Early detection of cognitive impairment in Parkinson's disease with the use of the Wisconsin Card Sorting Test: correlations with Montreal Cognitive Assessment and smell identification test.

Cognitive function is often impaired in early Parkinson's disease (PD). The Wisconsin Card Sorting Test (WCST) is a neuropsychological test of "set-shifting" ability. To see whether WCST is useful for detecting early changes of cognitive function in PD, we examined the correlations of WCST with the Montreal Cognitive Assessment (MoCA) and the Odor Stick Identification Test (OSIT). Subjects were 48 PD patients (age 66 ± 10 years; Hoehn & Yahr stage 2.3 ± 0.8; mean duration 3.1 ± 2.5 years). WCST sub-scores for categories achieved (CA), perseverative errors of Nelson type (PEN), and difficulties of maintaining set (DMS) were evaluated. MoCA-J (Japanese version) and OSIT-J (Japanese version) were done in that order, followed by the WCST. In PD patients, CA was 2.2 ± 2.0, PEN was 7.0 ± 6.4, and DMS was 2.3 ± 2.0, and all were worse than those of age-matched normal subjects. MoCA-J scores significantly correlated with PEN. OSIT-J scores were also significantly correlated with CA and DMS. As MoCA-J and OSIT-J show high sensitivity and specificity for detecting mild cognitive impairment in PD, WCST may also be a useful supplementary diagnostic tool for early and mild cognitive impairment in PD patients.

Association of Smell Identification Deficit with Alzheimer's Disease Assessment Scale-Cognitive Subscale, Japanese Version Scores and Brain Atrophy in Patients with Dementia.

INTRODUCTION: Olfactory dysfunction is commonly associated with Alzheimer's disease (AD) and may be related to disorder of the central olfactory processing system. In this work, therefore, we examined the relationships between olfactory changes and the most affected cognitive domain or degree of brain atrophy in patients with AD and mild cognitive impairment (MCI). METHODS: The subjects were 55 AD patients and 27 MCI patients. Smell identification tests were performed using Odor Stick Identification Test for Japanese -(OSIT-J). The severity and nature of cognitive dysfunctions were evaluated using the AD Assessment Scale-cognitive subscale, Japanese version (ADAS-Jcog). MRI with voxel-based specific regional analysis system for AD software was used for evaluation of brain atrophy. RESULTS: -OSIT-J scores were significantly correlated with total -ADAS-Jcog scores, as well as with ADAS-Jcog subscale items of word recall task, orientation (memory domain) and ideational praxis. Smell identification deficit was proportional to the degree of atrophy of the medial temporal lobe. CONCLUSION: Smell identification deficit in AD/MCI is strongly associated with the memory domain of cognitive function and with atrophy of the medial temporal lobe.

Characteristic deterioration of ADAS-Jcog subscale scores and correlations with regional cerebral blood flow reductions in Alzheimer's disease.

The Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale (ADAS-Jcog) is composed of a number of subscale tasks. However, it is not clear which subscale tasks are most susceptible to impairment in Alzheimer's disease (AD) or what is the relationship between reduction in regional cerebral blood flow (rCBF) and decreased ADAS-Jcog scores. Subjects were 32 AD patients, aged 52-86 years. We examined the relationship between subscale tasks that showed marked score changes and brain regions that showed reduced rCBF over a 2-year period. rCBF was measured by single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD), and the SPECT imaging data were analyzed with the easy Z-score imaging system (eZIS) and voxel-based stereotactic extraction estimation (vbSEE) methods. Total score of ADAS-Jcog deteriorated from 19.5 ± 7.0 to 35.7 ± 15.2 after 2 years. Subscale scores were significantly worse in all fields, particularly in orientation, word recall, remembering test instructions, commands, constructional praxis, and ideational praxis, in that order. Significant correlations were found between (1) word recall and commands and rCBF in the left middle temporal lobe, (2) naming objects/fingers and rCBF in the left temporal (middle, inferior) lobe, and (3) constructional and ideational praxis and rCBF in the right parietal (superior, inferior) lobe, temporal (superior, middle) lobe, angular gyrus, and cingulate gyrus. We identified the brain regions associated with specifically impaired subscales of ADAS-Jcog during progressive deterioration of AD over 2 years.

Neurological safety of fingolimod: An updated review.

