Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias.

Abstract

Synapse loss has been found to be the major correlate of cognitive decline in Alzheimer disease (AD), and prefrontal synapse loss has been found in patients with frontotemporal dementia (FTD). To see if our hypothesis that within each FTD case, regional synapse loss would correlate with lateralizing neuropsychologic and neurobehavioral deficits would be correct. We analyzed synaptophysin as a marker for synapse loss in snap-frozen brain samples, using an enzyme-linked immunosorbent assay technique. Quantitative results were obtained by comparing patient data with a standard curve made by analyzing serial dilutions of a recombinant synaptophysin protein fragment. A board-certified neuropsychologist and a board-certified neurologist, both unaware of the synaptophysin results, determined areas of primary neuropsychologic and neurobehavioral dysfunction. Relationships between areas of primary dysfunction and synapse loss were analyzed using the binomial test. Six cases of FTD, 28 cases of AD, and 16 nondemented control subjects. Five of 6 FTD cases had regional synaptophysins correlating with lateralizing frontal or temporal deficits. Three of 6 correlated in 2 or more regions. Although our results were higher than that expected based on a pure-chance mechanism (50% vs 34%), statistical significance was not attained. We found a trend for an association between synapse loss and lateralizing neuropsychologic and neurobehavioral deficits in FTD. Studies in larger numbers of FTD cases are planned with the goal of attaining statistically significant conclusions.