Kazuhiro Hara

Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation

Objectives To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinsons disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). Methods We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. Results Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. Conclusions Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects.

Cortical and subcortical brain atrophy in Parkinson's disease with visual hallucination.

The aim of this study was to investigate the cortical and subcortical brain structures in Parkinsons disease (PD) with visual hallucination (VH), and to elucidate the association between the proposed hypothesis of VH in PD and regional brain volume changes.

MRI mean diffusivity detects widespread brain degeneration in multiple sclerosis.

We investigated the magnetic resonance imaging (MRI) findings of 32 multiple sclerosis (MS) patients using voxel-based morphometry (VBM) and voxel-based analysis of white matter fluid-attenuated inversion recovery image (FLAIR) high-intensity lesions and diffusion tensor imaging (DTI). Compared with 18 healthy controls, MS patients showed gray matter volume reduction in the thalamus, hypothalamus, caudate, limbic lobe, and frontal lobe. A marked volume reduction of white matter was evident along the ventriculus lateralis and corpus callosum. FLAIR high-intensity lesions were observed beside the ventriculus lateralis. DTI revealed reduced fractional anisotropy areas similar to those of the FLAIR high-intensity lesions. Changes in the volume of increased mean diffusivity (MD) were the most widespread and extended to normal-appearing white matter (p<0.001). Multiple regression analysis revealed that MD values were significantly correlated with both disease duration (r=0.381, p=0.032) and expanded disability status scale scores (EDSS) (r=0.393, p=0.026). This study demonstrated that combined voxel-based analysis for volumetry, FLAIR high-intensity lesions, and DTI could reveal widespread brain abnormalities in MS patients. Furthermore, DTI, especially MD, showed far more widespread brain degeneration than other MRI parameters, and was significantly correlated with both severity and disease duration.

An autopsy case of lymphomatosis cerebri showing pathological changes of intravascular large B-cell lymphoma in visceral organs

We describe the case of a 61‐year‐old man presenting with subacute encephalopathy. The clinical manifestations included progressive dementia and pyramidal and extrapyramidal tract signs. Brain CT scan and MRI showed diffuse bilateral white matter changes in the cerebral hemispheres, basal ganglia, thalamus and brainstem. No contrast‐enhanced lesion was observed. Peripheral blood studies, CSF analysis, and brain and muscle biopsies were nonspecific and failed to reveal diagnostic evidence of any specific disease. The patient was diagnosed with and treated for a cerebral demyelinating disorder. Post mortem examination showed diffuse infiltration of lymphoma cells without mass lesions in the extensive cerebral white and gray matter with minimal intravascular patterns, particularly in the perivascular and periventricular spaces. These findings were consistent with lymphomatosis cerebri (LC). In other visceral organs such as the lungs, liver, kidneys and adrenal glands, blood vessels were plugged by numerous neoplastic cells which were morphologically and immunohistochemically similar to those observed in the CNS, consistent with intravascular malignant lymphoma (IVL). To our knowledge, this is the first autopsy report showing the coexistence of LC and IVL. This case suggests a possible link between LC and IVL.

Voice features of Parkinson’s disease patients with subthalamic nucleus deep brain stimulation

Voice and speech disorders are one of the most important issues after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease patients; however, their characteristics remain unclear. We performed a comprehensive voice evaluation including the multi-dimensional voice program for acoustic analysis, the GRBAS scale for perceptual analysis, and the evaluation of the voice handicap index (VHI) for psychosocial analysis. In total, 68 patients who had undergone STN-DBS (37 assessed in the on- and off-stimulation conditions) and 40 who had been treated with medical therapy alone were evaluated. Further, we performed laryngoscopic examinations in 13 STN-DBS and 19 medical-therapy-alone patients. The STN-DBS group, especially females, showed widespread impairment of voice parameters and significantly poorer VHI scores than the medical-therapy-alone group. The degree of voiceless (DUV) and strained voice were the most impaired factors in the STN-DBS group; and DUV significantly improved after stopping stimulation. Furthermore strained voice, breathiness, and asthenia improved after stopping stimulation. Laryngoscopic examination showed that abnormal laryngeal muscle contraction and incomplete glottal closure were more prominent in the STN-DBS group than in the medical-therapy-alone group. We demonstrated that (1) more widespread voice impairment in females, (2) poorer voice-related QOL, (3) worse DUV and strained voice, and (4) abnormal laryngeal muscle contraction were the characteristic voice and laryngeal findings in the STN-DBS group compared with those in the medical-therapy-alone group.

