[Show abstract][Hide abstract] ABSTRACT: Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.
[Show abstract][Hide abstract] ABSTRACT: To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS).
[Show abstract][Hide abstract] ABSTRACT: Polyglutamine diseases are a group of inherited neurodegenerative disorders that are caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in the protein-coding region of the respective disease genes. To date, nine polyglutamine diseases are known, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and six forms of spinocerebellar ataxia. These diseases share a salient molecular pathophysiology including the aggregation of the mutant protein followed by the disruption of cellular functions such as transcriptional regulation and axonal transport. The intraneuronal accumulation of mutant protein and resulting cellular dysfunction are the essential targets for the development of disease-modifying therapies, some of which have shown beneficial effects in animal models. In this review, the current status of and perspectives on therapy development for polyglutamine diseases will be discussed.
Expert Review of Neurotherapeutics 09/2014; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. Mutant AR has been postulated to alter the expression of genes important for mitochondrial function and induce mitochondrial dysfunction. Here, we show that the expression levels of peroxisome proliferator-activated receptor-γ (PPARγ), a key regulator of mitochondrial biogenesis, were decreased in mouse and cellular models of SBMA. Treatment with pioglitazone (PG), an activator of PPARγ, improved the viability of the cellular model of SBMA. The oral administration of PG also improved the behavioral and histopathological phenotypes of the transgenic mice. Furthermore, immunohistochemical and biochemical analyses demonstrated that the administration of PG suppressed oxidative stress, nuclear factor-κB (NFκB) signal activation and inflammation both in the spinal cords and skeletal muscles of the SBMA mice. These findings suggest that PG is a promising candidate for the treatment of SBMA.
Human Molecular Genetics 08/2014; · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ménière's disease (MD) is characterized by episodic vertigo, fluctuating hearing loss and tinnitus. Vestibular migraine (VM) is a relatively new disorder that is characterized by episodic vertigo or dizziness, coexisting migraine and absence of hearing loss. It is occasionally difficult to distinguish between VM and vestibular MD with headache. Because endolymphatic hydrops (EH) is a characteristic sign of MD, we attempted to evaluate endolymphatic space size in both diseases. Endolymphatic space size in the vestibule and the cochlea was evaluated in seven patients with VM and in seven age- and sex-matched patients with vestibular MD. For visualization of the endolymphatic space, 3T magnetic resonance imaging was taken 4 h after intravenous injection of gadolinium contrast agents using three-dimensional fluid-attenuated inversion recovery and HYbriD of reversed image of positive endolymph signal and native image of positive perilymph signal techniques. In the vestibule of VM patients, EH was not observed, with the exception of two patients with unilateral or bilateral EH. In contrast, in the vestibule of patients with vestibular MD, all patients had significant EH, bilaterally or unilaterally. These results indicate that endolymphatic space size is significantly different between patients with VM and vestibular MD.
Journal of Neurology 08/2014; · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases.
We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included.
Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles.
Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology.
PMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological profile. The remaining patterns have LMN degeneration with TDP-43 pathology without UMN degeneration, or a combination of UMN and LMN degeneration with FUS-positive basophilic inclusion body disease.
BMJ Open 05/2014; 4(5):e005213. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Olfactory dysfunction is considered to precede motor symptoms and early markers of Parkinson’s disease (PD), while the relative time at which cardiovascular dysautonomia appears in PD is not well understood. To assess the appearance of cardiovascular dysaunomomia in PD, we evaluated its relation to olfactory dysfunction in early-stage PD patients.
Twenty-three non-demented PD patients within 2 years from the onset of motor symptoms were enrolled. We evaluated olfactory dysfunction by the odor stick identification test for Japanese (OSIT-J) and analyzed its relationship to the results of other cardiovascular autonomic tests and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy.
There was a correlation between olfactory scores and increased blood pressure in both the norepinephrine (r=0.75, p<0.0001, n=21) and dobutamine (r=0.57, p=0.0087, n=20) infusion tests and cardiac MIBG uptake (r=0.42, p=0.049, n=23). The fall in orthostatic blood pressure during the head-up tilt test was not correlated with the olfactory scores, but the Valsalva maneuver revealed that OSIT-J scores correlated with the pressure recovery time from phase III to the return of blood pressure to baseline (r=0.54, p=0.037, n=15) and with the magnitude of blood pressure overshoot during phase IV (r = 0.67, p = 0.0016, n=20).
