Evaluation of olfactory dysfunction in neurodegenerative diseases

Journal of the Neurological Sciences 323 (2012) 16–24

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Evaluation of olfactory dysfunction in neurodegenerative diseases Marina Barresi, Rosella Ciurleo, Sabrina Giacoppo, Valeria Foti Cuzzola, Debora Celi, Placido Bramanti, Silvia Marino ⁎ IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy

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Article history: Received 19 April 2012 Received in revised form 29 August 2012 Accepted 30 August 2012 Available online 23 September 2012 Keywords: Parkinson's disease Alzheimer's disease Multiple sclerosis Huntington's disease Motor neuron disease Olfactory dysfunction Functional magnetic resonance imaging Olfactory event-related potentials

a b s t r a c t It is known that the olfactory dysfunction is involved in various neurological diseases, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, Huntington's disease and motor neuron disease. In particular, the ability to identify and discriminate the odors, as well as the odor threshold, can be altered in these disorders. These changes often occur as early manifestation of the pathology and they are not always diagnosed on time. The aim of this review is to summarize the major neurological diseases which are preceded or accompanied by olfactory dysfunction. In addition, new instrumental approaches, such as psychophysical testing, olfactory event-related potentials (OERPs) and functional magnetic resonance imaging (fMRI) measurements, supported by olfactometer for the stimuli delivery, and their combination in evaluation of olfactory function will be discussed. In particular, OERPs and fMRI might to be good candidates to become useful additional tools in clinical protocols for early diagnosis of neurological diseases. © 2012 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . Anatomy of the olfactory system . . . . . . . . . . Instrumental approaches assessing olfactory function . 3.1. Psychophysical methods . . . . . . . . . . . 3.2. Olfactory event-related potentials . . . . . . 3.3. Functional magnetic resonance imaging . . . . 4. Olfactory dysfunction in neurological diseases . . . . 4.1. Olfactory dysfunction in Parkinson's disease . . 4.2. Olfactory dysfunction in Alzheimer's disease . 4.3. Olfactory dysfunction in multiple sclerosis . . 4.4. Olfactory dysfunction in Huntington's disease . 4.5. Olfactory dysfunction in motor neuron disease 5. Conclusions . . . . . . . . . . . . . . . . . . . . Statement of conflict of interest . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Many factors and pathological conditions can affect the normal olfactory function. In the recent years, the smell problems are generating considerable interest in the neurological field. ⁎ Corresponding author at: IRCCS Centro Neurolesi “Bonino-Pulejo”, S.S. 113, Via Palermo, C.da Casazza, 98124 Messina, Italy. Tel.: +39 090 60128968; fax: +39 090 60128850. E-mail address: [email protected] (S. Marino). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.08.028

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Olfactory disorders are often misjudged and rarely rated the clinical setting. Nevertheless, they are described in a wide range of neurological disorders and their evaluation can be useful for diagnosis. In particular, several neurodegenerative diseases are partially associated to disorders of smell [1–3]. Indeed, severe changes in olfactory tests have been observed in Parkinson's disease (PD), Alzheimer's disease (AD) and other neurological disorders, such as multiple sclerosis (MS), Huntington's disease (HD) and motor neuron disease (MND).

