Superior cerebellar peduncle atrophy of progressive supranuclear palsy on phase difference enhanced imaging: a comparison with Parkinson's disease.

PURPOSE: Phase difference enhanced (PADRE) imaging can enhance myelin density and delineate the superior cerebellar peduncle (SCP). We aimed to determine if SCP atrophy was distinguishable on PADRE imaging and evaluate its diagnostic performance compared with previous MRI progressive supranuclear palsy (PSP) findings. METHODS: Two reviewers measured the SCP widths on PADRE in 20 PSP and 31 Parkinson's disease (PD) patients. The SCP and middle cerebellar peduncle (MCP) widths and the pons and midbrain areas were measured on 3D-T1WI, and the ratio of the area of the pons to the area of the midbrain, the MCP/SCP ratio, and the magnetic resonance parkinsonism index (MRPI) were calculated. We used the Steel-Dwass test to compare PSP, PD, and HS, and receiver operating characteristic curve (ROC) analyses to assess the sensitivity and specificity for diagnosing PSP from PD. A comparison of ROC curves was performed between the SCP on PADRE and these 3D-T1WI parameters. RESULTS: In radiologist 1, the SCP on PADRE in PSP (1.1 ± 0.3 mm) was significantly smaller than those in PD (2.4 ± 0.4 mm) (P < 0.001); the area under the curve (AUC) was 0.97. At a 1.75-mm cutoff value, the diagnostic sensitivity and specificity for differentiating PSP from PD were 93.5% and 100%, respectively. The AUC of the SCP on PADRE was significantly higher than the 3D-T1WI parameters (the SCP, MCP, pons area, MCP/SCP ratio, and MRPI). CONCLUSION: Assessing SCP with PADRE imaging may yield high diagnostic accuracy for discriminating PSP from PD.

Facial nerve atrophy in patients with amyotrophic lateral sclerosis: Evaluation with fast imaging employing steady-state acquisition (FIESTA).

BACKGROUND: In amyotrophic lateral sclerosis (ALS), motor neurons in the brainstem markedly deplete, whereas sensory neurons are less severely affected. PURPOSE: To determine whether facial nerve (FN) measurement on 3D fast imaging employing steady-state acquisition (FIESTA) is useful for ALS diagnosis. STUDY TYPE: Retrospective. SUBJECTS: Fifteen ALS patients and 16 controls. FIELD STRENGTH/SEQUENCE: 3T FIESTA MR. ASSESSMENT: The cross-sectional area of the FN and cochlear nerve (CN) were measured, and the FN/CN ratio (FCR) was assessed. For qualitative assessment, the FN cross-sectional area was compared with that of the CN and the following scores were assigned: score 1 (large), the FN is larger than the CN; score 2 (almost equal), the size difference between the FN and CN is within 10%; score 3 (small), the FN is smaller than the CN (10-50%); score 4 (significantly small), size of the FN is less than half the size of the CN. STATISTICAL TESTS: The differences in FCR between the ALS patients and the controls were tested using the Wilcoxon Mann-Whitney U-test. For the qualitative and quantitative assessments, we performed a receiver operating characteristic analysis for the diagnosis of ALS with an abnormal finding as score 3 or 4. RESULTS: The mean FCR was significantly smaller for ALS patients (0.71 ± 0.17) than for controls (0.95 ± 0.08) (P < 0.001) and the area under the curve was 0.93. When an FN score was 3 or 4, indicative of FN atrophy, the sensitivity and specificity values of FIESTA for discriminating ALS patients from controls were 93.3% (14/15) and 90.0% (18/20), respectively. DATA CONCLUSION: The FN atrophy revealed on FIESTA, which may reflect lower motor neuron impairment in ALS, allowed us to distinguish ALS patients from controls with a high degree of accuracy. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:757-766.

Potential usefulness of signal intensity of cerebral gyri on quantitative susceptibility mapping for discriminating corticobasal degeneration from progressive supranuclear palsy and Parkinson's disease.