Suppressor analysis of the mpt5/htr1/uth4/puf5 deletion in Saccharomyces cerevisiae

The MPT5/HTR1/UTH4/PUF5 gene encodes an RNA-binding Puf-family protein in Saccharomyces cerevisiae. The Δmpt5 cells exhibit pleiotropic phenotypes, including the G2/M arrest of the cell cycle and weakened cell wall at high temperatures. The Δmpt5 disruptant was also hydroxyurea (HU) sensitive. In this study we screened deletion suppressors to rescue the temperature sensitivity of Δmpt5, and identified dsf1 (YEL070W), dsf2 (YBR007C), sir2, sir3, sir4 and swe1. Multicopy suppressors identified were PKC1 and its upstream genes, but not the downstream MAPK cascade genes. The overexpression of PKC1, however, did not suppress the HU sensitivity of Δmpt5. In contrast, both the HU- and temperature-sensitivities of a-type Δmpt5 cells were suppressed by each sir deletion or a multicopy of MATα2, suggesting that a diploid-type expression is involved. We found that a diploid-specific IME4 gene encoding an RNA-modifying protein was responsible for the suppression of the temperature sensitivity, but not of the HU sensitivity. Furthermore, the suppression of the HU sensitivity depended on PUF4, another Puf-family gene, and overexpression of PUF4 suppressed only the HU sensitivity of Δmpt5. The protein level of Puf4 was not affected by the sir mutation. Thus, these Ime4 and Puf4 proteins play complementary roles to rescue the defects in Δmpt5 Δsir cells.

Potential of a new MRI for visualizing cerebellar involvement in progressive supranuclear palsy

OBJECTIVES We assessed the usefulness of differential diagnosis of parkinsonism by evaluating lesions of the decussation of the superior cerebellar peduncle (SCP) in patients with progressive supranuclear palsy (PSP) using a new MRI procedure known as readout segmentation of long variable echo-trains (RESOLVE). METHODS We evaluated 100 cases, consisting of 20 with PSP, 24 with Parkinsons disease (PD), 13 with multiple system atrophy with predominant parkinsonism (MSA-P), 18 with multiple system atrophy with predominant cerebellar ataxia (MSA-C), and 24 controls. All patients were scored on the Unified Parkinsons Disease Rating Scale Part III and the Scale for the Assessment and Rating Scale of Ataxia, and MRI using RESOLVE was conducted. RESULTS Images acquired by this MRI procedure clearly showed high intensity areas corresponding to the decussation of the SCP in all controls, PD, and MSA patients. In contrast, ten of the 20 PSP patients exhibited abnormal iso intensities of the decussation of the SCP, while the other 10 showed high intensity signals. Among the PSP patients, there were no differences in clinical features between those with and those without visualization of the decussation of the SCP. Iso intensity signals had a sensitivity of 50% and a specificity of 100% for differentiating PSP from PD, MSA, and controls. CONCLUSION This MRI procedure (RESOLVE) shows a potential for detecting the involvement of the decussation of the SCP in PSP, and can be used for discriminating PSP from PD and MSA-P.

HMGCR antibody-associated myopathy as a paraneoplastic manifestation of esophageal carcinoma

Immune-mediated myopathies with antibodies may be triggered by statin exposure, but some patients with these disorders are statin-naive; thus, there are probably other etiologies.1 Several malignant tumors, including esophageal squamous cell carcinoma (ESCC), overexpress 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein.2 To date, the relationship between anti-HMGCR antibody–associated myopathy (HMGCR-M) and malignancy remains unclear.3,4 Here, we report a case of HMGCR-M in a patient with ESCC and paraneoplastic syndrome.

Active brain changes after initiating fingolimod therapy in multiple sclerosis patients using individual voxel-based analyses for diffusion tensor imaging

ABSTRACT Voxel-based analysis (VBA) of diffusion tensor images (DTI) and voxel-based morphometry (VBM) in patients with multiple sclerosis (MS) can sensitively detect occult tissue damage that underlies pathological changes in the brain. In the present study, both at the start of fingolimod and post-four months clinical remission, we assessed four patients with MS who were evaluated with VBA of DTI, VBM, and fluid-attenuated inversion recovery (FLAIR). DTI images for all four patients showed widespread areas of increased mean diffusivity (MD) and decreased fractional anisotropy (FA) that were beyond the high-intensity signal areas across images. After four months of continuous fingolimod therapy, DTI abnormalities progressed; in particular, MD was significantly increased, while brain volume and high-intensity signals were unchanged. These findings suggest that VBA of DTI (e.g., MD) may help assess MS demyelination as neuroinflammatory conditions, even though clinical manifestations of MS appear to be in complete remission during fingolimod.

Severe hyposmia and aberrant functional connectivity in cognitively normal Parkinson’s disease

Objective Severe hyposmia is a risk factor of dementia in Parkinson’s disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear. Methods We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs). Results Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke’s Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH. Conclusion PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.