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According to Acebes et al., sensory perception changes, representing often subtle dysfunctions that precede the onset of a neurodegenerative disease, may be caused by synapse loss [4]. However, a cause–effect relationship between synapse loss and sensory perception deficits is very difficult to prove and quantify due to functional and structural adaptation of neural system. In this brief manuscript, we have reviewed the anatomy and physiology of the olfactory system, the new instrumental approaches assessing its function, and the neurological disorders to which the olfactory dysfunction is intimately associated. 2. Anatomy of the olfactory system The olfactory system is able to detect and discriminate a great variety of volatile molecules with high sensitivity and specificity. The human olfactory system can detect tens of thousands of chemicals, many at concentrations as low as a few parts per trillion [5,6]. This function is performed through molecular, anatomical and cellular trasductional pathways that amplify, encode and integrates an enormous array of incoming olfactory information. The olfactory epithelium is located inside the nasal cavity. It includes three basic cell types: olfactory receptor neurons (ORNs), supporting cells, and basal cells. Anatomical studies, explants cultures, and post mortem biopsies of olfactory neurons from different parts of the nasal cavity show that sensory epithelium extends from the olfactory cleft down to varying degrees into the superior aspect of the medial turbinate [7]. The turbinate structures are cartilaginous ridge covered with respiratory epithelium, a non-sensory ciliated columnar epithelial tissue also populated with mucus secreting goblet cells. This structure increases the surface area available for both warming and humidifying incoming air, as well as funneling volatile chemicals up into the sensory epithelium. Human ORNs have a generally similar morphology to those of other vertebrates, although there is variation among species. The receptor cell consists of a cell body with an apical dendrite terminating in a knob containing multiple non-motile cilia. The cilia project into the mucus overlying the nasal epithelium where they have direct contact with volatile chemicals in the air. Basally, an axon projects through the cribriform plate to synapse with the dendrites of mitral cells in the olfactory bulb. The mitral cells project via the olfactory nerve (cranial nerve I) to the entorhinal cortex, as well as regions involved in emotion and memory, such as the amygdala and hippocampus. Cortical input is relayed to the hippocampus through entorhinal cortex. Several types of interneurons modulate mitral cell activity, including periglomerular cells, tufted cells and granule cells. Granule cells are dopaminergic/GABAergic interneurons involved in signal processing and modulation [8,9]. About 1000 putative odorant receptors are believed to exist and each olfactory receptor is responsive to a determinate range of stimuli. The odorant-binding leads to a depolarizing current within the cilia of the bipolar receptor cells. These cells trigger the action potentials that collectively provide the neural code deciphered by higher brain centers [10]. An immunohistochemical study [11] has compared the molecular phenotype of olfactory epithelial cells of rodents and humans, allowing the correlation between the human histopathology and olfactory dysfunction. Using a comprehensive battery of proven antibodies, the authors identified two distinct types of basal cell progenitors in human olfactory epithelium similar to rodents. The similarities of human-rodent olfactory epithelium allowed to extend our knowledge of human olfactory pathophysiology provided useful information on the status of the epithelium and its connection with the olfactory bulb (OB) [11]. The OB, that plays an important role in the processing of olfactory information, collects the sensory afferents of the olfactory receptor cells located in the olfactory neuroepithelium. The OB ends with the olfactory tract and is closely related to the olfactory sulcus of the frontal lobe. Surprisingly, in the OB, near astrocytes, there are so-called Olfactory Ensheathing Cells (OECs). OECs are unique glia found only in the

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peripheral olfactory system close to axon of the first cranial nerve. They are considered promising candidate for cell-based repair following a variety of CNS lesion [12–15]. In fact, they are able to remyelinate demyelinated axon [16] and to transform into Schwam cell-like cells in their remyelinating process [17]. In humans, the perception of nasal chemical stimuli is related to multiple sensations mediated by the olfactory and the trigeminal system [18]. The brain structures involved in odor processing mainly consist of the primary olfactory cortex, which comprises the anterior olfactory nucleus, tenia tecta, olfactory tubercole, piriform cortex (PC), anterior cortical amygdaloid nucleus, periamygdaloid and entorhinal cortices [19–21]. The piriform cortex is connected to thalamus, hypothalamus, and orbitofrontal cortex (OFC). The nuclei of the thalamus have further connections towards the OFC and the insular cortex. From the enthorhinal cortex fibers lead to the hippocampus (Fig. 1). The olfactory processes are lateralized between the hemispheres. In particular, while areas located in the right hemisphere such as the OFC and PC are more involved in memory and familiarity ratings, those located in the left hemisphere, such as OFC, insula, piriform cortex, amygdala and superior frontal cortex participate more in the emotional response to odors [22]. 3. Instrumental approaches assessing olfactory function Olfactory function can be evaluated through the use of specific instrumental approaches, including psychophysical and electrophysiological methods and neuroimaging techniques. These approaches are described below (Fig. 2). 3.1. Psychophysical methods For the clinical assessment of human olfaction, numerous validated psychophysical tests exist. The best-validated olfactory tests include the University of Pennsylvania Smell Identification Test (UPSIT or SIT), the Connecticut Chemosensory Clinical Research Center Test (CCCRC Test) and the Sniffin' Sticks Test [23–25]. The SIT, comprising 40 different odors, is a quick self-administered easily applied test to quantitatively assess human olfaction; it has also high test–retest reliability (r= 0.94) [26,27]. Its scores correlate strongly with the traditional olfaction threshold detection test which uses phenyl-ethyl-alcohol [3]. The performance is quite uniform when the SIT is administered in different laboratories using a standard method [1]. The CCCRC identification test is composed of 7 olfactory stimuli (baby powder, chocolate, cinnamon, coffee, mothballs, peanut butter, and soap). Three stimuli (ammonia, Vicks VapoRub [Procter & Gamble, Cincinnati, Ohio], and wintergreen) are also presented to test trigeminal nerve nasal sensation but are not included in calculating the olfactory function test score. Ten jars, each containing 1 of the 7 odor stimuli or 1 of the 3 trigeminal stimuli, are presented, and the subject is asked to select the stimulus name from a list of odors [28]. The Sniffin' Sticks test is frequently used in Europe and normative data have been established and obtained on a group of more than 3.000 subjects [25]. This test is based on pen-like odor dispensing devices. It consists of three tests namely for odor threshold, discrimination and identification, the sum of which is defined as “TDI score”. This score can give an indication of patient's olfactory performance (normosmia: TDI ≥ 30.5, hyposmia: TDI≤ 30.5, functional anosmia: TDI≤ 16.5). During these procedures the patient cooperation is necessary. 3.2. Olfactory event-related potentials A useful addition for the clinical diagnosis of olfactory deficits is represented by olfactory event-related potentials (OERPs). It is an electrophysiological technique which allows to observe changes in olfactory function. OERPs are the result of the sequential activation of