PURPOSE: The typical MRI findings in corticobasal degeneration (CBD), which have been described in previous reports, may be non-specific. We evaluated cerebral gyri (CG) using quantitative susceptibility mapping (QSM) images of patients with CBD, progressive supranuclear palsy (PSP), and Parkinson's disease (PD) to determine the possibility of discriminating them on an individual basis. METHODS: After reviewing the normal appearances on QSM on 16 healthy subjects, two radiologists assessed abnormal findings from 12 CBD, 14 PSP, and 30 PD patients. For conventional MRI, two radiologists independently reviewed typical CBD findings that have been previously reported. We also investigated three autopsy cases including one each of CBD, PSP, and PD to reveal the histopathological basis of MRI findings. RESULTS: CBD-specific findings included three layers; a higher susceptibility layer in superficial GM, a lower susceptibility layer, and a higher susceptibility layer in corticomedullary junction, with frequencies of 83% (10/12) in CBD, 21% (3/14) in PSP, and 0% (0/30) in PD patients. The typical CBD findings on conventional MRI were observed in only 42% (5/12) of CBD patients. Ferritin-positive microglia accumulated in the superficial gray matter (third cortical layer) and corticomedullary junction in CBD patients. CONCLUSIONS: The CG findings on QSM images may be more useful than those on conventional MRI for discriminating CBD from PD on an individual basis. Based on postmortem pathological data, cortical QSM hyperintensity might be an expression of ferritin-positive microglia.

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

OBJECTIVE: Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. METHODS: This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. RESULTS: At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. CONCLUSIONS: Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01824251).

Zebra sign of precentral gyri in amyotrophic lateral sclerosis: A novel finding using phase difference enhanced (PADRE) imaging-initial results.

OBJECTIVE: We compared the precentral gyri (PG) on the PADRE of patients with amyotrophic lateral sclerosis (ALS) and healthy subjects (HSs) in order to determine whether it is possible to discriminate between ALS patients and HSs on an individual basis. METHODS: First, two radiologists reviewed the appearance of the normal PG and that of ALS patients on PADRE in a non-blinded manner, and deviations from the appearance of the normal PG were recorded. Next, based on the presence of PG abnormalities on PADRE, we performed an observer performance study using 16 ALS patients and 16 HSs. RESULTS: The radiologists were able to consensually define the PG as abnormal on PADRE when a low-signal-intensity layer was observed in the gray matter of the PG; a three- or four-layer organization (zebra sign) was characterized by the low-signal-intensity layer. The observer performance study demonstrated that the sensitivity, specificity, and accuracy of PG abnormalities on PADRE for discriminating ALS patients from HSs were 94 %, 94 %, and 94 %, respectively, for reviewers 1 and 2. CONCLUSIONS: It was possible to discriminate between ALS patients and HSs based on the presence of PG abnormalities on PADRE, which may reflect upper motor neuron impairment in ALS. KEY POINTS: • PADRE reveals low-signal-intensity layer in the PG of ALS • By PADRE findings on PG, we can discriminate ALS from HSs • PADRE may be a useful method for detecting UMN impairment in ALS.

Hydration structure of trimethylamine N-oxide in aqueous solutions revealed by soft X-ray emission spectroscopy and chemometric analysis.

The hydration structure of trimethylamine N-oxide (TMAO) in aqueous solutions has been investigated by means of soft X-ray spectroscopy and chemometric analysis. Soft X-ray absorption spectra in the O 1s region have a concentration-dependent shoulder at 533 eV, which is assigned to the 6a1 resonance of TMAO. Soft X-ray emission spectra acquired at this resonance comprise both TMAO and water components, with a prominent peak at 525.6 eV which is assigned to the emission caused by the 5e to O 1s transition. An apparent inverse concentration dependence of around 523 eV suggests that the electronic structure of water is modified by the strong interaction with TMAO. Such an effect has been included in the quantitative spectral analysis, called the classical least squares regression method, to obtain information on the hydration structure of the system. The analysis indicates that nine or more water molecules interact with a TMAO molecule. The present method offers a useful technique for probing the solvation structure around the solute which interacts strongly with the solvent.

Internal structures of the globus pallidus in patients with Parkinson's disease: evaluation with quantitative susceptibility mapping (QSM).

