, a higher proportion of men, a higher lesion load (p < 0.001), and a worse performance in some of the cognitive subdomain scores (p < 0.05). Voxels with significant associations to the subjects' cerebrovascular risk profiles were mainly found at locations of the corpus callosum, superior corona radiata, superior longitudinal fasciculus, internal and external capsule, and putamen. While several cognitive domains have shown significant associations with the participants' total lesion burden (p < 0.05), no focal WMH locations were found to be associated with cognitive impairment. CONCLUSION: Age, gender, several cognitive scores, and WMH lesion load were shown to be significantly associated with vascular risk factors in a population of older, but cognitively preserved adults. Vascular risk factors seem to promote lesion formation most severely at well-defined locations. While lesion load showed weak associations to some cognitive scores, no focal locations causing specific cognitive disturbances were identified in this large cohort of older adults.

Neural stem cell engraftment and myelination in the human brain.

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.

The pre-lymphatic pathway, the rooths of the lymphatic system in breast tissue: a 3D study.

Three-dimensional (3D) visualisation of microscopic structures provides useful information about their configuration and the spatial (hence functional) relationship between different components in tissues. This paper describes 3D dynamic reconstructions of the pre-lymphatic labyrinth in two cases of "normal" breast core biopsies and one case of pseudoangiomatous stromal hyperplasia. Direct anastomoses between pre-lymphatic channels and true lymphatics of the breast were demonstrated. It is concluded that pre-lymphatics are a way of communication between breast epithelial/stromal structures and the main lymphatic system. The present findings suggest that the existence of pre-lymphatics has to be taken in consideration in the intramammary spread of malignant tumours.

Pleomorphism of the nuclear envelope in breast cancer: a new approach to an old problem.

In routine practice, nuclear pleomorphism of tumours is assessed by haematoxylin staining of the membrane-bound heterochromatin. However, decoration of the nuclear envelope (NE) through the immunofluorescence staining of NE proteins such as lamin B and emerin can provide a more objective appreciation of the nuclear shape. In breast cancer, nuclear pleomorphism is one of the least reproducible parameters to score histological grade, thus we sought to use NE proteins to improve the reproducibility of nuclear grading. First, immuno-fluorescence staining of NE as well as confocal microscopy and three-dimensional reconstruction of nuclei in cultured cells showed a smooth and uniform NE of normal breast epithelium in contrast to an irregular foldings of the membrane and the presence of deep invaginations leading to the formation of an intranuclear scaffold of NE-bound tubules in breast cancer cells. Following the above methods and criteria, we recorded the degree of NE pleomorphism (NEP) in a series of 273 invasive breast cancers tested by immunofluorescence. A uniform nuclear shape with few irregularities (low NEP) was observed in 135 cases or, alternatively, marked folds of the NE and an intranuclear tubular scaffold (high NEP cases) were observed in 138 cases. The latter features were significantly correlated (P-value <0.002) with lymph node metastases in 54 histological grade 1 and in 173 cancers with low mitotic count. Decoration of the NE might thus be regarded as a novel diagnostic parameter to define the grade of malignancy, which parallels and enhances that provided by routine histological procedures.