نشانگرهای بویایی افسردگی و بیماری آلزایمر

Depression and Alzheimer's disease are two common and closely intertwined diseases in the elderly. Bio-markers for their early diagnosis would be helpful for clinicians. The brain areas involved in depression, Alzheimer's disease and in olfactory processing overlap, leading to suggestions that olfaction could constitute a potential marker of these diseases. Here, we review the literature in the relevant clinical and olfactory fields, and consider which olfactory measures and factors could serve as markers of these diseases. It has been reported repeatedly that there is an alteration of odor identification in Alzheimer's disease but not in depression. These observations provide strong arguments that this olfactory marker may serve as a complementary tool for the early screening of patients. Odor threshold detection and odor hedonic aspect may constitute complementary markers of the efficacy of depression therapy. However, there are numerous contradictory data and innovative methods are required to investigate whether investigations of olfaction can usefully contribute to routine clinical practice.

Depression and Alzheimer's disease (AD) are both common diseases in the elderly. Depression is also a major public health issue. Almost 1 in 5 of the United States population experience a depressive episode during their lifetime (Kessler et al., 2003); and it has been reported that 1 to 2% of people aged over 65 have major symptoms of depression and 13 to 27% minor symptoms of depression (Olin et al., 2002). AD is the commonest cause of dementia (Sun et al., 2008). Clinicians and researchers have observed close links between these two diseases, although the link between depression and AD is not easy to characterize: is depression a risk factor for, a symptom of, or a stress reaction to, AD? Depression is the non-cognitive symptom most frequently associated with AD (Aalten et al., 2007), mostly expressed as minor symptoms of depression (Janzing et al., 1999). Depression affects 15 to 25% of AD patients (Cummings, 1997) and 80% of these patients have neuropsychiatric symptoms including affective symptoms (Robert and Benoit, 2010). Depression could be considered to be a risk factor of AD. The neurotoxic effects of depression (Krishnan and Nestler, 2008) could lead to long-term neurological lesions which could lead to AD. These neurotoxic effects include atrophy of hippocampal cells due to oversecretion of cortisol or abnormally low concentrations of neurotrophic factors including BDNF (Brain-derived neurotrophic factor). Little is known about such interactions. However, a recent review suggests a model including the hypothalamic–pituitary–adrenal (HPA) axis and serotonergic system: substantial release of glucocorticoids due to abnormal functioning of the HPA axis in depression may alter receptors and lead to structural modification of the limbic system such that it becomes more vulnerable to AD neurodegeneration (Sierksma et al., 2010). Dysfunction of the HPA axis has been observed in AD, leading to abnormally high cortisol levels and this may influence the production of amyloid plaques (Lee et al., 2009). Besides, serotonin disfavoring the production of Aβ (Nitsch et al., 1996), and an abnormally low abundance of serotonin receptors have been observed in the hippocampus and the frontal cortex of AD patients (Reynolds et al., 1995). This model is consistent with findings that a history of depression may increase the risk of developing AD (Ownby et al., 2006). Another study reported an increase of amyloid plaques and neurofibrillary tangles in the hippocampus of depressed patients (Rapp et al., 2006). Also, a study with twins showed that the risk of developing dementia was three time higher for subjects with than without a history of depression (Brommelhoff et al., 2009). All these various studies illustrate how depression and AD are closely intertwined; early detection and discrimination between them can therefore be difficult. Appropriate bio-markers for early diagnosis would be clinically valuable. Some researchers have suggested that various olfactory characteristics may constitute markers of these two diseases (Atanasova et al., 2008 and Djordjevic et al., 2008). This review article presents arguments in favor of this hypothesis, describes the state-of-the-art concerning olfactory disorders associated with these two diseases and considers which olfactory features could be used to differentiate between depression and AD.

Olfactory deficits have been observed in 85 to 95% of AD patients tested, and therefore such deficits can be considered to be a sensitive marker of AD (Doty, 2003). However, no data regarding the sensitivity of olfactory disorders in depression are available. The determination of which olfactory parameters are specifically altered in each of these diseases could help to differentiate between them. Olfactory impairments have also been reported in others diseases including Parkinson disease (Hoyles and Sharma, 2013), epilepsy (Chen et al., 2003), multiple sclerosis (Tepavčević et al., 2012), migraine (Saisu et al., 2011) and Huntington's disease (Mitchell et al., 2005), and also in healthy elderly individuals (Sohrabi et al., 2012). The odor detection threshold increase by a factor of 2 every 10 years, between 20 and 70 years of age (Venstrom and Amoore, 1968). The decline in olfactory performance in healthy subjects with age appears to be positively correlated with the degeneration of olfactory structures both peripherally and centrally. The aim of the present review was to consider which olfactory parameters are specifically altered in AD or depressed patients. This overview of the literature reveals that odor identification is more severely impaired in AD patients than in depressed patients. It also indicates that odor threshold detection may constitute a complementary marker for evaluating the efficacy of depression therapy. However, there is substantial conflict between the reported results, and further studies are necessary before rigorous conclusions can be drawn. In addition to the potential interest of olfactory impairments as a marker of AD or depression, this review underlined the existence of sensory deficits in these two diseases. Probable AD is defined by the presence of dementia, insidious onset and numerous cognitive inabilities (McKhann et al., 2011). Besides, DSM-V (American Psychiatric Association, 2013) criteria defined depression as an affective disorder characterized by depressed mood, diminished interest of pleasure, appetitive and sleeping disorders, psychomotor and energy troubles, devaluation, diminished ability to concentrate and suicidal ideation (DSM-V; American Psychiatric Association, 2013). Thus, olfactory deficits are described neither in AD nor in depression clinical criteria. This review confirms the presence of sensory impairments and specifically the olfactory ones in the clinical spectrum of AD and depression patients. The psychophysics methods commonly used are based on verbalization and memorizing information, which generates semantics and memory biases. Thus, the use of other complementary methods is necessary to control for, and avoid, these biases. Zucco et al. (2014) studied the influence of short term memory on identification and discrimination olfactory tasks in healthy subjects. They used new discrimination and identification tasks requiring less short-term memory and showed better performances by elderly participants. Some studies have used other methods. Morgan and Murphy demonstrated significantly longer event-related potential latencies in AD patients than in healthy subjects; they suggest including olfactory measures in the clinical evaluation of AD. However, there is substantial inter-individual variability in human olfactory perception due to non-olfactory inputs (Morrot et al., 2001) or intrinsic physiological differences; and there is also substantial variability of activation in the main olfactory areas as assessed by fMRI (Morrot et al., 2013). For these reasons, the authors have major reservations about using fMRI as a diagnostic tool in this context. Schofield et al. (2012) proposed an olfactory “stress test”, a simple and cheap possible alternative test for detecting preclinical AD. AD is characterized by abnormally low concentrations of acetylcholine. In this test, participants are given an intranasal perfusion of atropine (anti-cholinergic); the concentration of anti-cholinergic in olfactory bulb may cause a greater reduction of olfactory performances in AD patients than in healthy controls. Thus, despite the conflicting results and contradictory data published, it is possible that innovative methods could be developed to determine whether and which olfactory markers are of value for investigations of depression and AD.