Fingolimod (FTY) is the first oral medication approved for treatment of relapsing-remitting multiple sclerosis (RRMS). Its effectiveness and safety were confirmed in several phase III clinical trials, but proper evaluation of safety in the real patient population requires long-term post-marketing monitoring. Since the approval of FTY for RRMS in Japan in 2011, it has been administered to approximately 5000 MS patients, and there have been side-effect reports from 1750 patients. Major events included infectious diseases, hepatobiliary disorders, nervous system disorders and cardiac disorders. In the present review, we focus especially on central nervous system adverse events. The topics covered are: (i) clinical utility of FTY; (ii) safety profile; (iii) post-marketing adverse events in Japan; (iv) white matter (tumefactive) lesions; (v) rebound after FTY withdrawal; (vi) relationship between FTY and progressive multifocal leukoencephalopathy; (vii) FTY and progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome; and (viii) neuromyelitis optica and leukoencephalopathy.

123I-Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy in patients showing scans without evidence of dopaminergic deficits (SWEDDs).

OBJECTIVE: Scans without evidence of dopaminergic deficits (SWEDDs) in dopamine transporter single-photon emission computed tomography (DAT-SPECT) are found in 3.6-19.6% of patients with clinically suspected Parkinson's disease (PD). We investigated whether combined use of 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy would be helpful to differentiate PD among SWEDDs patients. PATIENTS AND METHODS: 145 patients with clinically suspected PD underwent both DAT-SPECT and MIBG myocardial scintigraphy. Striatal binding ratio (SBR) of DAT-SPECT and heart-to-mediastinal (H/M) ratio and washout rate (WR) of MIBG myocardial scintigraphy were calculated. RESULTS: Among 18 SWEDDs patients (12.4%), 11 were finally diagnosed with PD based on follow-up for at least two years after the DAT-SPECT and MIGB myocardial scintigraphy scans. Among the latter group, 8 patients showed an H/M ratio of less than 2.2, and 9 showed WR above 30%. CONCLUSION: Our results indicate that the combination of low H/M ratio and high WR of MIBG myocardial scintigraphy of SWEDDs patients may be helpful for detection of PD patients.

Combined use of dopamine transporter imaging (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy for diagnosing Parkinson's disease.

BACKGROUND: To examine whether combined use of 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-MIBG myocardial scintigraphy (MIBG) is superior to either modality alone for diagnosing Parkinson's disease (PD). METHODS: Patients with probable PD (n=120) who underwent both DAT-SPECT and MIBG myocardial scintigraphy within short intervals were enrolled. Specific binding ratio (SBR) of DAT-SPECT images and heart-to-mediastinum (H/M) ratio of MIBG images were used as quantitative measures. We classified patients into 4 groups based on SBR value and H/M ratio, or into two groups based on the striatal asymmetry index (SAI) of DAT-SPECT, and examined the clinical features of each group. We also investigated the characteristics of SWEDDs (scans without evidence of dopaminergic deficits) patients. Finally, we calculated the sensitivity and specificity of each method and the combined method. RESULTS: SBR value was significantly correlated with both early and delayed H/M ratio values. Motor complications and hallucinations were observed at high frequency in the group with both lower SBR and H/M ratio, and hallucinations appeared in the group with larger SAI. SWEDDs were observed 8.3% of patients. The sensitivity and specificity of diagnosing PD were 91.7% and 15.0% by SBR of DAT-SPECT, 78.3% and 90.0% by H/M ratio of MIBG uptake, and 74.2% and 95.0% by the combined modalities, respectively. CONCLUSIONS: Combined use of DAT-SPECT and MIBG myocardial scintigraphy increases the specificity of PD diagnosis, and is helpful for understanding the clinical features or predicting complications.

MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias.

Fingolimod-induced leukoencephalopathy in a patient with neuromyelitis optica spectrum disorder.

Fingolimod (FTY720) is used for reducing the annualized relapse rate and slowing progression of neurological disability in relapsing-remitting forms of multiple sclerosis (MS). However, its safety is not confirmed in patients with neuromyelitis optica spectrum disorder (NMOSD), who characteristically have positive aquaporin-4 (AQP-4) antibody. A 54-year-old female with a relapsing-remitting course of optic neuritis and myelitis for six years, diagnosed initially as MS, had been treated with interferon beta-1b and oral corticosteroid. Magnetic resonance imaging (MRI) consistently revealed lesions on the optic nerve and spinal cord, but never on the brainstem or cerebral white matter during acute exacerbation. After treatment was switched to fingolimod from interferon beta-1b, multiple new lesions appeared at the brainstem and cerebral white matter. Following discontinuation of fingolimod, these lesions completely cleared, concomitantly with clinical improvement. During fingolimod treatment, she was recognized to be positive for AQP-4 antibody. Fingolimod may be contraindicated in patients with NMOSD.

