An olfactory ‘stress test’ may detect preclinical Alzheimer’s disease

Neuropsychiatry service, Hunter New England Area Health, Newcastle, Australia.
BMC Neurology (Impact Factor: 2.04). 05/2012; 12(1):24. DOI: 10.1186/1471-2377-12-24
Source: PubMed


The olfactory bulb (OB) receives extensive cholinergic input from the basal forebrain and is affected very early in Alzheimer's disease (AD). We speculated that an olfactory 'stress test' (OST), targeting the OB, might be used to unmask incipient AD. We investigated if change in olfactory performance following intranasal atropine was associated with several known antecedents or biomarkers of AD.
We measured change in performance on the University of Pennsylvania Smell Identification Test (UPSIT) in the left nostril before (20-items) and after (remaining 20-items) intranasal administration of 1 mg of atropine. We administered cognitive tests, measured hippocampal volume from MRI scans and recorded Apolipoprotein E genotype as indices relevant to underlying AD.
In a convenience sample of 56 elderly individuals (14 probable AD, 13 cognitive impairment no dementia, 29 cognitively intact) the change in UPSIT score after atropine ('atropine effect' = AE) correlated significantly with demographically scaled episodic memory score (r = 0.57, p < 0.001) and left hippocampal volume (LHCV) (r = 0.53, p < 0.001). Among non-demented individuals (n = 42), AE correlated with episodic memory (r = 0.52, p < 0.001) and LHCV (r = 0.49, p < 0.001) and hierarchical linear regression models adjusted for age, gender, education, and baseline UPSIT showed that the AE explained more variance in memory performance (24%) than did LHCV (15%). The presence of any APOE ϵ4 allele was associated with a more negative AE (p = 0.014).
The OST using atropine as an olfactory probe holds promise as a simple, inexpensive screen for early and preclinical AD and further work, including longitudinal studies, is needed to explore this possibility.

Download full-text


Available from: Peter W Schofield
  • Source
    • "In recent decades, it has been demonstrated that at very early stages, Alzheimer’s patients find it difficult to detect, discriminate, and identify odors [1-6]. Such dysfunction has been correlated with early pathological findings such as sparse accumulation of amyloid beta protein (Aβ) in the olfactory bulb (OB) [7-11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD) and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ) as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB) and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration- and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM) and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.
    Full-text · Article · Sep 2013 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: Olfaction is frequently mentioned as a “neglected sense”, although the olfactory system has several interesting and unique anatomical and physiological features. Olfactory involvement is present in several degenerative disorders, especially in Alzheimer’s disease (AD). The peripheral and central parts of the olfactory system are damaged even in the early stages of AD, manifesting in profound olfactory deficits. Besides the early pathology, the olfactory system may be involved in the pathogenesis of AD by providing a route of entry for pathological agents still unknown. In contrast to this olfactory vector hypothesis, the olfactory system can be used to deliver therapeutic agents in AD, such as nerve growth factor and insulin, by decreasing the side-effects of the therapy or providing a non-invasive method of delivery.
    No preview · Article · Mar 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HP π ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.
    Full-text · Article · Feb 2013
Show more