Faculty Bibliography

BACKGROUND AND PURPOSE: Radiologic markers in multicenter trials are often confounded by different instrumentation used. Our goal was to estimate the variance of the global concentration of the neuronal cell marker N-acetylaspartate (NAA) among research centers using MR imaging scanners of different models, from different manufacturers, and of different magnetic field strength. MATERIALS AND METHODS: Absolute millimolar amounts of whole-brain NAA (WBNAA) were quantified with nonlocalizing proton MR spectroscopy in the brains of 101 healthy subjects (53 women, 48 men) aged 16-59 years (mean, 34.2 years). Twenty-three were scanned at 1 institute in a 1.5T Siemens Vision; 31 from another institute were studied with a 1.5T Siemens SP63; 36 were scanned at a third institute (24 with a 1.5T Vision, 12 with a 3T Siemens Trio); and 11 were obtained at a fourth institute using a 4T GE Signa 5.x. The NAA amounts were quantified with phantom-replacement and divided by the brain volume, segmented from MR imaging, to yield the concentration, a metric independent of brain size suitable for cross-sectional comparison. RESULTS: The average WBNAA concentration among institutions was 12.2 +/- 1.2 mmol/L. The subjects' WBNAA distributions did not differ significantly (p > .237) among the 4 centers, regardless of scanner manufacturer, model, or field strength and irrespective of whether adjustments were made for age or sex. CONCLUSION: Absolute quantification against a standard makes the WBNAA concentration insensitive to the MR hardware used to acquire it. This important attribute renders it a robust surrogate marker for multicenter neurologic trials

LTP and other rapidly induced forms of synaptic modification tune individual synaptic weights, whereas slower forms of plasticity such as adaptation to inactivity are thought to keep neurons within their firing limits and preserve their capability for information processing. Here we describe progress in understanding the relationship between LTP and adaptation to inactivity. A prevailing view is that adaptation to inactivity is purely postsynaptic, scales synaptic strength uniformly across all synapses, and thus preserves relative synaptic weights without interfering with signatures of prior LTP or the relative capacity for future LTP. However, recent evidence in hippocampal neurons indicates that, like LTP, adaptation to AMPA receptor blockade can draw upon a repertoire of synaptic expression mechanisms including enhancement of presynaptic vesicular turnover and increased quantal amplitude mediated by recruitment of homomeric GluR1 AMPA receptors. These pre- and postsynaptic changes appeared coordinated and preferentially expressed at subset of synapses, thereby increasing the variability of miniature EPSCs. In contrast to the NMDA receptor-, Ca2+ entry-dependent induction of LTP, adaptation to inactivity may be mediated by attenuation of voltage-sensitive L-type Ca2+ channel function. The associated intracellular signaling involves elevation of betaCaMKII, which in turn downregulates alphaCaMKII, a key player in LTP. Thus, adaptation to inactivity and LTP are not strictly independent with regard to mechanisms of signaling and expression. Indeed, we and others have found that responses to LTP-inducing stimuli can be sharply altered by prior inactivity, suggesting that the slow adaptation changes the rules of plasticity-an interesting example of 'metaplasticity'