OBJECTIVES: The aim of this study was to assess the susceptibility change in medial and lateral globus pallidus (GPm and GPl) related to age separately, using quantitative susceptibility mapping (QSM) and to determine whether QSM can depict GPm in Parkinson's disease (PD) patients. METHODS: QSM was performed in 19 PD patients and in 41 normal control (NC) subjects. First, we quantitatively analysed age-related changes in QSM value in NC for GPl and GPm by a manual region of interest (ROI) technique. Then, in PD patients and age-matched NC subjects, we evaluated the depiction of GPm on QSM images qualitatively. RESULTS: In NC, the QSM value within GPl significantly increased gradually with age (r = 0.32, p = 0.04), whereas it did not change with age in GPm. The average QSM value was significantly larger for GPl than for GPm (205 vs 191, p < 0.05). In both PD patients and age-matched NC, the depiction of GPm on QSM images was good in most cases (87 %, 33 of 38 sides in PD patients) mainly because of the differences in susceptibility between GPm and GPl. CONCLUSIONS: The QSM value in GPl increases gradually with age, which allows for the identification of GPm in elderly PD subjects.

Parkinson's disease: diagnostic potential of high-resolution phase difference enhanced MR imaging at 3 T.

OBJECTIVES: To determine whether it is possible to diagnose patients with Parkinson's disease (PD) on an individual basis using magnetic resonance imaging with phase difference enhanced imaging (PADRE). METHODS: PADRE delineated the crural fibres as a layer of low signal intensity and the substantia nigra as a layer of medium signal intensity in a healthy volunteer, and showed a clear boundary between the crural fibres and the substantia nigra (BCS). Twenty-four PD patients and 24 control subjects were enrolled. Contrast ratios between the substantia nigra and occipital white matter were calculated, and two radiologists independently reviewed the PADRE findings regarding BCS obscuration. RESULTS: Mean contrast ratio in PD patients was significantly higher than in control subjects (0.56 vs 0.39, P < 0.01). The BCS on PADRE was obscured significantly more frequently in any subgroups with PD patients compared with control subjects (P < 0.01). The observation of BCS obscuration had a sensitivity, specificity and accuracy for the diagnosis of PD of 92 %, 88 % and 90 % for radiologist 1 and 83 %, 88 % and 85 % for radiologist 2, respectively. CONCLUSION: PADRE is able to identify PD in patients as a loss of delineation between the crural fibres and the substantia nigra on an individual basis.

[A case of Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation].

The patient is a 44-year-old man. His parents are consanguineous. He experienced muscle weakness in his toe and distal tingling sensation in his feet at 42 years of age, which gradually progressed. Additionally, a marked cyanotic discoloration of the feet appeared and worsened progressively. Neurological examination revealed loss of tendon reflexes and distal muscle weakness in the lower extremities. Findings from nerve conduction studies indicated axonal polyneuropathy. Upon detection of the MME gene mutation, the patient was diagnosed with autosomal-recessive Charcot-Marie-Tooth disease 2T (ARCMT2T). In this case, cyanosis of the lower extremities possibly was associated with ARCMT2T, and it was suggested to be due to neprilysin deletion linked with the MME mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with MME mutation.

Clinical features and haplotype analysis of newly identified Japanese patients with gelsolin-related familial amyloidosis of Finnish type.

Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant form of systematic amyloidosis characterized by lattice corneal dystrophy, cranial neuropathy, and cutis laxa. Although FAF has been frequently found in the Finnish population, FAF is a considerably rare disorder in other regions. In this study, we examined the clinical characteristics as well as the haplotypes of six Japanese patients with FAF from five families. They showed the typical clinical presentations of FAF, but we found a broad range of ages at onset of neurological symptoms. All members had the c.654G>A mutation in GSN. To evaluate the disease haplotypes, high-density single-nucleotide polymorphism (SNP) arrays were used and disease-relevant haplotypes were reconstructed. Haplotype analysis in the four apparently unrelated families suggested a common founder haplotype. In a sporadic FAF patient, however, the haplotype was dissimilar to the founder haplotype. The present study demonstrated that a founder mutation in most of the Japanese families with FAF, except for a sporadic patient in whom a de novo mutation event was suggested as the origin of the mutation.

Olfactory Dysfunction Reflects Disease Progression in Japanese Patients with Multiple Sclerosis.

