Clinical trial| Volume 38, 101507, February 2020

Olfactory identification associates with cognitive function and the third ventricle width in patients with relapsing-remitting multiple sclerosis

Published:November 05, 2019DOI:


      • Olfactory identification may decline early in some multiple sclerosis (MS) patients.
      • Olfactory identification correlates with processing speed and working memory in MS.
      • Decreased olfactory identification ability reflects central brain atrophy in MS.
      • Olfactory identification is a possible biomarker for MS disease progression.



      Olfactory dysfunction is a known clinical feature of multiple sclerosis (MS). Some studies have shown that odor identification impairment is an essential feature associated with cognitive function in MS. This study investigates the relationship between olfactory identification and the disease state, including cognitive function and central brain volume, to evaluate the utility of olfactory identification in the clinical assessment of relapsing-remitting (RR) MS.


      Forty patients with RRMS and 40 healthy controls (HCs) were included. Their olfactory identification was measured using the Odor Stick Identification Test for the Japanese (OSIT-J). Cognitive function was evaluated by the Japanese version of the Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III), and depressive mood was evaluated by the Center for Epidemiologic Studies Depression Scale. Magnetic resonance imaging was used to measure the third ventricle width (3rd VW) as a marker of central brain atrophy.


      RRMS patients had a significantly lower OSIT-J score than HCs. The OSIT-J score was significantly lower in RRMS patients with low processing speed (PS) and working memory (WM) scores than RRMS patients with normal PS or WM scores. The OSIT-J score was significantly related to the PS, WM, and the 3rd VW. The OSIT-J score also showed a mild correlation with the expanded disability status scale and disease duration, but not with the number of clinical attacks or patient's age.