Our results demonstrate that extensive components of the cardiovascular sympathetic system as well as the olfactory system are correlatively impaired in the early stage of PD, suggesting that degeneration of broad aspects of the cardiovascular sympathetic system occurs concurrently with olfactory system degeneration during the premotor phase of PD.
Parkinsonism & Related Disorders 05/2014; · 4.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to clarify myocardial involvement and its clinical implications in subjects with spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease affecting both neuronal and nonneuronal tissues.
Two independent cardiologists evaluated ECGs from a total of 144 consecutive subjects with SBMA. We performed immunohistochemical, immunoblot, and quantitative real-time PCR analyses of autopsied myocardium.
Abnormal ECGs were detected in 70 (48.6%) of 144 subjects. The most frequent findings were ST-segment abnormalities in V1-3 (19.4%), followed by ST-segment abnormalities in V5-6 (18.1%). We detected Brugada-type ECGs in 17 of 28 subjects with ST-segment abnormalities in V1-3. Of those, one subject presented with syncope that required an implantable cardioverter defibrillator and led to eventual sudden death, and another subject also died suddenly. No subjects with Brugada-type ECGs had mutations in SCN5A, CACNA1C, or CACNB2 genes. In autopsied cases, we detected nuclear accumulation of the mutant androgen receptor protein and decreased expression levels of SCN5A in the myocardium.
Subjects with SBMA often show Brugada-type ECG. The accumulation of the pathogenic androgen receptor may have a role in the myocardial involvement in SBMA.
[Show abstract][Hide abstract] ABSTRACT: The accumulation of abnormal proteins is a common characteristic of neurodegenerative diseases. This accumulation reflects a severe disturbance of cellular homeostasis in pathogenic protein clearance. Here, we demonstrated that the activation of the two major proteolytic machineries, the molecular chaperone-ubiquitin proteasome system (UPS) and the autophagy system, were simultaneously enhanced by paeoniflorin, a major component of Paeonia plants, and exerted therapeutic effects in models of spinal and bulbar muscular atrophy (SBMA). Paeoniflorin significantly increased the expression of nuclear factor-YA (NF-YA), which strongly upregulated the molecules involved in the proteolytic machinery (molecular chaperones, carboxyl terminus of Hsc70-interacting protein (CHIP) and transcription factor EB (TFEB)), which thus mitigated the behavioral and pathological impairments in an SBMA mouse model through the upregulation of pathogenic androgen receptor protein clearance in motor neurons and muscles. These findings demonstrated that paeoniflorin is able to enhance both the UPS and autophagy systems by upregulating the expression of NF-YA, which promotes therapeutic effects in an SBMA model.
Human Molecular Genetics 02/2014; · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac sympathetic denervation is associated with orthostatic hypotension (OH) in Parkinson's disease (PD); however, the physiological role of cardiac sympathetic nerves has yet to be elucidated. To clarify the role of the heart in orthostatic stress, we evaluated whether cardiac sympathetic nerves can alter cardiac activity and systolic blood pressure (BP) in association with elevations or depressions of total peripheral resistance during the head-up tilt test.
Ninety-five PD patients and 17 normal controls were enrolled. Using impedance cardiography, we measured total peripheral resistance, stroke volume, heart rate, and systolic BP during the head-up tilt test. Cardiac denervation was defined as a heart-to-mediastinum ratio <1.7 for cardiac (123)I-metaiodobenzylguanidine uptake on delayed images.
At 60° tilt, total peripheral resistance decreased from the initial value in 49 PD patients. Among these, 36 patients exhibited cardiac denervation with severe reductions in systolic BP but little change in stroke volume; among these patients 22 had OH. The remaining 13 patients without cardiac denervation exhibited significant increases in stroke volume and well-preserved systolic BP with no OH. On the other hand, 46 patients had elevations in total peripheral resistance and reduced stroke volume, but little change in systolic BP, regardless of the presence or absence of cardiac denervation. Only one of these patients experienced OH.