Objective Olfactory dysfunction is an important clinical feature in patients with multiple sclerosis (MS). The incidence and extent of olfactory dysfunction are reportedly higher in secondary progressive (SP) MS than in relapsing and remitting (RR) MS. We investigated the use of olfactory dysfunction for evaluating the disease status of Japanese patients with MS. Methods Olfactory identification was evaluated using the Odor Stick Identification Test for the Japanese (OSIT-J) in patients with RRMS (n=40) and SPMS (n=11) and compared the findings with those of healthy controls (n=40). Patients with RRMS for more than 10 years (L-RRMS, n=10) were included in the RRMS group. The cognitive function was evaluated using the Japanese version of the Wechsler Adult Intelligence Scale, 3rd edition. The third ventricle width (3rd VW) was measured as a marker of central brain atrophy using magnetic resonance imaging. Results SPMS patients had significantly lower OSIT-J scores than RRMS and L-RRMS patients. More SPMS patients had OSIT-J scores below the lower limit of the normal score (LLN) than RRMS patients. The LLN effectively discriminated between RRMS and SPMS (sensitivity 70%, specificity 91.5%, area under the curve 0.933, 95% confidence interval 0.874-1.000). Patients with SPMS had a significantly lower processing speed and larger 3rd VW than those with RRMS or L-RRMS. Conclusion The olfactory dysfunction was worse, along with cognitive impairment and brain atrophy, in SPMS patients than in RRMS patients, independent of disease duration, in our Japanese population. This directly reflected the disease progression and may have been able to distinguish SPMS from RRMS, independent of ethnic and cultural background.

Optic radiation atrophy in Lewy body disease with visual hallucination on phase difference enhanced magnetic resonance images.

Visual hallucinations (VH) occur commonly in Lewy body disease (LBD), including Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies. We aimed to use phase difference enhanced imaging (PADRE) to assess structural abnormalities of optic radiation (OR) in patients with Lewy body disease (LBD) concomitant with VH. Firstly, two radiologists reviewed the OR appearances in healthy subjects (HS) on PADRE. Next, based on the OR abnormalities, two reviewers assessed the PADRE images from 18 HS and 38 and 110 patients with LBD, with and without VH, respectively, in a blinded manner. Finally, all patients with LBD without VH were eventually followed up for at least 5 years after magnetic resonance imaging to determine the appearance of VH. The radiologists identified three layers, namely external sagittal stratum, internal sagittal stratum, and tapetum, in OR on the PADRE in HS. Moreover, they were able to consensually define the OR as abnormal when the layers were obscured and the disappearance of the cranial side. The sensitivity/specificity of abnormal OR for each case was 68%/81% (LBD with VH vs. LBD without VH). Furthermore, VH appeared in 12 of the 21 (57%) patients with LBD and abnormal OR during the follow-up period. However, no patients without abnormal OR reported VH. Patients with LBD and VH demonstrated the abnormal OR. This, in turn, might be a useful marker to distinguish the patients with VH from those without VH and HS. Moreover, abnormal OR on PADRE may precede the appearance of VH in LBD.

Compassionate open-label use of rituximab following a randomised clinical trial against neuromyelitis optica (RIN-2 study): B cell monitoring-based administration.

OBJECTIVE: The aim of the RIN-2 study was a compassionate use of rituximab (RTX) for patients who completed the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial of RTX. We also investigated the long-term safety and efficacy of RTX. METHODS: A study design was a prospective open-label extension study following the RIN-1 study. RTX was infused repeatedly under monthly monitoring of CD19-positive and CD 20-positive B cell lymphocyte subsets from 24 weeks after an infusion. RESULTS: Thirty-three (87%) of 38 patients of the RIN-1 study were enrolled from February 2016 to March 2019 at six sites in Japan. In RIN-2, RTX was administered three times (median, range 1-5 times), and the interval of RTX administrations were 9.5 [2.5] months (mean [SD]). The observation period was 20.5 [10.1] months. During the trial, three patients dropped out due to two withdrawals and one adverse event. During the study, 28 (90%) of 31 patients were treated with RTX monotherapy. Neuromyelitis optica (NMO) relapses were observed in two patients. The annualized relapse rate (ARR) was 0.035 counts per person-years, ∼1/10th compared with 0.321 in the placebo arm of the RIN-1 study. We observed 14 severe adverse events in six (18%) and 156 adverse events, of which 135 were grade 1, 11 were grade 2 and 10 were grade 3. CONCLUSIONS: Under B cell monitoring, the interval of RTX re-infusion was elongated to nine months, and NMO relapses were suppressed with 0.035 of ARR.