Postural deformities in Parkinson's disease -Mutual relationships among neck flexion, fore-bent, knee-bent and lateral-bent angles and correlations with clinical predictors.

BACKGROUND: Various postural deformities appear during progression of Parkinson's disease (PD), but the underlying pathophysiology of these deformities is not well understood. The angle abnormalities seen in individual patients may not be due to distinct causes, but rather they may have occurred in an interrelated manner to maintain a balanced posture. METHODS: We measured the neck flexion (NF), fore-bent (FB), knee-bent (KB) and lateral-bent (LB) angles in 120 PD patients, and examined their mutual relationships, and correlations with clinical predictors such as sex, age, disease duration, Hoehn and Yahr (H&Y) stage, medication dose (levodopa equivalent dose, LED; total dose of dopamine agonists, DDA). The relationship between the side of the initial symptoms and the direction of LB angle was also investigated. RESULTS: Our main findings were: (1) Significant relationships between NF and KB, NF and LB, FB and KB, KB and LB were observed. (2) NF angle was larger in males than in females, but FB, KB and LB angles showed no significant difference between the sexes. (3) FB and KB angles became larger with advancing age. (4) NF and FB angles were associated with disease duration. (5) NF, FB, KB and LB angles all increased significantly with increase of H&Y stage. (6) FB angle was significantly associated with LED, but DDA did not show a significant relationship with any of the measured angles. (7) Direction of LB angle was not associated with the side of initial symptoms. CONCLUSIONS: Postural abnormalities are interrelated, possibly to maintain a balanced posture.

Early Motor Fluctuations in a Patient with Striatonigral Degeneration.

We report a 44-year-old female with striatonigral degeneration (SND) who showed wearing-off oscillations after 4 months of levodopa treatment. The patient presented with asymmetric left-side dominant rigidity, and levodopa was effective at first. However, she began to show wearing-off oscillations of motor symptoms, which gradually worsened thereafter. Fluid-attenuated inversion recovery sequence magnetic resonance imaging (MRI) showed linear lateral putamen hyperintensities, and positron emission tomography (PET) studies using 18F-fluorodopa (FD) and 11C-N-methylspiperon (NMSP) showed a marked decrease of radioactivity in the right putamen, especially in the posterior putamen. The results of MRI and 2 PET studies with FD and NMSP were well consistent with the diagnosis of SND.

I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3ß signaling pathway.

Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinson's disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 still remain to be elucidated. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSC) derived from fibroblasts of PD patients with I2020T LRRK2 in the Sagamihara family. We found that I2020T mutant LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of glycogen synthase kinase-3ß (GSK-3ß) and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons. These results suggest that I2020T LRRK2-iPSC could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics.

Familial motor neuron disease with prominent onion-bulb-like structures and axonal swelling restricted to the spinal ventral root: autopsy findings in two siblings.

We report autopsy cases of two siblings who developed muscular atrophy and dementia, clinically considered to be familial motor neuron disease (MND). They presented with motor neuron signs predominantly in the distal limbs without sensory impairment. At autopsy, severe neuronal loss in the anterior horn consistent with MND was found, but histopathological hallmarks like Bunina bodies and skein-like inclusions were absent. Surprisingly, numerous huge axonal swellings (about 30 microm in diameter) and onion-bulb-like structures were found in the spinal ventral roots. These changes were not observed in spinal dorsal roots or peripheral nerves. However, obvious segmental demyelination of the ventral root was not found. In addition, neurofibrillary tangles (NFTs) and neuritic plaques were present in the frontal cortex, temporal cortex and hippocampus, and to a lesser degree, in the amygdala, substantia nigra and thalamus. Our two cases are a hitherto unreported type of MND, which shows focal giant axonopathy and prominent formation of onion-bulb-like structures due to Schwann cell proliferation restricted to the spinal ventral roots.