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M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 16–24

Fig. 1. Connections of central olfactory system.

numerous brain areas, starting from amygdala and regions of medial temporal lobe, followed by the mid‐OFC and insular cortex, along with regions of the temporal lobe. Unlike the auditory, visual or somatosensory modalities, exploration of the olfactory system using human electro-physiological methods such as event-related potentials (ERPs) has received little attention from the scientific or clinical community. The main reason for that is the lack of adequate methods to produce a selective and controlled stimulation of the olfactory system [29]. Based on the principles of air-dilution olfactometry, Kobal and Platting introduced, in the late 1970s, a chemosensory stimulation with stimuli having a rectangular shape with rapid onset, precisely controlled in terms of timing, duration and intensity and not simultaneously activating other sensory systems [30]. The olfactometer is a complex instrument for creation of well defined, reproducible smell or pain stimuli in the nose without tactile or thermal stimulation. OERPs have been used to investigate the olfactory disorders in PD, AD, MS, temporal lobe epilepsy and they are regarded to provide significant information especially in the evaluation of medico-legal cases [31]. OERPs can be obtained independently of the patient's response bias, allowing the investigation of subjects with difficulty/impossibility to respond properly. Especially in the severe neurological conditions in which it is impossible to have patient's cooperation, OERPs recording could become a useful technique to obtain new information about condition and progression of the clinical picture.

For stimulation are used substances non-toxic generating smell sensations, for example phenyl-ethyl alcohol (rose-like odor) and hydrogen sulfide (rotten eggs-like odor). These odorants are presented to the nostril of the patients through a Teflon tube connected to the instrument. The olfactometer also allows to produce a supply of CO2 by trigeminal stimulation. The olfactometer generates a clean air flow of, by standard, 8 liters per minute at the nose outlet in which stimuli of different types, concentrations and duration are embedded at virtually any desired point in time according to the user's settings. The clean air flow is humidified and warmed to inhibit irritation of the mucosa, which would negatively influence perception and induced pain at this flow rate after a while. Due to the switching technique and high flow rate, the rise time of the odorant concentration is fast enough to allow for recording of OERPs. The stimulus is free of an accompanying tactile stimulus, as the outlet flow is varying only very little when switching the stimulus on and off. It is also possible to create mixed and diluted stimuli with olfactometer. The IRCCS Centro Neurolesi “Bonino-Pulejo” in Messina has available the olfactometer, the first and the unique in Italy (Fig. 3) and compatible with MR scanner 3 T (the first installed in Sicily).

3.3. Functional magnetic resonance imaging Functional magnetic resonance imaging (fMRI) is a useful tool for the study of functional neuroanatomy of the human olfactory system.

Fig. 2. Methods assessing olfactory function. Legend: CCCR test (Connecticut Chemosensory Clinical Research Center test); fMRI (functional magnetic resonance imaging); OERPs (olfactory event‐related potentials); SIT (smell identification test).

