An early Alzheimer's disease functional imaging marker: Olfactory deficits in Alzheimer's disease and MCI reflect degeneration of central olfactory system


      Olfactory deficits are present in early AD and MCI (1-4). It is critical, however, to determine whether these deficits are due to degeneration of the central or peripheral olfactory system. We investigated involvement of the central olfactory system in AD and MCI with an implicit olfactory associative learning paradigm.


      Sixty-three subjects (15 AD, 21 MCI and 27 age-matched CN) were studied with cognitive tests, the University of Pennsylvania Smell Identification Test (UPSIT) and fMRI. The olfactory associative learning paradigm (Fig. 1) consisted of visual cues paired with lavender odor (visual+odor) followed by the same visual cue without an odor (visual-only).


      Visual-only cue activated in the primary olfactory cortex (POC) and hippocampus as did the preceded visual+odor cue for each group (p<0.05), suggesting a rapid implicit olfactory associative learning under this paradigm (Fig. 2). The CN subjects had greater activated volume in hippocampus and POC during both visual+odor and visual-only conditions than either the MCI or AD subjects (P < 0.05). Both conditions correlated with the cognitive and olfactory tests.


      The activation by visual-only cue in POC and hippocampus is likely a result of implicit learning/memory since it occurs only when preceded by the visual cue paired with odor. The significant decline in brain activation under this condition suggests that the central olfactory processing contributed the olfactory dysfunction in AD and MCI patients, which could lead a sensitive functional imaging marker for AD.
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      Figure. 1The fMRI paradigm. The visual cue, the words “Smell?”, was paired with lavender odor and then odorless air with a ”Rest“ in between. When “Smell?” is given, the subject responses with left hand button press if no smell and right hand if they smelled the stimulus. Four odorant concentrations were presented incrementally to offset the olfactory habituation.
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      Figure. 2Activated volume in POC and hippocampus (mean ± standard error) during visual + odor and visual- only conditions. The activated volume in the POC (A) and hippocampus (B) in MCI and AD) was decreased by more than 50 percent than that of the cognitively normal controls (CN) during odor presentation. Notes: * P ≤ 0.05, ANOVAwhen compared to CN-AII Odors
      + P <0.05, ANOVAwhen compared to CN-No Odor.