Selective 5HT3 antagonists and sensory processing: a systematic review.

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson's disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson's disease.

The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation.

Seizure outcomes and survival in adult low-grade glioma over 11 years: living longer and better.

BACKGROUND: There has been a trend toward earlier and more aggressive resection for low-grade gliomas (LGGs). This study set out to compare seizure control and survival of adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine whether a change in surgical philosophy has led to a corresponding improvement in outcomes. METHODS: We conducted a retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumor, and seizure characteristics between 2006 and 2017. RESULTS: We studied 79 patients in 2006 and 74 patients in 2017. There was no significant difference between the 2 groups in age at presentation, tumor location, or integrated pathological diagnosis. The numbers of complete or partial resections increased from 21.5% in 2006 to 60.8% in 2017 (P < .05). Five- and 10-year overall survival increased from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (P < .001); similarly, 5- and 10-year progression-free survival increased from 47.0% and 30.7% in 2006 to 93.1% and 68.7% in 2017. The proportion of patients with intractable epilepsy declined from 72.2% in 2006 to 43.2% in 2017 (P < .05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017). CONCLUSION: Management of LGG over the last 11 years has led to substantial improvements in survival and seizure control. This is most likely thanks to a change in surgical philosophy, with early resection now favored over watchful waiting where possible.

Quantitative analysis of whole-tumor Gd enhancement histograms predicts malignant transformation in low-grade gliomas.

PURPOSE: To quantify subtle gadolinium (Gd) enhancement (signal increase) in whole-tumor histograms and optimize their ability to predict subsequent malignant transformation in low-grade gliomas (LGGs). MATERIALS AND METHODS: We analyzed histograms from 21 adult subjects with LGGs (eight nontransformers and 13 transformers) who had been imaged every six months for periods of two to five years. Before transformation these tumors were reported as radiologically non-enhancing. Imaging included a T(1)-weighted volume sequence before and after a double dose of Gd-DTPA contrast agent. Image data sets were spatially registered and subtracted to obtain maps of percent enhancement (%E). Tumor outlines were defined on fluid-attenuated inversion recovery (FLAIR) images, and the volumes were calculated. Histogram tails were analyzed to obtain the volume (mL) of subtly enhancing tissue (%E > 10%). RESULTS: Baseline enhancing volumes were higher for Ts than for NTs (P < 0.005). Kaplan-Meier survival curves for a threshold of 4 mL showed clear differences at five years (P < 0.04). Pretransformation examinations predicted transformation (corrected threshold = 3.0 mL, P = 0.011). CONCLUSION: Clear histogram differences at presentation suggest that the process of transformation starts very early. It is now possible to identify individuals at high risk for transformation at baseline by quantifying the volume of subtly enhancing tumor tissue, and such findings could have an impact on patient management.