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4. Olfactory dysfunction in neurological diseases Alterations of olfactory perception occur in a large number of neurological diseases, including PD, AD, MS, HD and MND (Table 1). 4.1. Olfactory dysfunction in Parkinson's disease

Fig. 3. The olfactometer and its accessories available to the IRCCS Centro Neurolesi “Bonino-Pulejo” in Messina.

Several fMRI studies using different delivery systems to administer the odors to the subjects, provided the insights into the brain structures involved in olfactory process. In accordance with the expectations from anatomical data, neuroimaging studies on olfaction reported activation in OFC, piriform cortex, amygdala, and entorhinal or parahippocampal gyrus. Other areas have also been consistently found to be activated in response to olfactory stimulation with neuroimaging techniques, including the insula and the anterior cingulated gyrus [32–36]. In addition, fMRI is suitable for studying olfactory information processing. OFC is an area related to tasks involving semantic association or encoding. This area has been reported to be significantly activated during hedonicity judgments for the odor stimuli tasks [36,37]. In particular, Katata et al. [37] reported that left lateral/middle OFC and right lateral OFC were more often activated in the subjects who perceived the odor stimulation as unpleasant. In addition, this study showed that the right anterior cingulated gyrus, which is thought to be related to working memory during odor discrimination, was activated more often in subjects who perceived the odor as pleasant. The authors suggested that this area may be involved in the processing of pleasant emotions. Also the insular cortex responds to the hedonics of odors and is involved in the processing of the emotional aspects of odors. In the study of Royet et al. [36] unpleasant odors produced stronger activity than did pleasant odors in the left ventral insula in right-handers subjects and the right ventral insula in left-handers, suggesting lateralized processing of emotional odors as a function of handedness. FMRI studies have also confirmed human olfaction declines with advancing age. Indeed in a fMRI study, the aged adults, compared to young adults, showed less brain activity in olfactory structures, including the primary olfactory cortex, entorhinal cortex, hippocampus and parahippocampal cortex, thalamus, hypothalamus, OFC, and insular cortex and its extension into the inferior lateral frontal region [38]. Another study found in old subjects a significantly lower activation in piriform cortex, entorhinal cortex and amygdala [39]. The difference in patterns of activation seen in some studies could be due to different instructions in the control and stimulation conditions. Imaging studies of olfaction require a suitable method for presentation to the subject of odors stimulus. A MR scanner compatible olfactometer generates on olfactory stimulus distinguishing between signal (odor condition) and no-signal (control condition without odor) in block-design fMRI studies. The instrument allows an odor generation well standardized with good replication in stimulation exams.

The impairment of the sense of smell in PD has been well documented since 1975 [67,68]. Although the cellular and molecular mechanism underlying this condition is not known yet, it has been shown that olfactory impairment in PD is related to disease severity [69,40]. Hawkes and coworkers proposed that PD may start in the olfactory system before the damage in the basal ganglia [41]. In another study, olfactory dysfunction was seen in patients with an abnormal reduction in striatal dopamine transporter binding, who subsequently developed clinical parkinsonism. In addition, it was shown that none of 23 patients normosmic developed symptoms of parkinsonism [42]. These results suggest that olfactory impairment may precede clinical motor signs of PD and its assessment may be applied in the early diagnosis of this disease. PD-related olfactory dysfunction may relate to the function of dopamine receptors in both central [70] and peripheral components of the nervous system [71,72]. Centrally, dopamine modulates synaptic activity in the olfactory bulb and entorhinal cortex and influences the activity of several ion channels and enzymes involved in olfactory transduction. Both Coronas in 1997 and Feron two years later, using in vitro experiments have shown that dopamine would increase cell death [73,74]. If this results were fully transferable in vivo in humans, it is not clear now explain the presence of apoptosis of dopaminergic cells of the nigrostriatal substance in mid-brain and the reduction to the loss of smell in PD [75,76]. Braak et al. demonstrated that the pathological process progressed in a predictable sequence, although the earliest changes were found in the dorsal motor nuclei of the glossopharyngeal and vagus nerves, in the olfactory bulb and the associated anterior olfactory nucleus. So, they determined that the dorsal medulla and olfactory bulb were starting points for PD. Probably the clinical motor manifestations of PD represent the terminal stage of a process started many years previously. From what Braak said, the involvement of central olfactory areas, such as the entorhinal cortex, takes place much later in the third stage [43]. The cause of hyposmia in PD is not fully understood. The neuronal inclusion bodies usually develop starting from the medulla oblongata and the anterior olfactory nucleus, before the involvement of other central nervous structures [43]. So it has been proposed that this developmental sequence constitutes the reason of olfactory impairment before the motor symptoms appearance. Other studies assume that the possible cause of hyposmia is due to the increased number of inhibitory, dopaminergic neurons in the olfactory bulb [77]. So, the early involvement of central olfactory structures in PD is paralleled by research indicating that smell tests may aid the early diagnosis of neurodegenerative diseases [78]. A recent study based on a morphometric analysis of MRI has permitted to investigate gray matter atrophy related to psychophysically measured scores of olfactory function in early PD patients (n=15, median Hoehn and Yahr stage 1.5), moderately advanced PD patients (n=12, median Hoehn and Yahr stage 2.5) and age-matched healthy controls (n =17). It provided first evidence that olfactory dysfunction in PD is related to atrophy in olfactory-eloquent regions of the limbic and paralimbic cortex, sustaining the fact that olfactory impairment occurs early in PD probably because associated with extranigral pathology [44]. In a very recent study [45] based on the arbitrary cut-off score of olfactory performance measured by “five odors olfactory detection arrays”, the scores of olfactory performance were higher in both PD without olfactory impairment (n = 12) and in PD patients with olfactory impairment (n = 14) than in the healthy controls without olfactory impairment (n = 26), independent of age and disease duration.

