Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer's disease

Abstract

Patients with early-stage Alzheimer's disease exhibit perceptual deficits in odour identification, often before the appearance of overt memory loss. This impairment coincides with the initial accumulation of pathological lesions in limbic olfactory brain regions. Although these data imply that odour stimuli may be effectively used as biological probes of limbic dysfunction, the precise neural mechanisms underlying the olfactory deficits in early Alzheimer's disease remain poorly understood. In the current study, we combined functional magnetic resonance imaging with an olfactory cross-adaptation paradigm to test the hypothesis that perceptual codes of odour quality in posterior piriform cortex are degraded in patients with Alzheimer's disease. In elderly control subjects, sequential presentation of qualitatively similar (versus qualitatively different) odourant pairs elicited cross-adapting responses in posterior piriform cortex, in accord with the pattern observed in healthy young adults. However, this profile was significantly blunted in patients with Alzheimer's disease, reflecting a functional disruption of odour quality coding in this olfactory brain area. These results highlight the potential of olfactory functional magnetic resonance imaging as a non-invasive bioassay of limbic functional integrity, and suggest that such an index could possibly aid in the early diagnosis of Alzheimer's disease. Furthermore, as a putative lesion model of odour quality processing in the human brain, our study suggests a causal role of posterior piriform cortex in differentiating olfactory objects.

Figure 1

Schematic model illustrating the disruption of odour quality coding in Alzheimer’s disease and its impact on olfactory cross-adaptation. (A) In healthy subjects, the tuning curves in PPC demonstrate a modest degree of population overlap for two qualitatively distinct odourants (O1, solid blue line; O2, solid red line). Initial presentation of O1 induces adaptation of O1-responsive neurons (dashed blue line) and a reduction in neural activity (blue bracket). However, because some of the O1 neurons also respond to O2, the presentation of O1 will induce adaptation in a subset of O2-responsive neurons (red dashed line), resulting in a small reduction of neural activity when O1 is sequentially followed by O2 (red bracket). (B) In patients with Alzheimer’s disease, the prediction is that a loss of coding specificity for odour quality will yield wider and more overlapping tuning curves for O1 and O2. As a consequence, initial presentation of O1 will elicit adaptation in a larger subset of O2-responsive neurons (red dashed line), with a correspondingly greater decline in neural activity when O1 is followed by O2 (red bracket), and similar in magnitude to that elicited by repeated presentations of O1 (blue bracket).

Figure 2

Experimental paradigm. Four odourant pairs systematically varying in odour quality and odourant functional group were presented in an olfactory cross-adaptation paradigm, constituting a 2 × 2 factorial design. A fifth pair with odourant as the first sniff and odourless air as the second sniff was presented as a filler trial. Examples of the odourant pairings that comprise the different conditions are shown here. ACT = acetophenone; CV = carvone; MT = menthol; PEA = phenethyl alcohol.

Figure 3

Olfactory psychophysical ratings. (A) Perceptual ratings of intensity, valence and familiarity for the four odourants, averaged across control and Alzheimer’s disease groups. (B) Odour ratings of ‘floweriness’ and ‘mintiness’ for the floral odourants (average of ACT and PEA ratings) and for the minty odourants (average of CV and MT ratings) (left two panels), and similarity ratings of odour quality between all pair-wise combinations of odourants (right panel). *P < 0.05. ACT = acetophenone; CV = carvone; MT = menthol; PEA = phenethyl alcohol; NC = controls.

Figure 4

Cross-adaptation effects in the left posterior piriform cortex. (A) In normal control subjects, sequential presentation of odourants similar in quality elicited reliable fMRI adaptation upon the second sniff, when compared with odourants different in quality (left panel) (P = 0.05). In contrast, the magnitude of fMRI adaptation did not differ for odourants containing the same or different molecular functional group (right panel). (B) Patients with Alzheimer’s disease failed to demonstrate selective cross-adaptation in response to either odour quality of odourant functional group. Paradoxical response facilitation was observed following presentation of a structurally unrelated odour (P = 0.05). Insets illustrate the effect sizes of fMRI adaptation. SQ = same quality; DQ = different quality; SG = same functional group; DG = different functional group; NC = controls; RT = repetition time (error bars, ± SEM). *P < 0.05.

Figure 5

Subject-wise correlation analysis regressing the magnitude of quality-specific cross-adaptation against the spatial extent of quality-adaptive voxels, separately within left and right PPC, across the control group (open circles) and the Alzheimer’s disease (closed circles) group. Each dot represents data from a different subject.

Figure 6

Histograms depicting the frequency distributions (in numbers of voxels) for different effect sizes of odour quality adaptation in left PPC. (A) A hypothetical profile shows that the voxel distribution is left-shifted for Alzheimer’s disease compared with control (NC). (B) An alternative hypothetical profile shows that the voxel distribution is left-skewed for Alzheimer’s disease compared with control. (C) Histogram plots of voxel-level data (voxels pooled from all subjects in each group) indicate that the distribution of the Alzheimer’s disease group (red) is shifted to the left, in comparison with the control group (grey), consistent with hypothesis (A) above. Histogram areas containing overlapping information between the two groups are shown in brown. Dashed curves represent Gaussian fits to each distribution. Vertical lines mark the mean fMRI magnitudes of odour quality adaptation determined from the region-of-interest analyses depicted in Fig. 4.

Figure 7

Plots illustrate the two-sniff respiratory profiles for control (NC) and Alzheimer’s disease groups, averaged across each condition. Waveforms were time-locked to the onset of the first sniff and normalized to the maximal amplitude within each subject.