seases.

. . .

. . .olfacto. . .entialsnce imical diserkinson

Journal of the Neurological Sciences 323 (2012) 1624

Contents lists available at SciVerse ScienceDirect

Journal of the Neur

.e4.4. Olfactory dysfunction in Huntington's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214.5. Olfactory dysfunction in motor neuron disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Statement of conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1. Introduction Olfactory disorders are often misjudged and rarely rated the clin-Many factors and pathological conditionsfactory function. In the recent years, the smeing considerable interest in the neurological

Correspondingauthor at: IRCCS CentroNeurolesi BoniC.da Casazza, 98124 Messina, Italy. Tel.: +39 090 6012896

E-mail address: silvimarino@gmail.com (S. Marino).

0022-510X/$ see front matter 2012 Elsevier B.V. Alhttp://dx.doi.org/10.1016/j.jns.2012.08.028's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20clerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214.2. Olfactory dysfunction in Alzheimer4.3. Olfactory dysfunction in multiple sFunctional magnetic resonance imagingOlfactory event-related potentials

Contents

1. Introduction . . . . . . . . . .2. Anatomy of the olfactory system3. Instrumental approaches assessing

3.1. Psychophysical methods .3.2. Olfactory event-related pot3.3. Functional magnetic resona

4. Olfactory dysfunction in neurolog4.1. Olfactory dysfunction in Pa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17ry function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18ases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Olfactory dysfunction 2012 Elsevier B.V. All rights reserved.Huntington's diseaseMotor neuron disease

OERPs and fMRI might to bediagnosis of neurological diMultiple sclerosis the stimuli delivery, and theEvaluation 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

a b s t r a c ta r t i c l e i n f o

Article history:Received 19 April 2012Received in revised form 29 August 2012Accepted 30 August 2012Available online 23 September 2012

Keywords:Parkinson's diseaseAlzheimer's disease

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 abilityto identify and discriminate the odors, as well as the odor threshold, can be altered in these disorders. Thesechanges 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 accompaniedby 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

ir combination in evaluation of olfactory function will be discussed. In particular,good candidates to become useful additional tools in clinical protocols for earlyj ourna l homepage: wwwcan affect the normal ol-ll problems are generat-eld.

no-Pulejo, S.S. 113, ViaPalermo,8; fax: +39 090 60128850.

l rights reserved.ological Sciences

l sev ie r .com/ locate / jnsical setting. Nevertheless, they are described in a wide range of neu-rological disorders and their evaluation can be useful for diagnosis.In particular, several neurodegenerative diseases are partially asso-ciated to disorders of smell [13]. Indeed, severe changes in olfactorytests have been observed in Parkinson's disease (PD), Alzheimer'sdisease (AD) and other neurological disorders, such as multiple scle-rosis (MS), Huntington's disease (HD) and motor neuron disease(MND).

17M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624According to Acebes et al., sensory perception changes, representingoften subtle dysfunctions that precede the onset of a neurodegenerativedisease, may be caused by synapse loss [4].

However, a causeeffect relationship between synapse loss andsensory perception decits is very difcult to prove and quantifydue to functional and structural adaptation of neural system.

In this brief manuscript, we have reviewed the anatomy and physiol-ogy of the olfactory system, the new instrumental approaches assessingits function, and the neurological disorders to which the olfactory dys-function is intimately associated.