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Table 1 Principal results of studies of correlation between olfactory dysfunction and neurological diseases. Neurological diseases

Results

Author and year

Parkinson's disease

Relation of olfactory impairment to PD severity PD start in the olfactory system before the damage in the basal ganglia Patients with olfactory dysfunction and an abnormal reduction in striatal dopamine transporter binding subsequently develop symptoms of parkinsonism The dorsal medulla and olfactory bulb are starting points in PD Olfactory dysfunction in PD is related to atrophy in olfactory-eloquent regions of the limbic and paralimbic cortex Atrophy in piriform cortex and OFC is associated with olfactory dysfunction in early PD No difference between PD patients with anosmia/hyposmia and healthy normosmic controls in terms of olfactory bulb Decrement of PD neuronal activity in the left posterior putamen during right-sides stimulation Association between the expression of olfactory ERPs and olfactory-induced brain activity in PD Olfactory dysfunction in AD correlates with disease progression Degenerative process in AD characterized by plaque and neurofibrillary tangles starts in the enthorinal cortex and proceeds to other temporal lobe structures Increase of number of dopaminergic periglomerular neurons and volumetric decrease in the olfactory bulb Correlation between olfactory bulb volume and Mini Mental State Examination Introduction in the clinical routine of the olfactory test for early identification of the progression of the decline from aMCI to AD Degeneration of neural structures responsible for olfactory functions in AD: primary olfactory cortex, hippocampus, insula, thalamus and hypothalamus Correlation between smell alteration and severity of neurological impairments Direct correlation between plaque numbers and olfactory function Direct correlation between plaques number in the frontal and temporal lobes and olfactory function Direct correlation between olfactory bulb volume and olfactory function The frequency of smell identification impairments is higher for patients with secondary progressive than relapsing-remitting or primary progressive courses of MS HC patients exhibit significant deficits in odor identification but odor recognition memory is not found to be affected In an animal model of HC disease the olfactory system exhibits early and significant accumulation of huntingtin protein containing aggregates Olfactory deficit in HC is primarily associated with involvement of the entorhinal cortex, the parahippocampal gyrus, the thalamus and the caudate nucleus 28/37 MND patients have significant lower scores on the UPSIT-40 compared to age matched controls; 4/37 MND patients are nearly or totally anosmics Excess of lipofuscin deposition and bunina bodies in olfactory bulb of MND patient

Tissingh et al., 2001 [40] Hawkes et al., 1999 [41] Berendse et al., 2001 [42]

