Background: There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and ␤-amyloid 42 (A␤42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. Objective: To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. Design: Cross-sectional study to correlate levels of CSF A␤42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain.

Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.

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Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n=25) and autopsy controls (n=7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM-positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.

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The highly polysialylated neural cell adhesion molecule (PSA-NCAM) is one of the most promising molecules that contributes to plasticity in the central nervous system. We evaluated PSA-NCAM immunoreactivity in the hippocampal formation of Alzheimer's disease (AD) patients. We found significant increases over control levels in the optical density ratios of PSA-NCAM immunoreactivity in the outer molecular layer/granule cell layer (ODoml/grl) and in the inner molecular layer/granule cell layer (ODiml/grl) in the dentate gyrus of AD patients. The optical density of the granule cell layer in the dentate gyrus did not differ significantly between AD patients and control subjects. However, the number of PSA-NCAM-immunopositive infragranule cells was higher in the AD group compared with control subjects. The major finding in the CA1, subiculum and entorhinal cortex of AD patients was the disorganization of PSA-NCAM-immunoreactive fibres. These results indicate that neuronal remodelling occurs, especially in the dentate gyrus of patients with AD.