There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results.To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes.We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10− 3 mm2/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I2 = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I2 = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = − 0.5, p = 0.22, I2 = 28%).The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker.

Background and Purpose-Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34 ϩ peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. Methods-G-CSF (10 g/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34 ϩ count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34 ϩ cells reinjected on day 6. Results-Sixty patients were recruited at mean of 8 days (SD Ϯ5) post ictus, with mean age 71 years (Ϯ12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3Ϯ1.3, placebo 3.0Ϯ1.3) at 90 days, or the number of injections received. G-CSF increased CD34 ϩ and total white cell counts of 9.5-and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF-treated patients (Pϭ0.06). In 1 participant, there was suggestion that labeled CD34 ϩ cells had migrated to the ischemic lesion. Conclusions-This

BackgroundThe mechanisms driving osteoarthritic pain remain poorly understood, but there is increasing evidence for a role of the central nervous system in the chronification of pain. We used functional magnetic resonance imaging to investigate the influence of a model of unilateral knee osteoarthritis on nociceptive processing.ResultsFour to five weeks post intra-articular injection of monosodium iodoacetate (MIA, 1 mg) into the left knee, Sprague Dawley rats were anesthetized for functional magnetic resonance imaging studies to characterize the neural response to a noxious stimulus (intra-articular capsaicin injection). In a two-arm cross-over design, 5 µM/50 µl capsaicin was injected into either the left knee (n = 8, CAPS-MIA) or right control knee (n = 8, CAPS-CON), preceded by contralateral vehicle (SAL) injection. To assess neural correlates of mechanical hyperalgesia, hindpaws were stimulated with von Frey hairs (8 g: MIA; 15 g: control knee, based on behavioral withdrawal responses). The CAPS-MIA group exhibited significant activation of the periaqueductal gray, unilateral thalamus and bilateral mensencephalon, superior-colliculus, and hippocampus, with no significant activation in the other groups/conditions. Capsaicin injection increased functional connectivity in the mid-brain network and mediodorsal thalamic nucleus, hippocampus, and globus pallidus, which was significantly stronger in CAPS-MIA compared to CAPS-CON groups. Mechanical stimulation of the hyperalgesic (ipsilateral to MIA knee) and normalgesic (contralateral) hindpaws evoked qualitatively different brain activation with more widespread brainstem and anterior cingulate (ACC) activation when stimulating the hyperalgesic paw, and clearer frontal sensory activation from the normalgesic paw.ConclusionsWe provide evidence for modulation of nociceptive processing in a chronic knee osteoarthritis pain model with stronger brain activation and alteration of brain networks induced by the pro-nociceptive stimulus. We also report a shift to a medial pain activation pattern following stimulation of the hyperalgesic hindpaw. Taken together, our data support altered neural pain processing as a result of peripheral and central pain sensitization in this model.

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ObjectivesTo compare the magnetisation transfer ratio (MTR) and volume of incidental white matter (WM) lesions of patients who have had anti-tumour necrosis factor-α (TNFα) therapy to that of healthy controls, in order to test the hypothesis that anti-TNFα therapy may cause clinically silent white matter changes.MethodsTen patients (seven rheumatoid arthritis, three ankylosing spondylitis) who had at least 3 months of anti-TNFα therapy and were free of neurological symptoms and 10 matched healthy controls were recruited and scanned on a 3T MRI with the following protocol-T2 FLAIR, T1 MPRAGE and two sets of T1 gradient-recalled sequences with and without a saturation pulse. WM lesions were defined semi-automatically and graded as small/large (ie, less/more than the 95th centile of lesion sizes in the control group). Lesion MTR histograms for both groups were generated.ResultsThere was no difference in the total lesion load between both groups but the total number of large lesions was higher in patients (p=0.017). Mean lesion MTR values in both groups were not significantly different from each other (0.54 vs 0.52). Lesion MTR histograms of both groups showed no difference in their peak height and position suggesting that incidental white matter lesions seen in our group of patients are unlikely to be pathologically different to those commonly detected in the healthy population, which are likely ischaemic in origin rather than inflammatory demyelinating. Rheumatoid patients may have more confluent/larger lesions due to an inherently higher ischaemic risk. Therefore we have not shown that anti-TNFα therapy causes white matter changes in neurologically asymptomatic patients.