10 research outputs found
WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity
<p>Abstract</p> <p>Background</p> <p>The <it>Wld<sup>S </sup></it>mouse mutant ("Wallerian degeneration-slow") delays axonal degeneration in a variety of disorders including <it>in vivo </it>models of Parkinson's disease. The mechanisms underlying <it>Wld<sup>S </sup></it>-mediated axonal protection are unclear, although many studies have attributed <it>Wld<sup>S </sup></it>neuroprotection to the NAD<sup>+</sup>-synthesizing Nmnat1 portion of the fusion protein. Here, we used dissociated dopaminergic cultures to test the hypothesis that catalytically active Nmnat1 protects dopaminergic neurons from toxin-mediated axonal injury.</p> <p>Results</p> <p>Using mutant mice and lentiviral transduction of dopaminergic neurons, the present findings demonstrate that <it>Wld<sup>S </sup></it>but not Nmnat1, Nmnat3, or cytoplasmically-targeted Nmnat1 protects dopamine axons from the parkinsonian mimetic N-methyl-4-phenylpyridinium (MPP<sup>+</sup>). Moreover, NAD<sup>+ </sup>synthesis is not required since enzymatically-inactive <it>Wld<sup>S </sup></it>still protects. In addition, NAD<sup>+ </sup>by itself is axonally protective and together with <it>Wld<sup>S </sup></it>is additive in the MPP<sup>+ </sup>model.</p> <p>Conclusions</p> <p>Our data suggest that NAD<sup>+ </sup>and <it>Wld<sup>S </sup></it>act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP<sup>+ </sup>is thought to impair mitochondrial function, these results suggest that <it>Wld<sup>S </sup></it>might be involved in preserving mitochondrial health or maintaining cellular metabolism.</p
Motor asymmetry and substantia nigra volume are related to spatial delayed response performance in Parkinson disease
Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD (n = 35) and control (n = 28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory
Emotional eating phenotype is associated with central dopamine D2 receptor binding independent of body mass index
PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[(11)C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI
Diffusion Tensor Imaging Of the Brain in Type 1 Diabetes
Individuals with Type 1 diabetes mellitus (T1DM) are required to carefully manage their insulin dosing, dietary intake, and activity levels in order to maintain optimal blood sugar levels. Over time, exposure to hyperglycaemia is known to cause significant damage to the peripheral nervous system, but its impact on the central nervous system has been less well studied. Researchers have begun to explore the cumulative impact of commonly experienced blood glucose fluctuations on brain structure and function in patient populations. To date, these studies have typically used magnetic resonance imaging to measure regional grey and white matter volumes across the brain. However, newer methods, such as diffusion tensor imaging (DTI) can measure the microstructural properties of white matter, which can be more sensitive to neurological effects than standard volumetric measures. Studies are beginning to use DTI to understand the impact of T1DM on white matter structure in the human brain. This work, its implications, future directions, and important caveats, are the focus of this review
Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans
PET measurements of dopaminergic D(2)-like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The PET radioligand [(18) F] (N-Methyl)Benperidol ([(18)F]-NMB) has high affinity and selectivity for D(2)-like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate use of a graphical method utilizing a reference tissue region for ([(18)F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (p<0.0001 by repeated measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward; thereby simplifying these measurements