A novel tract imaging technique of the brainstem using phase difference enhanced imaging: normal anatomy and initial experience in multiple system atrophy.

OBJECTIVES: To develop a new tract imaging technique for visualising small fibre tracts of the brainstem and for detecting the abnormalities in multiple system atrophy of the cerebellar type (MSA-C) using a phase difference enhanced (PADRE) imaging technique, in which the phase difference between the target and surrounding tissue is selectively enhanced. METHODS: Two neuroradiologists compared the high-spatial-resolution PADRE imaging, which was acquired from six healthy volunteers, three patients with MSA-C, and 7 patients with other types of neurodegenerative diseases involving the brainstem or cerebellum. RESULTS: Various fine fibre tracts in the brainstem, the superior and inferior cerebellar peduncles, medial lemniscus, spinothalamic tract, medial longitudinal fasciculus, central tegmental tract, corticospinal tract and transverse pontine fibres, were identified on PADRE imaging. PADRE imaging from MSA-C demonstrated the disappearance of transverse pontine fibres and significant atrophy of the inferior cerebellar peduncles, while the superior cerebellar peduncles were intact. PADRE imaging also demonstrated that the transverse pontine fibres and inferior cerebellar peduncle were not involved in the other neurodegenerative diseases. CONCLUSION: PADRE imaging can offer a new form of tract imaging of the brainstem and may have the potential to reinforce the clinical utility of MRI in differentiating MSA from other conditions.

Hydration of the Zwitterionic and Protonated Forms of Glycine Betaine Probed by Soft X-ray Emission Spectroscopy Coupled with Chemometrics.

Soft X-ray absorption and emission spectra of glycine betaine (GB) have been measured at the O K-edge in neutral and strongly acidic solutions. The absorption spectra of the neutral solutions have a resonance peak at 532.6 eV, assigned to the transition to the π* orbital, whereas in the acidic solutions, the peak is shifted by -0.3 eV. The emission spectra taken as a function of the GB concentration have been analyzed by means of a modified classical least-squares regression method to obtain the hydration number of the solute. The analysis is successful when the emission spectra have been acquired at the energy of a slightly detuned resonance, giving 28 and 24 as the minimum values for the zwitterionic and protonated GB, respectively. The number of 28 accords with the reported values for the number of water molecules in the first hydration layer of the zwitterion and is greater than that obtained by other experimental techniques. The obtained numbers are used to discuss the hydration structure of GB with the aid of ab initio molecular orbital calculations. The hydration structure of the protonated form of GB is explored for the first time.

Unclassified subtype of Guillain-Barré syndrome is associated with quick recovery.

Electrophysiological classification of Guillain-Barré syndrome (GBS) is important for predicting its clinical course; however, few reports discuss GBS patients who do not conform to the acute inflammatory demyelinating polyneuropathy (AIDP) or acute motor axonal neuropathy (AMAN) classifications. Therefore, the present study assessed the features of unclassified types of GBS and compared them to those of AIDP and AMAN. We compared clinical symptoms, nerve conduction, and laboratory data among patients with AIDP, AMAN, and unclassified subtypes of GBS, according to criteria developed by Rajabally, Hadden, and Ho. According to the Rajabally criteria, the F wave frequency in the upper and lower extremities was higher in the unclassified subgroup than in the AIDP and AMAN subgroups; however, according to the Hadden and Ho criteria, the F wave frequency in only the lower extremities was higher in the unclassified subgroup than in the other subgroups. The unclassified subgroup showed better prognosis using the Rajabally criteria. Classification with the Rajabally criteria is useful for predicting prognosis and determining treatment in patients with GBS. Moreover, unclassified patients exhibit the quickest recovery.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.