Synapse stability in the precuneus early in the progression of Alzheimer's disease

Abstract

Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD.

Fig. 1

Representative electron micrographs of lamina 3 of the precuneus showing synaptic complexes in tissue from the three different cohorts studied: no cognitive impairment (NCI); amnestic mild cognitive impairment (aMCI); Alzheimer’s disease (AD). In all tissues, the synaptic complexes appeared normal with synaptic vesicles observed in the presynaptic compartment and a synaptic density observed in the postsynaptic component. Calibration bar = 0.5μm.

Fig. 2

Estimates of the total number of synapses (A) in lamina 3 of the precuneus cortex. Subjects were categorized clinically as no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or Alzheimer’s disease (AD). Estimates were obtained using unbiased stereology coupled with electron microscopic imaging of synapses. The total volume (B) of lamina 3 of the precuneus cortex was estimated with the Cavalieri method directly from tissue sections immediately adjacent to regions used for synaptic counts. Single points represent individual subjects. Horizontal lines indicates group median. *p < 0.05 compared to NCI.

Fig. 3

Scatterplot showing the relationship between estimates of total number of synapses in lamina 3 of the precuneus cortex and the subject’s score on the Mini Mental Status Examination (MMSE).

Fig. 4

Scatterplot showing the relationship between estimates of total number of synapses in lamina 3 of the precuneus cortex and [³H]PiB binding in tissue immediately adjacent to that used for ultrastructural examination.

Fig. 5

Scatterplot showing the relationship between estimates of total number of synapses in lamina 3 of the precuneus cortex and levels of soluble Aβ42 in tissue immediately adjacent to that used for ultrastructural examination.