2. Anatomy of the olfactory system

The olfactory system is able to detect and discriminate a great va-riety of volatile molecules with high sensitivity and specicity. Thehuman olfactory system can detect tens of thousands of chemicals,many at concentrations as low as a few parts per trillion [5,6]. Thisfunction is performed through molecular, anatomical and cellulartrasductional pathways that amplify, encode and integrates an enor-mous array of incoming olfactory information. The olfactory epitheli-um 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 ofolfactory neurons from different parts of the nasal cavity show thatsensory epithelium extends from the olfactory cleft down to varyingdegrees into the superior aspect of the medial turbinate [7]. The tur-binate structures are cartilaginous ridge covered with respiratoryepithelium, a non-sensory ciliated columnar epithelial tissue alsopopulated with mucus secreting goblet cells. This structure increasesthe surface area available for both warming and humidifying incom-ing air, as well as funneling volatile chemicals up into the sensory ep-ithelium. Human ORNs have a generally similar morphology to thoseof other vertebrates, although there is variation among species. Thereceptor cell consists of a cell body with an apical dendrite terminat-ing in a knob containing multiple non-motile cilia. The cilia projectinto the mucus overlying the nasal epithelium where they have directcontact with volatile chemicals in the air. Basally, an axon projectsthrough the cribriform plate to synapse with the dendrites of mitralcells in the olfactory bulb. The mitral cells project via the olfactorynerve (cranial nerve I) to the entorhinal cortex, as well as regions in-volved in emotion and memory, such as the amygdala and hippocam-pus. Cortical input is relayed to the hippocampus through entorhinalcortex. Several types of interneurons modulate mitral cell activity, in-cluding periglomerular cells, tufted cells and granule cells. Granulecells are dopaminergic/GABAergic interneurons involved in signalprocessing andmodulation [8,9]. About 1000 putative odorant receptorsare believed to exist and each olfactory receptor is responsive to a deter-minate range of stimuli. The odorant-binding leads to a depolarizing cur-rent within the cilia of the bipolar receptor cells. These cells trigger theaction potentials that collectively provide the neural code decipheredby higher brain centers [10]. An immunohistochemical study [11] hascompared the molecular phenotype of olfactory epithelial cells of ro-dents and humans, allowing the correlation between the human histo-pathology and olfactory dysfunction. Using a comprehensive battery ofproven antibodies, the authors identied two distinct types of basal cellprogenitors in human olfactory epithelium similar to rodents. The simi-larities of human-rodent olfactory epithelium allowed to extend ourknowledge of human olfactory pathophysiology provided useful infor-mation on the status of the epithelium and its connectionwith the olfac-tory bulb (OB) [11]. The OB, that plays an important role in theprocessing of olfactory information, collects the sensory afferents of theolfactory receptor cells located in the olfactory neuroepithelium. TheOB endswith the olfactory tract and is closely related to the olfactory sul-cus 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 theperipheral olfactory system close to axon of the rst cranial nerve.They are considered promising candidate for cell-based repair followinga variety of CNS lesion [1215].

In fact, they are able to remyelinate demyelinated axon [16] and totransform into Schwam cell-like cells in their remyelinating process [17].

In humans, the perception of nasal chemical stimuli is related tomultiple sensations mediated by the olfactory and the trigeminal sys-tem [18]. The brain structures involved in odor processing mainlyconsist of the primary olfactory cortex, which comprises the anteriorolfactory nucleus, tenia tecta, olfactory tubercole, piriform cortex(PC), anterior cortical amygdaloid nucleus, periamygdaloid and ento-rhinal cortices [1921].

The piriform cortex is connected to thalamus, hypothalamus, andorbitofrontal cortex (OFC). The nuclei of the thalamus have further con-nections towards the OFC and the insular cortex. From the enthorhinalcortex bers lead to the hippocampus (Fig. 1).

The olfactory processes are lateralized between the hemispheres.In particular, while areas located in the right hemisphere such asthe OFC and PC are more involved in memory and familiarity ratings,those located in the left hemisphere, such as OFC, insula, piriform cor-tex, amygdala and superior frontal cortex participate more in theemotional response to odors [22].

3. Instrumental approaches assessing olfactory function

Olfactory function can be evaluated through the use of specic in-strumental approaches, including psychophysical and electrophysio-logical methods and neuroimaging techniques. These approachesare described below (Fig. 2).

3.1. Psychophysical methods

For the clinical assessment of human olfaction, numerous validatedpsychophysical tests exist. The best-validated olfactory tests includethe University of Pennsylvania Smell Identication Test (UPSIT or SIT),the Connecticut Chemosensory Clinical Research Center Test (CCCRCTest) and the Snifn' Sticks Test [2325]. The SIT, comprising 40 differ-ent odors, is a quick self-administered easily applied test to quantita-tively assess human olfaction; it has also high testretest reliability(r=0.94) [26,27]. Its scores correlate strongly with the traditionalolfaction threshold detection test which uses phenyl-ethyl-alcohol [3].The performance is quite uniform when the SIT is administered in dif-ferent laboratories using a standard method [1].

The CCCRC identication 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], andwintergreen) are also presented to test trigeminalnerve nasal sensation but are not included in calculating the olfactoryfunction test score. Ten jars, each containing 1 of the 7 odor stimuli or1 of the 3 trigeminal stimuli, are presented, and the subject is asked toselect the stimulus name from a list of odors [28].

The Snifn' Sticks test is frequently used in Europe and normativedata have been established and obtained on a group of more than3.000 subjects [25]. This test is based on pen-like odor dispensing de-vices. It consists of three tests namely for odor threshold, discriminationand identication, the sum of which is dened as TDI score. This scorecan give an indication of patient's olfactory performance (normosmia:TDI30.5, hyposmia: TDI30.5, functional anosmia: TDI16.5). Dur-ing these procedures the patient cooperation is necessary.

3.2. Olfactory event-related potentials

A useful addition for the clinical diagnosis of olfactory decits isrepresented by olfactory event-related potentials (OERPs). It is anelectrophysiological technique which allows to observe changes in ol-

factory function. OERPs are the result of the sequential activation of

cen

18 M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624numerous brain areas, starting from amygdala and regions of medialtemporal lobe, followed by the midOFC and insular cortex, alongwith regions of the temporal lobe.

Unlike the auditory, visual or somatosensorymodalities, explorationof the olfactory system using human electro-physiological methodssuch as event-related potentials (ERPs) has received little attentionfrom the scientic or clinical community. The main reason for that isthe lack of adequate methods to produce a selective and controlledstimulation of the olfactory system [29]. Based on the principles ofair-dilution olfactometry, Kobal and Platting introduced, in the late1970s, a chemosensory stimulation with stimuli having a rectangularshapewith rapid onset, precisely controlled in terms of timing, durationand intensity and not simultaneously activating other sensory systems[30]. The olfactometer is a complex instrument for creation of well de-

Fig. 1. Connections ofned, reproducible smell or pain stimuli in the nose without tactile orthermal stimulation.

OERPs have been used to investigate the olfactory disorders in PD,AD,MS, temporal lobe epilepsy and they are regarded to provide signif-icant information especially in the evaluation ofmedico-legal cases [31].

OERPs can be obtained independently of the patient's response bias,allowing the investigation of subjects with difculty/impossibility to re-spond properly.

Especially in the severe neurological conditions in which it is im-possible to have patient's cooperation, OERPs recording could becomea useful technique to obtain new information about condition andprogression of the clinical picture.

Fig. 2. Methods assessing olfactory function. Legend: CCCR test (Connecticut Chemosensory(olfactory eventrelated potentials); SIT (smell identication test).For stimulation are used substances non-toxic generating smellsensations, for example phenyl-ethyl alcohol (rose-like odor) and hy-drogen sulde (rotten eggs-like odor). These odorants are presentedto the nostril of the patients through a Teon tube connected to theinstrument. The olfactometer also allows to produce a supply of CO2by trigeminal stimulation.

The olfactometer generates a clean air ow of, by standard, 8 litersperminute at the nose outlet in which stimuli of different types, concen-trations and duration are embedded at virtually any desired point in timeaccording to the user's settings. The clean air ow is humidied andwarmed to inhibit irritation of the mucosa, which would negatively in-uence perception and induced pain at this ow rate after a while. Dueto the switching technique and high ow rate, the rise time of the odor-ant concentration is fast enough to allow for recording of OERPs. The

tral olfactory system.stimulus is free of an accompanying tactile stimulus, as the outlet owis varying only very little when switching the stimulus on and off. It isalso possible to create mixed and diluted stimuli with olfactometer.

The IRCCS Centro Neurolesi Bonino-Pulejo in Messina has avail-able the olfactometer, the rst and the unique in Italy (Fig. 3) andcompatible with MR scanner 3 T (the rst installed in Sicily).

3.3. Functional magnetic resonance imaging

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

Clinical Research Center test); fMRI (functional magnetic resonance imaging); OERPs

19M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624Several fMRI studies using different delivery systems to adminis-ter the odors to the subjects, provided the insights into the brainstructures involved in olfactory process. In accordance with the ex-pectations from anatomical data, neuroimaging studies on olfactionreported activation in OFC, piriform cortex, amygdala, and entorhinalor parahippocampal gyrus. Other areas have also been consistentlyfound to be activated in response to olfactory stimulation with neuro-imaging techniques, including the insula and the anterior cingulatedgyrus [3236].

In addition, fMRI is suitable for studying olfactory information pro-cessing. OFC is an area related to tasks involving semantic associationor encoding. This area has been reported to be signicantly activatedduring hedonicity judgments for the odor stimuli tasks [36,37]. In par-ticular, Katata et al. [37] reported that left lateral/middle OFC andright lateral OFC were more often activated in the subjects who per-ceived the odor stimulation as unpleasant. In addition, this studyshowed that the right anterior cingulated gyrus, which is thought tobe related to workingmemory during odor discrimination, was activat-ed more often in subjects who perceived the odor as pleasant. The au-thors suggested that this area may be involved in the processing of

Fig. 3. The olfactometer and its accessories available to the IRCCS Centro NeurolesiBonino-Pulejo in Messina.pleasant emotions. Also the insular cortex responds to the hedonics ofodors and is involved in the processing of the emotional aspects ofodors. In the study of Royet et al. [36] unpleasant odors produced stron-ger activity than did pleasant odors in the left ventral insula inright-handers subjects and the right ventral insula in left-handers,suggesting lateralized processing of emotional odors as a function ofhandedness.

FMRI studies have also conrmed human olfaction declines withadvancing age. Indeed in a fMRI study, the aged adults, compared toyoung adults, showed less brain activity in olfactory structures, in-cluding the primary olfactory cortex, entorhinal cortex, hippocampusand parahippocampal cortex, thalamus, hypothalamus, OFC, and in-sular cortex and its extension into the inferior lateral frontal region[38]. Another study found in old subjects a signicantly lower activa-tion in piriform cortex, entorhinal cortex and amygdala [39].

The difference in patterns of activation seen in some studies could bedue to different instructions in the control and stimulation conditions.

Imaging studies of olfaction require a suitable method for presenta-tion to the subject of odors stimulus. A MR scanner compatible olfac-tometer generates on olfactory stimulus distinguishing between signal(odor condition) and no-signal (control condition without odor) inblock-design fMRI studies. The instrument allows an odor generationwell standardized with good replication in stimulation exams.4. Olfactory dysfunction in neurological diseases

Alterations of olfactory perception occur in a large number of neu-rological diseases, including PD, AD, MS, HD and MND (Table 1).

4.1. Olfactory dysfunction in Parkinson's disease

The impairment of the sense of smell in PD has been well docu-mented since 1975 [67,68]. Although the cellular and molecularmechanism underlying this condition is not known yet, it has beenshown that olfactory impairment in PD is related to disease severity[69,40]. Hawkes and coworkers proposed that PD may start in the ol-factory system before the damage in the basal ganglia [41]. In anotherstudy, olfactory dysfunction was seen in patients with an abnormalreduction in striatal dopamine transporter binding, who subsequent-ly developed clinical parkinsonism. In addition, it was shown thatnone of 23 patients normosmic developed symptoms of parkinsonism[42]. These results suggest that olfactory impairment may precedeclinical motor signs of PD and its assessment may be applied in theearly diagnosis of this disease. PD-related olfactory dysfunction mayrelate 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 ento-rhinal cortex and inuences the activity of several ion channels andenzymes involved in olfactory transduction. Both Coronas in 1997and Feron two years later, using in vitro experiments have shownthat dopamine would increase cell death [73,74]. If this results werefully transferable in vivo in humans, it is not clear now explain thepresence of apoptosis of dopaminergic cells of the nigrostriatalsubstance in mid-brain and the reduction to the loss of smell in PD[75,76]. Braak et al. demonstrated that the pathological processprogressed in a predictable sequence, although the earliest changeswere found in the dorsal motor nuclei of the glossopharyngeal andvagus nerves, in the olfactory bulb and the associated anterior olfac-tory nucleus. So, they determined that the dorsal medulla and olfacto-ry bulb were starting points for PD. Probably the clinical motormanifestations of PD represent the terminal stage of a process startedmany years previously. From what Braak said, the involvement ofcentral olfactory areas, such as the entorhinal cortex, takes placemuch later in the third stage [43].

The cause of hyposmia in PD is not fully understood. The neuronalinclusion bodies usually develop starting from the medulla oblongataand the anterior olfactory nucleus, before the involvement of othercentral nervous structures [43]. So it has been proposed that this de-velopmental sequence constitutes the reason of olfactory impairmentbefore the motor symptoms appearance. Other studies assume thatthe possible cause of hyposmia is due to the increased number of in-hibitory, dopaminergic neurons in the olfactory bulb [77]. So, theearly involvement of central olfactory structures in PD is paralleledby research indicating that smell tests may aid the early diagnosis ofneurodegenerative diseases [78]. A recent study based on a morpho-metric analysis of MRI has permitted to investigate gray matter atrophyrelated to psychophysically measured scores of olfactory function inearly PD patients (n=15, median Hoehn and Yahr stage 1.5), moderate-ly advanced PD patients (n=12, median Hoehn and Yahr stage 2.5) andage-matched healthy controls (n=17). It providedrst evidence that ol-factory dysfunction in PD is related to atrophy in olfactory-eloquent re-gions of the limbic and paralimbic cortex, sustaining the fact thatolfactory impairment occurs early in PD probably because associatedwith extranigral pathology [44].

In a very recent study [45] based on the arbitrary cut-off score ofolfactory performance measured by ve odors olfactory detectionarrays, the scores of olfactory performance were higher in both PDwithout olfactory impairment (n=12) and in PD patients with olfac-tory impairment (n=14) than in the healthy controls without olfac-

tory impairment (n=26), independent of age and disease duration.

al d

salon

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menfaction Murphy et al., 1990 [49]robrillary tangles starts in theture

Braak et al., 1993 [50]; Pearson,

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20 M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624Table 1Principal results of studies of correlation between olfactory dysfunction and neurologic

Neurological diseases Results

Parkinson's disease Relation of olfactory impairment to PD severityPD start in the olfactory system before the damage in the baPatients with olfactory dysfunction and an abnormal reductibinding subsequently develop symptoms of parkinsonismThe dorsal medulla and olfactory bulb are starting points inOlfactory dysfunction in PD is related to atrophy in olfactorylimbic and paralimbic cortexAtrophy in piriform cortex and OFC is associated with olfactNo difference between PD patients with anosmia/hyposmiacontrols in terms of olfactory bulbDecrement of PD neuronal activity in the left posterior putaAssociation between the expression of olfactory ERPs and ol

Alzheimer's disease Olfactory dysfunction in AD correlates with disease progressDegenerative process in AD characterized by plaque and neuenthorinal cortex and proceeds to other temporal lobe strucIncrease of number of dopaminergic periglomerular neuronsolfactory bulbCorrelation between olfactory bulb volume and Mini MentalIntroduction in the clinical routine of the olfactory test for eof the decline from aMCI to ADDegeneration of neural structures responsible for olfactory fhippocampus, insula, thalamus and hypothalamus

Multiple sclerosis Correlation between smell alteration and severity of neuroloDirect correlation between plaque numbers and olfactory fuDirect correlation between plaques number in the frontal anDirect correlation between olfactory bulb volume and olfactThe frequency of smell identication impairments is higherthan relapsing-remitting or primary progressive courses of M

Huntington's disease HC patients exhibit signicant decits in odor identicationto be affectedIn an animal model of HC disease the olfactory system exhibhuntingtin protein containing aggregatesThis study indicated that PD patients without olfactory impairmenthad not borderline deciency of olfactory though not meet the cutoff score for abnormal olfactory function. Moreover, both PD patientswithout olfactory impairment and PD patients with olfactory impair-ment had cortical atrophy in the parahippocampal gyrus, but only PDpatients with olfactory impairment also had changes in OFC. The re-sults of that latest study shown that atrophy in piriform cortex andOFC is associated with olfactory dysfunction in early PD, becomingthus signicant as olfactory damage progresses [45].

Studies based on biopsies from the olfactory epithelium did notdetect specic changes in the nasal mucosa of PD patients comparedto those who were hyposmic for other reasons (rhinitis, smoking ortoxic agents). Studies about OB volume indicated that there was littleor no difference between PD patients with anosmia/hyposmia andhealthy normosmic controls in terms of OB volume [46].

Several studies have demonstrated an absence of correlation be-tween the olfactory loss and the duration of disease [79,80], whileother studies have found a correlation between the severity of PDand certain measures of olfactory function, such as latencies of olfac-tory OERPs [81] and results from an odor discrimination task [40].

In patients with PD, upregulated activity in regions participatingin cortico-striatal loops has been reported as a characteristic phenom-enon during motor, cognitive and linguistic tasks [82,83].

In a fMRI studyused to investigate brain olfactory activity in hyposmicpatients with PD ofmild-moderate degree, it has been reported that theyexhibited higher activation than controls bilaterally in the inferior frontalgyrus and in the anterior cingulated gyrus, in anterior portions of the leftstriatum and the right ventral striatum. Further, the same authors dem-onstrated that in PD neuronal activity was signicantly decreased in theleft posterior putamen during right-sided stimulation [47].

Olfactory decit in HC is primarily associated with involvementgyrus, the thalamus and the caudate nucleus

Motor neuron disease 28/37 MND patients have signicant lower scores on the UPSIT-4/37 MND patients are nearly or totally anosmicsExcess of lipofuscin deposition and bunina bodies in olfactory bs 1996 [51]; Attems et al., 2005 [52]d volumetric decrease in the Mundiano et al., 2011 [53]

te Examination Thomann et al., 2009 [54]identication of the progression Fusetti et al., 2010 [55]

tions in AD: primary olfactory cortex, Wang et al., 2010 [56]

l impairments Zivadinov et al., 1999 [57]on Zorzon et al., 2000 [58]mporal lobes and olfactory function Doty et al., 1999 [59]function Goektas et al., 2011 [60]patients with secondary progressive Silva et al., 2011 [61]

odor recognition memory is not found Bacon Moore et al., 1999 [62]

early and signicant accumulation of Menalled et al., 2003 [63]iseases.

Author and year

Tissingh et al., 2001 [40]ganglia Hawkes et al., 1999 [41]in striatal dopamine transporter Berendse et al., 2001 [42]

Braak et al., 2003 [43]quent regions of the Wattendorf et al., 2009 [44]

dysfunction in early PD Wu et al., 2011 [45]healthy normosmic Hummel et al., 2010 [46]

during right-sides stimulation Westermann et al., 2008 [47]ory-induced brain activity in PD Welge-Lssen et al., 2009 [48]The rst study in patients with PD, that combined fMRI and OERPanalysis applying olfactory stimuli by the olfactometer, demonstratedan association between the expression of olfactory ERPs and olfactory-induced brain activity in PD.

Using fMRI, central activation during olfactory stimulation wasexamined.

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 asthe amygdala, parahippocampal regions, and temporal regions. Com-parison of both groups revealed higher activation in ERP+patients, es-pecially in the amygdala, parahippocampal cortex, inferior frontalgyrus, 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 iscrucial to ensure medical and social intervention for both patients andfamily [84].

Several studies have demonstrated that loss of the sense of smellmay be an early sign of AD [85,86]. In fact, Devanand et al. demon-strated that of 90 patients affected by mild cognitive impairment(MCI) (examined at 6-month intervals for 2 years follow-up), thosewith low olfaction scores (34 of 40) and those who reported nosubjective problems smelling through the UPSIT, were more likelyto develop AD than other patients. In specic, low olfaction scores(34) predicted the diagnosis of AD at follow-up (19 of 47 withlow olfaction scores developed AD compared to zero of 30 with

of the entorhinal cortex, the parahippocampal Barrios et al., 2007 [64]

40 compared to age matched controls; Sajjadian et al., 1994 [65]

ulb of MND patient Hawkes et al., 1998 [66]

21M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624high olfaction scores); all 19 patients with MCI who developed ADhad low olfaction scores [86].

Indeed, the olfactory function testing has revealed compromised ol-factory function in early AD [87,49]. In this disease neuroanatomicalchanges in the central portion of the olfactory systemoccur early and ol-factory testing has been explored as a promising and possible diagnosticmarker [62,88]. Olfactory dysfunction in AD correlateswith disease pro-gression [49,89], aiding in the differential diagnosis of AD versus otherforms of dementia [89], and being clinically useful as an early diagnosticmarker in predicting incident of AD in high-risk individuals [86,90].

It has been suggested by Braak and others that one of the rstdamaged areas in patients with AD is transentorhinal cortex, areas in-volved in memory, emotion and olfaction. It has been also suggestedthat the degenerative process in AD characterized by plaque and neu-robrillary tangles starts in the enthorinal cortex, and then proceedsto other temporal lobe structures, including hippocampus [5052].

Additionally, it has been found that subjects with hyposmia andapolipoprotein E epsilon 4 allele (ApoE4) have approximately 5 timeshigher risk of developing AD late [90]. Talamo et al. suggested that ADcould be identiedby autopsy sample of nasal olfactory neuroepithelium,in which distribution, morphology, immunoreactivity of neuronal struc-tures change [91]. However, it is very difcult to identify olfactory neu-rons because the mechanism, with which the neuropithelium tends tobe replaced gradually by respiratory epithelium in aging, may be morerapid in AD. In fact, a Yamagishi's immunohistochemical study demon-strated that only 6/13 sample contained olfactory neurons [92].

The olfactory decits is usually evaluated through the use of teststhat measure the ability to identify and discriminate the odors, as wellas the odor detection threshold (sensitivity).

AD patients have relative preservation of threshold in the earlystages [93].

In addition, the decline of smell identication could therefore actas a biomarker of future cognitive impairment. Using a stereologicaltechniques, it has been found an increased number of dopaminergicperiglomerular neurons and a signicant volumetric decrease in theolfactory bulb of AD patients compared with age-matched controls[53]. Moreover, changes in OB have also been well-recognized andits volume correlated to Mini Mental State Examination in patientswith AD [54].

A recent study of Fusetti et al., evaluating the amnesic MCI by theSnifn' Sticks test and its relationshipwith AD, concluded that the olfac-tory decit occurs early in aMCI. So they suggested the introduction ofthe olfactory test in the clinical routine for early identication of theprogression of the decline from aMCI to AD [55].

In addition , fMRI studies in AD patients showed the degeneration ofneural structures responsible for olfactory functions (primary olfactorycortex, hippocampus, insula, thalamus and hypothalamus) [56].

4.3. Olfactory dysfunction in multiple sclerosis

Multiple sclerosis (MS) is a chronic, complex neurological diseasewith a variable clinical course in which several pathophysiologicalmechanisms such as axonal/neuronal damage, demyelination, in-ammation, gliosis, remyelination and repair, oxidative injury andexcitotoxicity, alteration of the immune system are involved [94].

Olfactory dysfunction may also be an early indicator of diseaseprogression in MS.

A study based on smell identication test indicated that patientswith MS scored signicantly worse than control groups. They alsofound a signicant correlation between smell alteration and symp-toms of anxiety and depression and the severity of neurological im-pairments [57]. In several clinical and MR studies, neuropathologybased on plaque numbers were directly correlated to olfactory func-tion [58].

As plaque numbers declined or increased in the inferior frontal

and temporal lobes, olfactory function declined or improved incorrelation [59,95]. There was proof of a clear inverse correlation be-tween the number of plaques in the olfactory cortex and the olfactoryfunction in patients with MS [58,95].

These reports are suggestive of olfactory involvement and poten-tial utility in diagnostic approaches for this disease. It remains unclearwhether olfactory disturbances occur as an initial symptom of MS[96]. A recent study assessed OB volume of MS patients with MRIand related it to the olfactory function. They found that, in patientswith a decreased OB volume, there was a positive correlation be-tween volumetry of the OB and olfactory function [60]. These ndingshowed that OB may provide valuable information about olfactorydysfunction of MS patients. A diminished sense of smell in MS hasalso been reported in a recent study [97]. Silva et al. have character-ized the olfactory identication capacity in MS using the Brief SITand have explored possible associations between smell identicationimpairments and patient's clinical characteristics. They found that thefrequency of impairment was higher for patients with secondaryprogressive (SPMS) than RelapsingRemitting (RRMS) or primaryprogressive courses and they demonstrated that a brief odor identi-cation measure provided a good discrimination between SPMS andRRMS courses [61].

4.4. Olfactory dysfunction in Huntington's disease

HD is an autosomal dominant disorder of basal ganglia functiontypied by choreic movement, dementia and rarely muscular rigiditysimilar to PD. Initial studies have documented early defective odormemory sometimes prior to cognitive defect or the onset of markedinvoluntary movement [2].

Following studies, using identication and detection tests, haveconrmed the presence of moderate olfactory impairment, affectingthe identication in particular, although it was less than that seen inPD. Olfactory testing of presymptomatic relatives at 50% risk has notshown abnormalities, implying that olfaction is impaired at theonset of motor or cognitive disorder [98]. In another study [99],odor detection presented good classication of sensitivity and speci-city between the patients and controls, suggesting that olfactorytesting may provide a sensitive measure of early disease process inHD patients. The utility of this observation is offset by the widelyavailable and specic DNA test for HD.

Patients with HD exhibited signicant decits in odor identication,but odor recognitionmemorywas not found to be affected [62,98]. In ananimal model of the disease, the olfactory system exhibited early andsignicant accumulation of huntingtin protein containing aggregates,which may account for the early olfactory impairment [63].

Recent study by voxel-basedmorphometric analysis has shown thatolfactory decits in patients with HD was primarily associated with in-volvement of the entorhinal cortex, the parahippocampal gyrus, thethalamus and the caudate nucleus. Although various neuroimagingstudies have previously shown that the caudate nucleus is involved inolfaction, this study is the rst demonstration of its involvement alsoin a neurodegenerative disease associated to olfactory loss [64].

4.5. Olfactory dysfunction in motor neuron disease

Anatomical and electrophysiological evidences suggest also theinvolvement of sensory pathways in MND. There has been just onestudy of the OB in 8 cases of MND [65]. There was marked accumula-tion of lipofuscin in olfactory neurons compared to age-matched con-trols, suggesting defective lipid peroxidation. A clinically based pilotstudy [100], examined 15 patients with MND, whom 8 had moderateor severe bulbar involvement and 8 were chair bound. No test for de-mentia or snifng was administered but signicant lowering of theUPSIT40 scores was documented.

In another study of 37 patients with MND [66], 28 (75.7%) had sig-

nicantly lower scores on the UPSIT-40 compared to age-matched

22 M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624controls. There were 4 (11%) with near or total anosmia. Olfactoryfunctions may not be totally unimpaired in MND from pathologicalviewpoint. Histopathological studies of OB shown excess lipofuscin de-position [101] and Bunina bodies, known to occur in sporadicMNDwithdementia and Guamian Amyotrophic Lateral Sclerosis [102]. However,these researcheswere regarded as not likely being of clinical value. A re-cent study [103] did not shown signicant correlation between diseaseduration and smell. In this study the authors assessed 26 patients diag-nosed as suffering fromMNDat various stages and compared themwith26 matched controls using Snifn Sticks for smell. The smell test cor-related with age, but not with the duration of the disease. According tothese researches, olfaction do not seem to be linked to or inuenced bythe disease, but it may be caused by a toxin entering the body via thenasal or oral route rather unlikely as well as a degenerative process in-volving sensory pathways [103].

5. Conclusions

It is evident from the studies reviewed in this paper that olfactorydysfunction is involved in various neurological disease, including PD,AD, MS, HD, and MND.

Accumulating evidences indicate that olfactory decit is an earlymanifestation of PD and AD. However, the olfactory decit has beenalso observed in early stage of HD. Although the olfactory loss is amajor component of aging, a number of studies highlighted that PDand AD patients show changes in detection, discrimination and iden-tication of odors, compared to aged healthy controls.

In recent years, great achievements have been obtained in eluci-dating the mechanism of olfactory dysfunction in neurodegenerativediseases. In PD and AD olfactory impairment may relate to changes inthe OB, atrophy and degeneration of primary or secondary olfactorycortices, or both. Also the alterations of neurotransmitters may con-tribute to olfactory loss. In addition, the genetic risk factor ApoE4may allow to individuate among healthy people with hyposmia thesubjects who present high risk to be affected by AD.

The assessment of olfactory function is very important, especiallyin the early stage of these diseases, because it may be a good and use-ful indicator for clinical diagnosis.

In MS, it is yet not clear if the olfactory impairment is an early hall-mark of disease. However the evaluation of functionality of olfactorysystem may provide insight into progression of disease.

The OECs, located within the peripheral olfactory system andcharacterized by exceptional plasticity, could be responsible for func-tional recovery in young patients with RRMS. The RRMS is character-ized by stages of relapses and remissions, in which there is a partialreconstitution of glia and following functional recovery. The studyof the olfactory performance, using the methods described above,might be a useful prognostic marker for the evaluation of functionalrecovery in these patients. The mechanism of olfactory neurons re-generation deserves further attention and others intensied studiesin order to investigate the succession of stages which lead from re-lapse to remission.

From reported studies, it seem that the olfactory impairment is in-volved also in MND. However further investigations are needed inorder to establish the correlation between the olfactory impairmentand the neurodegenerative process in MND.

Although several drugs may potentially cause smell or taste disor-ders [104], in these studies it was not taken into account if pharmaco-logical treatments may contribute in some way to the worsening ofolfactory performances in neurological diseases. It is desirable that,in the near future, a possible goal of research in this eld is the inves-tigation of pharmacological treatments effects on olfactory function inneurological diseases.

Numerous functional and structural approaches are available forassessing the integrity of the olfactory system in neurodegenerative

diseases, such as psychophysical, electrophysiological and imagingprocedures. Although psychophysical methods are widely used, latelythe other techniques are begin to be available for clinical diagnosis.The data reported from the majority of studies are the result of theapplication of one or two among olfactory evaluation methods. Onthe contrary, a reliable assessment of olfactory function should in-clude all of these instrumental approaches. This could make the olfac-tory function measure more objective and, at the same time, useful asbiomarkers of neurological diseases. In addition, the use of objectiveelectrophysiological and neuroimaging techniques, supported by ol-factometer for generation of olfactory stimuli, could help not only inthe understanding of olfactory dysfunction pathogenesis in neurolog-ical disorders, but also in the monitoring of disease progression andthe assessing of effects of disease-modifying therapies.

Statement of conict of interest

The authors report no conict of interest.

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24 M. Barresi et al. / Journal of the Neurological Sciences 323 (2012) 1624

Evaluation of olfactory dysfunction in neurodegenerative diseases1. Introduction2. Anatomy of the olfactory system3. Instrumental approaches assessing olfactory function3.1. Psychophysical methods3.2. Olfactory event-related potentials3.3. Functional magnetic resonance imaging

4. Olfactory dysfunction in neurological diseases4.1. Olfactory dysfunction in Parkinson's disease4.2. Olfactory dysfunction in Alzheimer's disease4.3. Olfactory dysfunction in multiple sclerosis4.4. Olfactory dysfunction in Huntington's disease4.5. Olfactory dysfunction in motor neuron disease

5. ConclusionsStatement of conflict of interestReferences