Creation of Computerized 3D MRI-Integrated Atlases of the Human Basal Ganglia and Thalamus

Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo

p73 Regulates Neurodegeneration and Phospho-Tau Accumulation during Aging and Alzheimer's Disease

SummaryThe genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/− mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/− mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/− neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders

Impaired TrkB signaling underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington’s Disease

The principal projection neurons of the striatum are critically dependent on an afferent supply of brain derived neurotrophic factor (BDNF) for neurotrophic support. These neurons express TrkB, the cognate receptor for BDNF, which activates signaling pathways associated with neuronal survival and phenotypic maintenance. Impairment of the BDNF-TrkB pathway is suspected to underlie the early dysfunction and prominent degeneration of striatal neurons in Huntington Disease (HD). Some studies in HD models indicate that BDNF supply is reduced, while others suggest that TrkB signaling is impaired earlier in disease progression. It remains important to determine whether a primary defect in TrkB signaling underlies reduced neurotrophic support and the early vulnerability of striatal neurons in HD. Using the transgenic R6/2 mouse model of HD we found that prior to striatal degeneration there are early deficits in striatal protein levels of activated phospho-TrkB and the downstream-regulated protein DARPP-32. In contrast, total-TrkB and BDNF protein levels remained normal. Primary neurons cultured from R6/2 striatum exhibited reduced survival in response to exogenous BDNF applications. Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures. These results suggest that neurotrophic support of striatal neurons is attenuated early in disease progression due to defects in TrkB signal transduction in the R6/2 model of HD

Association of candidate gene polymorphisms for autoimmune thyroid diseases in patients with familial diffuse toxic goiter and autoimmune thyroiditis

Aim: to study the relation polymorphism of some genes of the immune response with familial autoimmune thyroid disease. Materials and methods. 100 patients from 49 families were examined. At least 2 first-degree affected relatives with autoimmune thyroiditis or diffuse toxic goiter were included from each family. 76 persons were included to control group without thyroid pathology and negative history of any thyroid disease in families. Clinical, hormonal, ultra-sound data was collected for each subject. Genotyping ofCTLA4 A49G and PTPN22 C1858T polymorphisms was performed for 70 patients (35 families) with familial autoimmune thyroid disease and for all subjects from the control group. Results. Autoimmune thyroid disease was observed among one generation (siblings) in 11 families (22.5%) and among two generations (parent-child) in 38 families (75.5%). Patients with chronic autoimmune thyroiditis with hypothyroidism in the outcome were dominated – 66%, 34% experienced diffuse toxic goiter. Autoimmune thyroiditis was observed in parent and offspring from 21 families (55%). In the group of siblings autoimmune thyroiditis was diagnosed for both relatives in 6 families (54%). Frequency of genotypes of CTLA4 A49G polymorphism is not differ between patients with familial autoimmune thyroid disease and control group. Carriage of T allele of PTPN22 C1858T polymorphism is associated with the risk of autoimmune thyroid disease developing in a group of female offspring: OR = 3.175; 95% CI 1,423–7,262. These results allow us to recommend to test this polymorphism to identify patients with the risk of autoimmune thyroid diseases in families. Conclusion. Taking into account that DNA testing is one of the most important part of personalized approach in medicine, the current results of molecular genetic study for familial cases of autoimmune thyroid disease creates prerequisites for optimizing the diagnostic pathway of these patients

The metabolic syndrome as a risk factor for colorectal cancer

Objective. To evaluate the prognostic significance of metabolic syndrome (MS) in the development of colorectal cancer (CRC) using various MS criteria in Novosibirsk population. Materials and Methods. The study was designed as nested «case-control». Baseline population cohort (9360 men, women aged 45–69) was examined in the HAPIEE project and followed-up during 11 years. The “cases” included all subjects, who had CRC during 11-year follow-up according to the Register of Cancer (n=99, M-52, M-47). The matched control group (2/1) was selected from HAPIEE cohort (n=198, m-104, w-94). The prospective study of CRC was supported by RSF. MS criteria were determined in accordance to VNOK (2009), IDF (2005), NCEP ATP III (2001). Statistical package SPSS v.11.0 was used. Logistic regression was used to estimate the association between MS and risk of CRC. Results. Women with glucose levels ≥6.1 mmol/l had 3 times higher 11-year risk of CRC then those with glucose <6.1 mmol/l (OR=3.11; 95%CI:1.23–7.87, VNOK, 2009; OR=3.20; 95%CI:1.27–8.08, NCEP ATP III, 2001). Blood pressure (BP) ≥130/85 mmHg was associated with decreased risk of CRC in women and in both sexes, but the relationship became insignificant after controlling for antihypertensive treatment. Other components of the MS were not significantly associated with CRC risk. Conclusions. In studied sample the 11-year risk of developing CRC was significantly increased in women with elevated glucose levels. The negative relationship between elevated BP and the risk of CRC in women and both sexes became insignificant when adjusted for antihypertensive treatment; this finding requires further exploration

Flow-Based Fiber Tracking With Diffusion Tensor and Q-Ball Data:

this paper, we extend our previously proposed flow-based fiber tracking approaches (Campbell et al., 2002a,b) in order to use the information in the full diffusion pdf estimated using either HARD or DT techniques. This algorithm is a modification and extension of the Fast Marching Tractography (FMT) technique (Parker et al., 2002a), which uses the principal diffusion direction only, and is similar to several surface evolution approaches that use the full diffusion tensor (Batchelor et al., 2001; O'Donnell et al., 2002; Tournier et al., 2003). Our extension of the FMT technique consists of using all of the information in the diffusion tensor or, if available, HARD measurements. The surface evolution approach has the advantage that it allows tracking to proceed in a continuum of directions, as may be desired in cases where there is uncertainty and/or multiple fiber directions. We show fiber tracking results using both HARD and DT data in the human brain, noting that the diffusion tensor can provide more information than that given by its principal eigenvector only and that HARD reconstruction can give us more information still. Additionally, we quantitatively compare the performance of the flow-based approach to that of line propagation using the PDD. To do so, we designed a physical phantom with known connectivity from excised rat spinal cord. Previous validation studies have been done using a single excised cord (Campbell et al., 2002b; Vemuri et al., 2002) and in the macaque (Parker et al., 2002b): in this study, complex known configurations of subvoxel curvature and fiber crossing are created and scanned at a standard human imaging resolution. While simulated data can provide a gold standard to which tracking results can be compared (Lazar and Alexander, 2003; Lori et..