Volume Estimation of the Thalamus Using Freesurfer and Stereology: Consistency between Methods

Freely available automated MR image analysis techniques are being increasingly used to investigate neuroanatomical abnormalities in patients with neurological disorders. It is important to assess the specificity and validity of automated measurements of structure volumes with respect to reliable manual methods that rely on human anatomical expertise. The thalamus is widely investigated in many neurological and neuropsychiatric disorders using MRI, but thalamic volumes are notoriously difficult to quantify given the poor between-tissue contrast at the thalamic gray-white matter interface. In the present study we investigated the reliability of automatically determined thalamic volume measurements obtained using FreeSurfer software with respect to a manual stereological technique on 3D T1-weighted MR images obtained from a 3 T MR system. Further to demonstrating impressive consistency between stereological and FreeSurfer volume estimates of the thalamus in healthy subjects and neurological patients, we demonstrate that the extent of agreeability between stereology and FreeSurfer is equal to the agreeability between two human anatomists estimating thalamic volume using stereological methods. Using patients with juvenile myoclonic epilepsy as a model for thalamic atrophy, we also show that both automated and manual methods provide very similar ratios of thalamic volume loss in patients. This work promotes the use of FreeSurfer for reliable estimation of global volume in healthy and diseased thalami.</p

Early microstructural white matter changes in patients with HIV: A diffusion tensor imaging study

Background: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV).Methods: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests.Results: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients ( HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV- MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV- associated neurocognitive disorder showed widespread FA-reduction.Conclusion: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients.</p

Monocyte Chemoattractant Protein-1-Deficiency Impairs the Expression of IL-6, IL-1β and G-CSF after Transient Focal Ischemia in Mice

Monocyte chemoattractant protein-1 (MCP-1), a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1) performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2) analyzed a possible impact of MCP-1 on astrocyte activation (3) investigated the cellular origin of respective inflammatory cytokines and (4) analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

Neuromyelitis optica and pregnancy during therapeutic B cell depletion: infant exposure to anti-AQP4 antibody and prevention of rebound relapses with low-dose rituximab postpartum

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum

Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2

BACKGROUND Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of \geq70% European Carotid Surgery Trial (ECST) criteria. METHODS SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported. FINDINGS It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates. INTERPRETATION The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials