Affiliations: [a] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [b] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [c] Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, Pittsburgh, PA, USA | [d] Rush University Medical Center, Department of Neurological Sciences, Chicago, IL, USA
Correspondence:
[*]
Correspondence to: Stephen W. Scheff, PhD, 101 Sanders-Brown, Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA. Tel.: +1 859 218 2397; Fax: +1 859 323 2866; E-mail: [email protected].
Abstract: Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD.