Alzheimer's disease

Multiple sclerosis

Huntington's disease

Motor neuron disease

This study indicated that PD patients without olfactory impairment had not borderline deficiency of olfactory though not meet the cut off score for abnormal olfactory function. Moreover, both PD patients without olfactory impairment and PD patients with olfactory impairment had cortical atrophy in the parahippocampal gyrus, but only PD patients with olfactory impairment also had changes in OFC. The results of that latest study shown that atrophy in piriform cortex and OFC is associated with olfactory dysfunction in early PD, becoming thus significant as olfactory damage progresses [45]. Studies based on biopsies from the olfactory epithelium did not detect specific changes in the nasal mucosa of PD patients compared to those who were hyposmic for other reasons (rhinitis, smoking or toxic agents). Studies about OB volume indicated that there was little or no difference between PD patients with anosmia/hyposmia and healthy normosmic controls in terms of OB volume [46]. Several studies have demonstrated an absence of correlation between the olfactory loss and the duration of disease [79,80], while other studies have found a correlation between the severity of PD and certain measures of olfactory function, such as latencies of olfactory OERPs [81] and results from an odor discrimination task [40]. In patients with PD, upregulated activity in regions participating in cortico-striatal loops has been reported as a characteristic phenomenon during motor, cognitive and linguistic tasks [82,83]. In a fMRI study used to investigate brain olfactory activity in hyposmic patients with PD of mild-moderate degree, it has been reported that they exhibited higher activation than controls bilaterally in the inferior frontal gyrus and in the anterior cingulated gyrus, in anterior portions of the left striatum and the right ventral striatum. Further, the same authors demonstrated that in PD neuronal activity was significantly decreased in the left posterior putamen during right-sided stimulation [47].

Braak et al., 2003 [43] Wattendorf et al., 2009 [44] Wu et al., 2011 [45] Hummel et al., 2010 [46] Westermann et al., 2008 [47] Welge-Lüssen et al., 2009 [48] Murphy et al., 1990 [49] Braak et al., 1993 [50]; Pearson, 1996 [51]; Attems et al., 2005 [52] Mundiñano et al., 2011 [53] Thomann et al., 2009 [54] Fusetti et al., 2010 [55] Wang et al., 2010 [56] Zivadinov et al., 1999 [57] Zorzon et al., 2000 [58] Doty et al., 1999 [59] Goektas et al., 2011 [60] Silva et al., 2011 [61] Bacon Moore et al., 1999 [62] Menalled et al., 2003 [63] Barrios et al., 2007 [64] Sajjadian et al., 1994 [65] Hawkes et al., 1998 [66]

The first study in patients with PD, that combined fMRI and OERP analysis applying olfactory stimuli by the olfactometer, demonstrated an association between the expression of olfactory ERPs and olfactoryinduced brain activity in PD. Using fMRI, central activation during olfactory stimulation was examined. The results demonstrated that both ERP+ and ERP− patients (group of patients separated on the basis of detectability of ERPs) showed activity in brain areas relevant to olfactory processing, such as the amygdala, parahippocampal regions, and temporal regions. Comparison of both groups revealed higher activation in ERP + patients, especially in the amygdala, parahippocampal cortex, inferior frontal gyrus, insula, cingulate gyrus, striatum, and inferior temporal gyrus [48].

4.2. Olfactory dysfunction in Alzheimer's disease AD is a most frequent form of dementia, and the early diagnosis is crucial to ensure medical and social intervention for both patients and family [84]. Several studies have demonstrated that loss of the sense of smell may be an early sign of AD [85,86]. In fact, Devanand et al. demonstrated that of 90 patients affected by mild cognitive impairment (MCI) (examined at 6-month intervals for 2 years follow-up), those with low olfaction scores (≤ 34 of 40) and those who reported no subjective problems smelling through the UPSIT, were more likely to develop AD than other patients. In specific, low olfaction scores (≤34) predicted the diagnosis of AD at follow-up (19 of 47 with low olfaction scores developed AD compared to zero of 30 with

