BDNF and TRiC-inspired reagent rescue cortical synaptic deficits in a mouse model of Huntington's disease.

Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.

Can Apparent Diffusion Coefficient (ADC) maps replace Diffusion Tensor Imaging (DTI) maps to predict the volumetric response of meningiomas to Gamma Knife Radiosurgery?

PURPOSE: Noninvasive methods are desired to predict the treatment response to Stereotactic Radiosurgery (SRS) to improve individual tumor management. In a previous study, we demonstrated that Diffusion Tensor Imaging (DTI)-derived parameter maps significantly correlate to SRS response. This study aimed to analyze and compare the predictive value of intratumoral ADC and DTI parameters in patients with meningiomas undergoing radiosurgery. METHODS: MR images of 70 patients treated with Gamma Knife SRS for WHO grade I meningiomas were retrospectively reviewed. MR acquisition included pre- and post-treatment DWI and DTI sequences, and subtractions were calculated to assess for radiation-induced changes in the parameter values. RESULTS: After a mean follow-up period (FUP) of 52.7 months, 69 of 70 meningiomas were controlled, with a mean volume reduction of 34.9%. Whereas fractional anisotropy (FA) values of the initial exam showed the highest correlation to tumor volume change at the last FU (CC = - 0.607), followed by the differences between first and second FU values of FA (CC = - 0.404) and the first longitudinal diffusivity (LD) value (CC = - 0.375), the correlation coefficients of all ADC values were comparably low. Nevertheless, all these correlations, except for ADC measured at the first follow-up, reached significance. CONCLUSION: For the first time, the prognostic value of ADC maps measured in meningiomas before and at first follow-up after Gamma Knife SRS, was compared to simultaneously acquired DTI parameter maps. Quantities assessed from ADC maps present significant correlations to the volumetric meningioma response but are less effective than correlations with DTI parameters.

A missense point mutation in nerve growth factor (NGFR100W) results in selective peripheral sensory neuropathy.

The R100W mutation in nerve growth factor is associated with hereditary sensory autonomic neuropathy V in a Swedish family. These patients develop severe loss of perception to deep pain but with apparently normal cognitive functions. To better understand the disease mechanism, we examined a knockin mouse model of HSAN V. The homozygous mice showed significant structural deficits in intra-epidermal nerve fibers (IENFs) at birth. These mice had a total loss of pain perception at ∼2 months of age and often failed to survive to adulthood. Heterozygous mutant mice developed a progressive degeneration of small sensory fibers both behaviorally and functionally: they showed a progressive loss of IENFs starting at the age of 9 months accompanied with progressive loss of perception to painful stimuli such as noxious temperature. Quantitative analysis of lumbar 4/5 dorsal root ganglia revealed a significant reduction in small size neurons, while analysis of sciatic nerve fibers revealed the heterozygous mutant mice had no reduction in myelinated nerve fibers. Significantly, the amount of NGF secreted from mouse embryonic fibroblasts were reduced from both heterozygous and homozygous mice compared to their wild-type littermates. Interestingly, the heterozygous mice showed no apparent structural alteration in the brain: neither the anterior cingulate cortex nor the medial septum including NGF-dependent basal forebrain cholinergic neurons. Accordingly, these animals did not develop appreciable deficits in tests for brain function. Our study has thus demonstrated that the NGFR100W mutation likely affects the structure and function of peripheral sensory neurons.