By combining psychophysical measures of odour identification with an fMRI cross-adaptation paradigm, we established that in patients with mild-stage Alzheimer’s disease, perceptual impairment of odour quality discrimination occurs in conjunction with a disruption of odour quality coding in PPC (). These effects were observed despite matched odour detection thresholds for Alzheimer’s disease and control groups. In addition, the percentage of PPC voxels exhibiting quality-adaptive responses showed a decline in patients with Alzheimer’s disease, compared with age-matched controls, accounting for 44% of the total variance (R2
) in the overall magnitude of fMRI cross-adaptation (). That the disruption of fMRI adaptation appears evenly distributed over the population of PPC voxels in Alzheimer’s disease suggests a general disorganization of odour quality coding in this region (as opposed to a patchy or sparse effect) as a result of Alzheimer’s disease neuropathology. These translational research findings follow closely from predictions based on our previous work (Gottfried et al., 2006
) about how odour quality information is encoded in the healthy human brain, and they provide one of the first mechanistic accounts for the well-recognized olfactory perceptual deficits in early Alzheimer’s disease.
Insofar as cognitive decline in the patients with Alzheimer’s disease could have independently contributed to the group differences in fMRI adaptation, it is important to emphasize that our study was explicitly designed to minimize such a confound. In particular, the use of a low-level odour detection task (rather than an odour discrimination task) during scanning helped eliminate the chance that greater cognitive effort in the Alzheimer’s disease group could have biased the results. In other words, neither patients with Alzheimer’s disease nor control subjects were asked to perform a discrimination task while in the scanner, precisely to ensure that perceptual differences in odour discrimination performance could not have confounded the results. The fact that Alzheimer’s disease and control groups were matched for odour detection thresholds () and complied equally well with the two-sniff task instruction () further demonstrates that the two groups were matched in olfactory performance and demand during the fMRI experiment, excluding the confound of cognitive disparity between the two samples. Finally, the lack of a significant subject-wise correlation between Alzheimer’s disease cognitive status (MMSE score) and magnitude of fMRI adaptation in PPC additionally suggests that cognitive deficits per se had no direct bearing on the imaging results in Alzheimer’s disease.
It thus seems likely that the observed disorganization of PPC cross-adaptation in patients with Alzheimer’s disease is due to defective odour quality coding in PPC. This is not to say that the defect of odour quality coding in PPC is necessarily selective for Alzheimer’s disease. Indeed, other neurodegenerative disorders with olfactory perceptual deficits, including Parkinson’s disease and Huntington’s disease (Nordin et al., 1995
; Mesholam et al., 1998
), are likely to target olfactory-related limbic areas, and it follows that similar defects of fMRI odour quality adaptation might be seen in these conditions. These observations underscore the principal goal of our study to elucidate the mechanisms underlying olfactory perceptual dysfunction in Alzheimer’s disease—the neural basis of which has been largely unexplored—rather than to establish the specificity of these mechanisms to Alzheimer’s disease. The application of a hypothesis-driven framework, drawing from our findings in healthy subjects (Gottfried et al., 2006
), has provided a novel way of exploring the neuroscientific aspects of olfactory perceptual impairment in Alzheimer’s disease.
It is also worth noting that the effects reported here are not necessarily specific to the piriform region. For example, in the absence of concurrent measurements of activity in the olfactory bulb and anterior olfactory nucleus, it remains possible that a pathological deficit upstream to PPC could partially account for the observed findings. However, the robustness of ‘first-sniff’ odour-evoked responses in PPC (statistically comparable magnitudes in Alzheimer’s disease and control groups, P
0.20), the perceptual specificity of the effects and the preservation of odour detection thresholds (in comparison with the control group) together suggest that the flow of olfactory information from the periphery to piriform cortex is largely uninterrupted in the patients with Alzheimer’s disease.
Interestingly, the absence of quality-specific cross-adaptation in Alzheimer’s disease stemmed from comparable posterior piriform response suppression to odours of similar and different qualities, rather than a lack of suppression to the similar odour pairs. This generalized ‘adaptation’ effect coincides well with our schematic model of odour quality miscoding in Alzheimer’s disease (B), which hypothesizes that a widening of population tuning curves in PPC leads to progressive loss of coding specificity. As a consequence, fMRI adaptation in PPC would be expected to occur just as likely for odour qualities outside the tuning range as it would for odour qualities optimally within the tuning range. In principle, these results may additionally reflect a generalized response fatigue, whereby PPC is unable to sustain excitability during repeated olfactory stimulation in spite of distinct odour qualities. This complementary mechanism accentuates the idea that pathological changes in PPC disrupt odour-specific firing profiles, to the extent that responses to new smells cannot be preserved. Such a framework would be consistent with the psychophysical data showing that patients with Alzheimer’s disease were essentially unable to extract quality-specific information from the different odourants during identification and discrimination tasks.