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high olfaction scores); all 19 patients with MCI who developed AD had low olfaction scores [86]. Indeed, the olfactory function testing has revealed compromised olfactory function in early AD [87,49]. In this disease neuroanatomical changes in the central portion of the olfactory system occur early and olfactory testing has been explored as a promising and possible diagnostic marker [62,88]. Olfactory dysfunction in AD correlates with disease progression [49,89], aiding in the differential diagnosis of AD versus other forms of dementia [89], and being clinically useful as an early diagnostic marker in predicting incident of AD in high-risk individuals [86,90]. It has been suggested by Braak and others that one of the first damaged areas in patients with AD is transentorhinal cortex, areas involved in memory, emotion and olfaction. It has been also suggested that the degenerative process in AD characterized by plaque and neurofibrillary tangles starts in the enthorinal cortex, and then proceeds to other temporal lobe structures, including hippocampus [50–52]. Additionally, it has been found that subjects with hyposmia and apolipoprotein E epsilon 4 allele (ApoEε4) have approximately 5 times higher risk of developing AD late [90]. Talamo et al. suggested that AD could be identified by autopsy sample of nasal olfactory neuroepithelium, in which distribution, morphology, immunoreactivity of neuronal structures change [91]. However, it is very difficult to identify olfactory neurons because the mechanism, with which the neuropithelium tends to be replaced gradually by respiratory epithelium in aging, may be more rapid in AD. In fact, a Yamagishi's immunohistochemical study demonstrated that only 6/13 sample contained olfactory neurons [92]. The olfactory deficits is usually evaluated through the use of tests that measure the ability to identify and discriminate the odors, as well as the odor detection threshold (sensitivity). AD patients have relative preservation of threshold in the early stages [93]. In addition, the decline of smell identification could therefore act as a biomarker of future cognitive impairment. Using a stereological techniques, it has been found an increased number of dopaminergic periglomerular neurons and a significant volumetric decrease in the olfactory bulb of AD patients compared with age-matched controls [53]. Moreover, changes in OB have also been well-recognized and its volume correlated to Mini Mental State Examination in patients with AD [54]. A recent study of Fusetti et al., evaluating the amnesic MCI by the Sniffin' Sticks test and its relationship with AD, concluded that the olfactory deficit occurs early in aMCI. So they suggested the introduction of the olfactory test in the clinical routine for early identification of the progression of the decline from aMCI to AD [55]. In addition , fMRI studies in AD patients showed the degeneration of neural structures responsible for olfactory functions (primary olfactory cortex, hippocampus, insula, thalamus and hypothalamus) [56]. 4.3. Olfactory dysfunction in multiple sclerosis Multiple sclerosis (MS) is a chronic, complex neurological disease with a variable clinical course in which several pathophysiological mechanisms such as axonal/neuronal damage, demyelination, inflammation, gliosis, remyelination and repair, oxidative injury and excitotoxicity, alteration of the immune system are involved [94]. Olfactory dysfunction may also be an early indicator of disease progression in MS. A study based on smell identification test indicated that patients with MS scored significantly worse than control groups. They also found a significant correlation between smell alteration and symptoms of anxiety and depression and the severity of neurological impairments [57]. In several clinical and MR studies, neuropathology based on plaque numbers were directly correlated to olfactory function [58]. As plaque numbers declined or increased in the inferior frontal and temporal lobes, olfactory function declined or improved in

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correlation [59,95]. There was proof of a clear inverse correlation between the number of plaques in the olfactory cortex and the olfactory function in patients with MS [58,95]. These reports are suggestive of olfactory involvement and potential utility in diagnostic approaches for this disease. It remains unclear whether olfactory disturbances occur as an initial symptom of MS [96]. A recent study assessed OB volume of MS patients with MRI and related it to the olfactory function. They found that, in patients with a decreased OB volume, there was a positive correlation between volumetry of the OB and olfactory function [60]. These finding showed that OB may provide valuable information about olfactory dysfunction of MS patients. A diminished sense of smell in MS has also been reported in a recent study [97]. Silva et al. have characterized the olfactory identification capacity in MS using the Brief SIT and have explored possible associations between smell identification impairments and patient's clinical characteristics. They found that the frequency of impairment was higher for patients with secondary progressive (SPMS) than Relapsing–Remitting (RRMS) or primary progressive courses and they demonstrated that a brief odor identification measure provided a good discrimination between SPMS and RRMS courses [61]. 4.4. Olfactory dysfunction in Huntington's disease HD is an autosomal dominant disorder of basal ganglia function typified by choreic movement, dementia and rarely muscular rigidity similar to PD. Initial studies have documented early defective odor memory sometimes prior to cognitive defect or the onset of marked involuntary movement [2]. Following studies, using identification and detection tests, have confirmed the presence of moderate olfactory impairment, affecting the identification in particular, although it was less than that seen in PD. Olfactory testing of presymptomatic relatives at 50% risk has not shown abnormalities, implying that olfaction is impaired at the onset of motor or cognitive disorder [98]. In another study [99], odor detection presented good classification of sensitivity and specificity between the patients and controls, suggesting that olfactory testing may provide a sensitive measure of early disease process in HD patients. The utility of this observation is offset by the widely available and specific DNA test for HD. Patients with HD exhibited significant deficits in odor identification, but odor recognition memory was not found to be affected [62,98]. In an animal model of the disease, the olfactory system exhibited early and significant accumulation of huntingtin protein containing aggregates, which may account for the early olfactory impairment [63]. Recent study by voxel-based morphometric analysis has shown that olfactory deficits in patients with HD was primarily associated with involvement of the entorhinal cortex, the parahippocampal gyrus, the thalamus and the caudate nucleus. Although various neuroimaging studies have previously shown that the caudate nucleus is involved in olfaction, this study is the first demonstration of its involvement also in a neurodegenerative disease associated to olfactory loss [64]. 4.5. Olfactory dysfunction in motor neuron disease Anatomical and electrophysiological evidences suggest also the involvement of sensory pathways in MND. There has been just one study of the OB in 8 cases of MND [65]. There was marked accumulation of lipofuscin in olfactory neurons compared to age-matched controls, suggesting defective lipid peroxidation. A clinically based pilot study [100], examined 15 patients with MND, whom 8 had moderate or severe bulbar involvement and 8 were chair bound. No test for dementia or sniffing was administered but significant lowering of the UPSIT‐40 scores was documented. In another study of 37 patients with MND [66], 28 (75.7%) had significantly lower scores on the UPSIT-40 compared to age-matched