      Our results suggest that olfactory identification impairment occurs in association with cognitive dysfunction and central brain atrophy. Thus, olfactory identification is a possible disease marker of RRMS as with cognitive impairment, especially PS, reflecting the diffuse neurodegeneration in RRMS.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Azevedo C.J.
        • Cen S.Y.
        • Khadka S.
        • et al.
        Thalamic atrophy in multiple sclerosis: a magnetic resonance imaging marker of neurodegeneration throughout disease.
        Ann. Neurol. 2018; 83: 223-234
        • Azevedo C.J.
        • Overton E.
        • Khadka S.
        • et al.
        Early cns neurodegeneration in radiologically isolated syndrome.
        Neurol. Neuroimmunol. Neuroinflamm. 2015; 2: e102
        • Batur Caglayan H.Z.
        • Irkec C.
        • Nazliel B.
        • Akyol Gurses A.
        • Capraz I.
        Olfactory functioning in early multiple sclerosis: Sniffin' sticks test study.
        Neuropsychiatr. Dis. Treat. 2016; 12: 2143-2147
        • Benedict R.H.
        • Weinstock-Guttman B.
        • Fishman I.
        • Sharma J.
        • Tjoa C.W.
        • Bakshi R.
        Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden.
        Arch. Neurol. 2004; 61: 226-230
        • Benedict R.H.
        • Bruce J.M.
        • Dwyer M.G.
        • et al.
        Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis.
        Arch. Neurol. 2006; 63: 1301-1306
        • Benedict R.H.
        • DeLuca J.
        • Phillips G.
        • LaRocca N.
        • Hudson L.D.
        • Rudick R.
        Multiple sclerosis outcome assessments consortium. Validity of the symbol digit modalities test as a cognition performance outcome measure for multiple sclerosis.
        Mult. Scler. 2017; 23: 721-733
        • Bisecco A.
        • Stamenova S.
        • Caiazzo G.
        • et al.
        Attention and processing speed performance in multiple sclerosis is mostly related to thalamic volume.
        Brain Imaging Behav. 2018; 12: 20-28
        • Bsteh G.
        • Hegen H.
        • Ladstätter F.
        • et al.
        Transient impairment of olfactory threshold in acute multiple sclerosis relapse.
        Mult. Scler. Relat. Disord. 2018; 23: 74-77
        • Bsteh G.
        • Berek K.
        • Hegen H.
        • et al.
        Smelling multiple sclerosis: different qualities of olfactory function reflect either inflammatory activity or neurodegeneration.
        Mult. Scler. 2018;
        • Bsteh G.
        • Hegen H.
        • Ladstätter F.
        • et al.
        Change of olfactory function as a marker of inflammatory activity and disability progression in MS.
        Mult. Scler. 2019; 25: 267-274
        • Bsteh G.
        • Steiger R.
        • Tuovinen N.
        • et al.
        Impairment of odor discrimination and identification is associated with disability progression and gray matter atrophy of the olfactory system in MS.
        Mult. Scler. 2019;
        • Brochet B.
        • Ruet A.
        Cognitive impairment in multiple sclerosis with regards to disease duration and clinical phenotypes.
        Front Neurol. 2019; 10: 261
        • Carotenuto A.
        • Costabile T.
        • Moccia M.
        • et al.
        Olfactory function and cognition in relapsing-remitting and secondary-progressive multiple sclerosis.
        Mult. Scler. Relat. Disord. 2019; 27: 1-6
        • Courtiol E.
        • Wilson D.A.
        The olfactory mosaic: bringing an olfactory network together for odor perception.
        Perception. 2017; 46: 320-332
        • DeLuca J.
        • Chelune G.J.
        • Tulsky D.S.
        • Lengenfelder J.
        • Chiaravalloti N.D.
        Is speed of processing or working memory the primary information processing deficit in multiple sclerosis?.
        J. Clin. Exp. Neuropsychol. 2004; 26: 550-562
        • DeLuca G.C.
        • Yates R.L.
        • Beale H.
        • Morrow S.A.
        Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights.
        Brain. Pathol. 2015; 25: 79-98
        • Doty R.L.
        • Marcus A.
        • Lee W.W.
        Development of the 12-item Cross-Cultural Smell Identification Test (CC-SIT).
        Laryngoscope. 1996; 106: 353-356
        • Doty R.L.
        Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate?.
        Lancet Neurol. 2017; 16: 478-488
        • Erb K.
        • Bohner G.
        • Harms L.
        • et al.
        Olfactory function in patients with multiple sclerosis: a diffusion tensor imaging study.
        J. Neurol. Sci. 2012; 316: 56-60
        • Fagundo A.B.
        • Jiménez-Murcia S.
        • Giner-Bartolomé C.
        • et al.
        Modulation of higher-order olfaction components on executive functions in humans.
        PLoS. One. 2015; 10e0130319
        • Feinstein A.
        • DeLuca J.
        • Baune B.T.
        • Filippi M.
        • Lassman H.
        Cognitive and neuropsychiatric disease manifestations in MS.
        Mult. Scler. Relat. Disord. 2013; 2: 4-12
        • Houtchens M.K.
        • Benedict R.H.
        • Killiany R.
        • et al.
        Thalamic atrophy and cognition in multiple sclerosis.
        Neurology. 2007; 69: 1213-1223
        • Iijima M.
        • Kobayakawa T.
        • Saito S.
        • et al.
        Smell identification in Japanese Parkinson's disease patients: using the odor stick identification test for Japanese subjects.
        Inter. Med. 2008; 47: 1887-1892
        • Japanese WAIS-III Publication Committee
        Japanese Wechsler Adult Intelligence Scale.
        3rd ed. Nihon Bunka Kagakusha Tokyo, Tokyo2006 (in Japanese)
        • Joseph A.
        • DeLuca G.C.
        Back on the scent: the olfactory system in CNS demyelinating diseases.
        J. Neurol. Neurosurg. Psychiatry. 2016; 87: 1146-1154
        • Lucassen E.B.
        • Turel A.
        • Knehans A.
        • Huang X.
        • Eslinger P.
        Olfactory dysfunction in multiple sclerosis: a scoping review of the literature.
        Mult. Scler. Relat. Disord. 2016; 6: 1-9
        • Lassmann H.
        Pathogenic mechanisms associated with different clinical courses of multiple sclerosis.
        Front. Immunol. 2019; 9: 3116
        • Manca R.
        • Sharrack B.
        • Paling D.
        • Wilkinson I.D.
        • Venneri A.
        Brain connectivity and cognitive processing speed in multiple sclerosis: a systematic review.
        J. Neurol. Sci. 2018; 388: 115-127
        • Menascu S.
        • Stern M.
        • Aloni R.
        • Kalron A.
        • Magalshvili D.
        • Achiron A.
        Assessing cognitive performance in radiologically isolated syndrome.
        Mult. Scler. Relat. Disord. 2019; 32: 70-73
        • Minagar A.
        • Barnett M.H.
        • Benedict R.H.
        • et al.
        The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects.
        Neurology. 2013; 80: 210-219
        • Okada K.
        • Kobata M.
        • Sennari Y.
        • et al.
        Levels of nitric oxide metabolites in cerebrospinal fluid correlate with cognitive impairment in early stage multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2017; : 892-893
        • Papathanasiou A.
        • Messinis L.
        • Zampakis P.
        • et al.
        Thalamic atrophy predicts cognitive impairment in relapsing remitting multiple sclerosis. Effect on instrumental activities of daily living and employment status.
        J. Neurol. Sci. 2015; 358: 236-242
        • Polman C.H.
        • Reingold S.C.
        • Banwell B.
        • et al.
        Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
        Ann. Neurol. 2011; 69: 292-302
        • Saito S.
        • Ayabe-Kanamura S.
        • Takashima Y.
        • et al.
        Development of a smell identification test using a novel stick-type odor presentation kit.
        Chem. Senses. 2006; 31: 379-391
        • Schmidt F.A.
        • Maas M.B.
        • Geran R.
        • et al.
        Olfactory dysfunction in patients with primary progressive MS.
        Neurol. Neuroimmunol. Neuroinflamm. 2017; 4: e369
        • Silva A.M.
        • Santos E.
        • Moreira I.
        • et al.
        Olfactory dysfunction in multiple sclerosis: association with secondary progression.
        Mult. Scler. 2012; 18: 616-621
        • Silva P.H.R.
        • Spedo C.T.
        • Baldassarini C.R.
        • et al.
        Brain functional and effective connectivity underlying the information processing speed assessed by the Symbol Digit Modalities Test.
        Neuroimage. 2019; 184: 761-770
        • Van Schependom J.
        • D'hooghe M.B.
        • Cleynhens K.
        • et al.
        Reduced information processing speed as primum movens for cognitive decline in MS.
        Mult. Scler. 2015; 21: 83-91
        • Vilagut G.
        • Forero C.G.
        • Barbaglia G.
        • Alonso J.
        Screening for depression in the general population with the center for epidemiologic studies depression (CES-D): a systematic review with meta-analysis.
        PLOS One. 2016; 11e0155431