Prodromal non-motor symptoms of Parkinson’s disease

The motor symptoms of Parkinson’s disease (PD), bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, the intraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascending gradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported. Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder. Additionally, the neuropathological alterations outside the substantia nigra are soundly correlated with the non-motor symptoms of PD. As a result of these findings, interest is growing in the identification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest that autonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleep behavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available to detect most of these symptoms. Thus, the identification of prodromal non-motor symptoms may contribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy of neuroprotective agents

Optimising biomarkers for accurate ependymoma diagnosis, prognostication and stratification within International Clinical Trials: A BIOMECA study

BACKGROUND: Accurate identification of brain tumour molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study. METHODS: Across six European BIOMECA laboratories we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via FISH and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH. RESULTS: DNA Methylation profiling classified 65.3% (n=96/147) of cases as EPN-PFA and 15% (n=22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99-100% across three centres). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP1- fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-centre concordance and low sensitivity and specificity whilst MIP, MLPA and DNA methylation-based approaches demonstrated greater accuracy. CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q and CDKN2A loss whilst FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

GENE SILENCING BY S-ADENOSYLMETHIONINE IN MUSCLE DIFFERENTIATION

if (2001) 3.60

Neurotoxicity of Kainate to the hippocampus is not accrued by aging, stress and exogenous corticosterone in wistar kyoto and spontaneously hypertensive rats.

It has been reported that a high corticosterone milieu can exacerbate various experimental insults to the nervous system, in particular to the hippocampus. However, in many of these studies the above milieu was attained by injecting corticosterone in doses (e.g. 10 mg/rat) producing supraphysiological concentrations. In the present study we have investigated whether high plasma corticosterone levels, such as those associated with aging or stress, potentiate a hippocampal excitotoxic insult. Male Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) at the age of 6, 12, 18 and 24 months (only WKY for the oldest age) were used. As in other strains, aging in these rats was marked by an increase in basal plasma corticosterone levels. Rats were infused in the dorsal hippocampus with kainic acid (0.035 µg/hippocampus) and the neuronal injury was evaluated within the areas CA3 and CA4. Results indicated that neither aging nor the hypertensive condition affected kainic acid neurotoxicity. In order to study the effect of stress, rats were stressed twice a day, with alternate types of stressors to avoid possible habituation, 3 days prior to and 3 days following the kainic acid infusion. Using this experimental paradigm the hippocampal damage in stressed rats was of the same degree as in non-stressed controls. In a complementary set of experiments, 6 month old WKY and SHR rats were injected with corticosterone (10 mg/rat s.c.). Four hours after administration plasma corticosterone levels in the range of 60-70 µg/100 ml were found. Moreover, a time-course study showed a plasma corticosterone peak in the range of 240 µg/100 ml. Daily corticosterone administration for 3 days before and 3 days after kainic acid infusion potentiated the hippocampal damage in 6 months old SHR but not in the WKY. These results demonstrate that elevation of corticosterone levels within physiological range does not exacerbate hippocampal kainate neurotoxicity and that pharmacological doses of glucocorticoid hormone, which produces plasma levels well above those observable in any physiopathological condition, might, with some strain dependency, potentiate a hippocampal neurotoxic insult