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controls. There were 4 (11%) with near or total anosmia. Olfactory functions may not be totally unimpaired in MND from pathological viewpoint. Histopathological studies of OB shown excess lipofuscin deposition [101] and Bunina bodies, known to occur in sporadic MND with dementia and Guamian Amyotrophic Lateral Sclerosis [102]. However, these researches were regarded as not likely being of clinical value. A recent study [103] did not shown significant correlation between disease duration and smell. In this study the authors assessed 26 patients diagnosed as suffering from MND at various stages and compared them with 26 matched controls using “Sniffin Sticks” for smell. The smell test correlated with age, but not with the duration of the disease. According to these researches, olfaction do not seem to be linked to or influenced by the disease, but it may be caused by a toxin entering the body via the nasal or oral route rather unlikely as well as a degenerative process involving sensory pathways [103]. 5. Conclusions It is evident from the studies reviewed in this paper that olfactory dysfunction is involved in various neurological disease, including PD, AD, MS, HD, and MND. Accumulating evidences indicate that olfactory deficit is an early manifestation of PD and AD. However, the olfactory deficit has been also observed in early stage of HD. Although the olfactory loss is a major component of aging, a number of studies highlighted that PD and AD patients show changes in detection, discrimination and identification of odors, compared to aged healthy controls. In recent years, great achievements have been obtained in elucidating the mechanism of olfactory dysfunction in neurodegenerative diseases. In PD and AD olfactory impairment may relate to changes in the OB, atrophy and degeneration of primary or secondary olfactory cortices, or both. Also the alterations of neurotransmitters may contribute to olfactory loss. In addition, the genetic risk factor ApoEε4 may allow to individuate among healthy people with hyposmia the subjects who present high risk to be affected by AD. The assessment of olfactory function is very important, especially in the early stage of these diseases, because it may be a good and useful indicator for clinical diagnosis. In MS, it is yet not clear if the olfactory impairment is an early hallmark of disease. However the evaluation of functionality of olfactory system may provide insight into progression of disease. The OECs, located within the peripheral olfactory system and characterized by exceptional plasticity, could be responsible for functional recovery in young patients with RRMS. The RRMS is characterized by stages of relapses and remissions, in which there is a partial reconstitution of glia and following functional recovery. The study of the olfactory performance, using the methods described above, might be a useful prognostic marker for the evaluation of functional recovery in these patients. The mechanism of olfactory neurons regeneration deserves further attention and others intensified studies in order to investigate the succession of stages which lead from relapse to remission. From reported studies, it seem that the olfactory impairment is involved also in MND. However further investigations are needed in order to establish the correlation between the olfactory impairment and the neurodegenerative process in MND. Although several drugs may potentially cause smell or taste disorders [104], in these studies it was not taken into account if pharmacological treatments may contribute in some way to the worsening of olfactory performances in neurological diseases. It is desirable that, in the near future, a possible goal of research in this field is the investigation of pharmacological treatments effects on olfactory function in neurological diseases. Numerous functional and structural approaches are available for assessing the integrity of the olfactory system in neurodegenerative diseases, such as psychophysical, electrophysiological and imaging

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