The concomitant dysfunction of odour quality processing at both the behavioural and neural levels in Alzheimer’s disease holds important implications for clarifying the functional organization of the human olfactory system. As discussed earlier, converging evidence in the literature suggests that odour quality coding in humans is subserved by PPC (Gottfried et al., 2006
; Li et al., 2006
; Howard et al., 2009
), but these data are restricted to neuroimaging studies in healthy subjects, from which one can infer correlation but not causation. Here, the regional disruption of odour-adaptive responses in PPC—specifically in an area of medial temporal lobe overlapping with the initial site of Alzheimer’s disease neuropathology—highlights the key involvement of PPC in the perceptual coding of odour quality. Thus, to the extent that the current study can be considered a lesion model of olfactory limbic brain function, it is plausible to infer causal evidence for PPC being a necessary substrate of odour object recognition.
An unexpected finding was the reversal of the fMRI cross-adaptation effect for odourant molecular functional group in the PPC of patients with Alzheimer’s disease. Specifically, the first-sniff presentation of a given odourant actually induced greater habituation in voxels responsive to different functional groups, such that second-sniff presentation of same group evoked greater activity than that of different group. This result presumably reflects abnormal structure coding as a result of Alzheimer’s disease neuropathology, though it is important to note that PPC has no apparent role in functional group coding in healthy young individuals (Gottfried et al., 2006
), suggesting that this region has become more stimulus driven in Alzheimer’s disease. For example, one possibility is that repetition of the same odourant functional group effectively comprises twice the stimulus input, eliciting a relative summation of odour-evoked responses, or a suprathreshold level of activation, at the time of the second sniff, compared with single presentations of different group odourants whose inputs do not summate. Alternatively, this ‘gain-of-dysfunction’ response profile in Alzheimer’s disease may underscore a derangement, or compensation, of information exchange between PPC and orbitofrontal cortex, or between PPC and anterior piriform cortex, all of which are reciprocally connected, or even a region-by-condition haemodynamic disruption in neurovascular coupling (Buckner et al., 2000
; D'Esposito et al., 2003
). These different possibilities are not mutually exclusive; at any rate, this paradoxical finding awaits future investigation.
While our study does not address underlying pathophysiological mechanisms, it is likely that the disruption of odour coding in PPC arises from a variety of effects. For example, the early accumulation of Alzheimer’s disease cytopathology in the medial temporal lobe, including piriform cortex, can induce direct neuronal and synaptic loss (Yankner et al., 2008
; Arendt, 2009
; Giannakopoulos et al., 2009
). Such a process would be in keeping with the current data indicating that the proportion of PPC voxels preferentially adapting to similar versus different odour qualities is diminished in the Alzheimer’s disease group. Neurodegenerative changes can also impact on neuronal function irrespective of neuronal loss. Alzheimer’s disease-related decreases in dendritic spine density, synaptic failure and impaired synaptic plasticity (Yankner et al., 2008
; Arendt, 2009
; Giannakopoulos et al., 2009
) would cause a disorganization—or a failure to maintain the organization—of odour quality information across piriform cortical ensembles. Alternatively, to the extent that piriform codes of odour quality rely on feedback from olfactory-related brain regions such as orbitofrontal cortex or entorhinal cortex, a pathological disruption in these circuits could indirectly impair coding specificity in PPC. In addition, on the basis of animal models suggesting that acetylcholine can enhance olfactory perceptual learning, reduce interference among stored odour memories and support fine odour discrimination in piriform cortex (Hasselmo et al., 1992
; Saar et al., 2001
; Wilson, 2001
), our results would be consistent with the profound perturbation of cholinergic innervation to the medial temporal lobes that is a hallmark of Alzheimer’s disease (Geula and Mesulam, 1996
; Mesulam, 2004
We note that some of the reported null effects might have arisen from insufficient statistical power due to the use of a relatively small study sample (10 participants each in the Alzheimer’s disease and control groups). This limitation is especially pertinent to measurement of odour detection thresholds (), testing of which can be highly variable and correlated to odour identification performance (Doty et al., 1994
). It thus remains possible that an impairment of odour sensitivity is already present in early stages of Alzheimer’s disease, but because of a lack of power, any such threshold differences between Alzheimer’s disease and control groups would have been missed in the present study. Future research with a larger cohort of patients with Alzheimer’s disease may help to elucidate this issue, thereby further disambiguating basic and higher-level mechanisms that contribute to the neural disruption of olfactory processing.
In summary, the imaging results presented here demonstrate that odour quality coding is disorganized in limbic olfactory regions that are early targets of Alzheimer’s disease pathology. That two separate fMRI measures of odour quality (adaptation magnitude and spatial extent) were both diminished in the Alzheimer’s disease group attests to the robustness of the technique and helps validate the use of fMRI cross-adaptation as a sensitive probe of limbic olfactory function. With the emergence of novel therapeutic and preventative interventions for Alzheimer’s disease on the horizon (Sigurdsson, 2009
), the need for novel diagnostic tools, particularly for asymptomatic stages, and before irreversible neuropathological damage sets in, will become increasingly imperative. The current study warrants future longitudinal investigations among high-risk groups (e.g. individuals with mild cognitive impairment, or ApoE4) (Bacon et al., 1998
; Larsson et al., 1999
; Calhoun-Haney and Murphy, 2005
; Wilson et al., 2007
) to assess the prevalence of defective odour quality coding in these populations and to explore the predictive validity of fMRI odour quality adaptation as an adjunctive diagnostic biomarker that can distinguish healthy elderly individuals with age-associated smell loss (Murphy et al., 2002
) from those on a clinical trajectory towards Alzheimer’s disease.