National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

NMDA antagonists exacerbate neuronal death caused by proteasome inhibition in cultured cortical and striatal neurons.

The proteasome is involved in multiple cellular processes including control of the cell cycle, apoptosis and intracellular signalling; loss of proteasome function has been postulated to participate in the pathogenesis of triplet repeat diseases. We examined the vulnerability of central neurons to proteasome inhibition and tested the ability of anti-excitotoxic and anti-apoptotic treatments to attenuate proteasome inhibition-induced neuronal death. Exposure of murine neocortical cultures to proteasome inhibitors (0.1-10 microm clasto-lactacystin beta-lactone or MG-132) for 48 h resulted in widespread neuronal death associated with a reduction in intracellular free calcium; higher inhibitor concentrations killed astrocytes. Cultured striatal neurons were more vulnerable than cortical neurons. Within each population, the NADPH diaphorase-positive neuronal subpopulation was more vulnerable than the general neuronal population. Enhancing calcium entry with S(-)BayK8644 or kainate, or blocking apoptosis with cycloheximide, actinomycin D or Z-VAD.FMK attenuated neuronal death, whereas, reducing calcium entry with NMDA antagonists or R(+)BayK8644 potentiated neuronal death. These findings suggest that proteasome inhibition can induce selective neuronal apoptosis associated with intracellular calcium starvation, and point to manipulation of intracellular calcium as a specific therapeutic strategy. In particular, concern is raised that glutamate receptor antagonists might exacerbate, rather than attenuate, proteasome inhibition-induced neuronal death.

Raising intracellular calcium attenuates neuronal apoptosis triggered by staurosporine or oxygen-glucose deprivation in the presence of glutamate receptor blockade.

The relationship between intracellular Ca(2+) ([Ca(2+)](i)) regulation and programmed cell death is not well-defined; both increases and decreases in [Ca(2+)](i) have been observed in cells undergoing apoptosis. We determined [Ca(2+)](i) in cultured murine cortical neurons undergoing apoptosis after exposure to staurosporine or following oxygen-glucose deprivation in the presence of glutamate receptor antagonists. Neuronal [Ca(2+)](i) was decreased 1-4 h after exposure to staurosporine (30 nM). A [Ca(2+)](i) decrease was also observed 1 h after the end of the oxygen-glucose deprivation period when MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were added to the bathing medium during the deprivation period. A similar decrease in [Ca(2+)](i) produced by reducing extracellular Ca(2+) or chelating intracellular Ca(2+) was sufficient to induce neuronal apoptosis. Raising [Ca(2+)](i) either by activating voltage-sensitive Ca(2+) channels with (-) Bay K8644 or by application of low concentrations of kainate attenuated both staurosporine and oxygen-glucose deprivation-induced apoptosis.