See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article.Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

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Previous studies in humans have shown that bilateral loss of vestibular function is associated with a significant bilateral atrophy of the hippocampus, which correlated with the patients’ spatial memory deficits. More recently, patients who had recovered from unilateral vestibular neuritis have been reported to exhibit a significant atrophy of the left posterior hippocampus. Therefore, we investigated whether bilateral vestibular deafferentation (BVD) would result in a decrease in neuronal number or volume in the rat hippocampus, using stereological methods. At 16 months post-BVD, we found no significant differences in hippocampal neuronal number or volume compared to sham controls, despite the fact that these animals exhibited severe spatial memory deficits. By contrast, using bromodeoxyuridine (BrdU) as a marker of cell proliferation, we found that the number of BrdU-labeled cells significantly increased in the dentate gyrus of the hippocampus between 48 h and 1 week following BVD. Although a substantial proportion of these cells survived for up to 1 month, the survival rate was significantly lower in BVD animals when compared with that in sham animals. These results suggest a dissociation between the effects of BVD on spatial memory and hippocampal structure in rats and humans, which cannot be explained by an injury-induced increase in cell proliferation.

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