Brain Diffusivity and Structural Changes in the R6/2 Mouse Model of Huntington Disease.

Diffusion-weighted magnetic resonance (DW-MR) is an important diagnostic tool in Huntington disease (HD), a fatal hereditary neurodegenerative disorder. To clarify the nature of diffusivity changes in HD, we compared the apparent diffusion coefficient of water (ADCW ) acquired by DW-MR with extracellular space volume fraction α and tortuosity λ, measured by the iontophoretic method in the R6/2 mouse model of HD and in wild-type controls (WT). In anisotropic globus pallidus (GP), diffusion measurements were performed in the mediolateral (x), rostrocaudal (y), and ventrodorsal (z) axes. In HD animals, we detected an increase in ADCW in all axes and larger α than in WT mice. No significant difference between WT and HD mice was found in the values of tortuosity (λx , λy , λz ). Despite structural changes in GP, diffusion anisotropy was unaffected in HD mice. Immunohistochemical analysis revealed in HD mice weaker expression of extracellular matrix and a decrease in neuron numbers compared with WT mice. Glial fibrillary acidic protein staining detected astrogliosis-like changes in the morphology of astrocytic processes in HD GP. In the somatosensory cortex, no significant differences in the studied parameters were found. We conclude that in the R6/2 model of HD, a decrease in the number of neurons in the GP results in increased ADCW and α values. Values of λ were not significantly changed as the increase of diffusion obstacles formed by reactive astrocytes was compensated for by the extracellular matrix reduction. © 2016 Wiley Periodicals, Inc.

Diffusion tensor imaging in the characterization of multiple system atrophy.

PURPOSE: Multiple system atrophy (MSA) is a rare neurodegenerative disease that remains poorly understood, and the diagnosis of MSA continues to be challenging. We endeavored to improve the diagnostic process and understanding of in vivo characteristics of MSA by diffusion tensor imaging (DTI). MATERIALS AND METHODS: Twenty MSA subjects, ten parkinsonian dominant (MSA-P), ten cerebellar dominant (MSA-C), and 20 healthy volunteer subjects were recruited. Fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity maps were processed using tract-based spatial statistics. Diffusion data were additionally evaluated in the basal ganglia. A support vector machine was used to assess diagnostic utility, leave-one-out cross-validation in the evaluation of classification schemes, and receiver operating characteristic analyses to determine cutoff values. RESULTS: We detected widespread changes in the brain white matter of MSA subjects; however, no group-wise differences were found between MSA-C and MSA-P subgroups. Altered DTI metrics in the putamen and middle cerebellar peduncles were associated with a positive parkinsonian and cerebellar phenotype, respectively. Concerning clinical applicability, we achieved high classification performance on mean diffusivity data in the combined bilateral putamen and middle cerebellar peduncle (accuracy 90.3%±9%, sensitivity 86.5%±11%, and specificity 99.3%±4%). CONCLUSION: DTI in the middle cerebellar peduncle and putamen may be used in the diagnosis of MSA with a high degree of accuracy.

Utilizing Autologous Multipotent Mesenchymal Stromal Cells and ß-Tricalcium Phosphate Scaffold in Human Bone Defects: A Prospective, Controlled Feasibility Trial.

The purpose of this prospective controlled study was to compare healing quality following the implantation of ultraporous ß-tricalcium phosphate, containing either expanded autologous mesenchymal stromal cells (trial group, 9 patients) or ß-tricalcium phosphate alone (control group, 9 patients), into femoral defects during revision total hip arthroplasty. Both groups were assessed using the Harris Hip Score, radiography, and DEXA scanning at 6 weeks and 3, 6, and 12 months postoperatively. A significant difference in the bone defect healing was observed between both groups of patients (P < 0.05). In the trial group, trabecular remodeling was found in all nine patients and in the control group, in 1 patient only. Whereas, over the 12-month follow-up period, no significant difference was observed between both groups of patients in terms of the resorption of ß-tricalcium phosphate, the significant differences were documented in the presence of radiolucency and bone trabeculation through the defect (P < 0.05). Using autologous mesenchymal stromal cells combined with a ß-tricalcium phosphate scaffold is a feasible, safe, and effective approach for management of bone defects with compromised microenvironment. The clinical trial was registered at the EU Clinical Trials Register before patient recruitment has begun (EudraCT number 2012-005599-33).

Correlation between relaxometry and diffusion tensor imaging in the globus pallidus of Huntington's disease patients.

Huntington's disease (HD) is an inherited neurodegenerative disorder with progressive impairment of motor, behavioral and cognitive functions. The clinical features of HD are closely related to the degeneration of the basal ganglia, predominantly the striatum. The main striatal output structure, the globus pallidus, strongly accumulates metalloprotein-bound iron, which was recently shown to influence the diffusion tensor scalar values. To test the hypothesis that this effect dominates in the iron-rich basal ganglia of HD patients, we examined the globus pallidus using DTI and T2 relaxometry sequences. Quantitative magnetic resonance (MR), clinical and genetic data (number of CAG repeats) were obtained from 14 HD patients. MR parameters such as the T2 relaxation rate (RR), fractional anisotropy (FA) and mean diffusivity (MD) were analysed. A positive correlation was found between RR and FA (R2=0.84), between CAG and RR (R2=0.59) and between CAG and FA (R2=0.44). A negative correlation was observed between RR and MD (R2=0.66). A trend towards correlation between CAG and MD was noted. No correlation between MR and clinical parameters was found. Our results indicate that especially magnetic resonance FA measurements in the globus pallidus of HD patients may be strongly affected by metalloprotein-bound iron accumulation.

MR relaxometry in Huntington's disease: correlation between imaging, genetic and clinical parameters.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease. It has been hypothesized that changes of iron content in the brain may be involved in the pathogenesis of HD. To ascertain the hypothesis, we investigated the relationship between T2 relaxation time (T2), the number of cytosine-adenine-guanine triplet repeats (CAG) and clinical status in patients suffering from HD. 34 HD patients (mean age 50.1+/-11.8 standard deviation (SD) years) and 34 control subjects (49.6+/-13.3) were scanned using a 1.5 tesla magnetic resonance (MR) scanner and the patients underwent clinical and genetic testing. A multiple echo sequence was employed for T2 measurements. T2 from healthy volunteers matched previous studies. A T2 shortening was found in the pallidum of HD patients compared to controls (65.4+/-6.4 ms vs. 71.8+/-3.6 ms, P<0.00001). A correlation between the number of CAG and T2 was found for the left pallidum (decrease in T2, P<0.05) and an inverse correlation for the left caudate (increase in T2, P<0.05). In HD patients, alterations in iron levels may be caused by an alteration in its axonal transport. The observed T2/CAG covariations may reflect changes in levels and forms of iron: this suggests that HD patients with a higher genetic load have more ferritin-bound ("safe form") iron in the pallidum and/or more low-molecular ("toxic") iron in the caudate. An increase in "toxic" iron in the caudate may enable oxidative stress and thus underlie progression of the disease.