Under orthostatic stress, cardiac sympathetic denervation with failure to increase total peripheral resistance leads to large reductions in systolic BP. However, patients without cardiac denervation exhibited a positive inotropic response against vasodilatation, which may prevent OH.
Parkinsonism & Related Disorders 01/2014; · 4.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Development and growth of hematopoietic tissue outside of the bone marrow is termed extramedullary hematopoiesis (EMH). It occurs in patients with hematological diseases such as myelofibrosis and thalassemia. Liver and spleen are the usual sites of EMH. However, spinal cord compression caused by EMH is a rare complication. A 65-year-old man with myelofibrosis was admitted to our hospital with progressive paraparesis. Thoracic spine MRI revealed epidural masses causing cord compression. Histological examination of the epidural mass showed evidence of EMH consisting of megakaryocytic and erythroid hyperplasia. After surgical decompression and radiotherapy, lower limb weakness and sensory disturbance were significantly improved. MRI showed disappearance of the spinal cord compression. With this therapy, he had no recurrence until he died of myelofibrosis. Spinal EMH should be considered as a differential diagnosis in patients with hematological diseases presenting with paraparesis. Surgical decompression and radiotherapy are effective approaches for the treatment of paraparesis due to EMH.
[Show abstract][Hide abstract] ABSTRACT: Recent reports suggest that rhinorrhea, defined as the presence of a runny nose unrelated to respiratory infections, allergies, or sinus problems, occurs more frequently among patients with Parkinson’s disease (PD) than among healthy controls. We conducted a questionnaire survey in a multicenter study throughout Japan and compared the frequency of rhinorrhea between 231 PD and 187 normal control (NC) subjects. After excluding patients with rhinitis or paranasal sinusitis, a total of 159 PD and 59 NC subjects were included in our analysis. Rhinorrhea occurred more frequently in PD patients than NC subjects (33.3% vs. 11.9%; P = 0.01). Among PD patients, rhinorrhea was more common in men than women (P = 0.005). Rhinorrhea was not correlated with disease duration, modified Hoehn and Yahr score, disease type (akinesia rigidity vs. tremor dominant), or cardiac sympathetic function (evaluated by 123I-metaiodobenzylguanidine uptake). To our knowledge, this is the first multicenter study on the frequency of PD-related rhinorrhea in Asian countries.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge. OBJECTIVE To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. DESIGN AND SETTING A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). MAIN OUTCOMES AND MEASURES Neuronal TDP-43 pathological changes and neuronal loss. RESULTS Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. CONCLUSIONS AND RELEVANCE The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to explore the reliability and validity of tongue pressure measurement as a quantitative evaluation of swallowing function in patients with spinal and bulbar muscular atrophy (SBMA).
This study enrolled 47 genetically confirmed patients with SBMA and 38 age- and sex-matched healthy controls. In both groups we measured tongue pressure using an intraoral pressure probe and assessed questionnaires that evaluated swallowing functions. We then analyzed the relationship between tongue pressure, functional scales, and the muscle weakness of other regions.
Levels of tongue pressure were decreased in patients with SBMA within 3 years from the onset of the disease compared to healthy controls (SBMA 15.3 ± 6.4 kPa; healthy controls 37.3 ± 9.6 kPa; p < 0.001). Test-retest analysis showed a high reliability in patients with SBMA (intraclass correlation coefficient = 0.986). Tongue pressure showed a strong correlation with bulbar-related functional scales. Decrease of tongue pressure was detected in patients who reported no subjective dysphagia, and repetition of swallowing compensated for tongue weakness in such subjects. In patients with SBMA, tongue pressure more strongly correlates with the strength of pharyngeal, neck, and upper limb musculatures than with that of the lower limbs.
Tongue pressure measurement is reliable and reflects swallowing function in patients with SBMA. The muscle strength of the tongue appears to decrease in SBMA before the awareness of subjective dysphagia, suggesting that tongue pressure measurement is a novel biomarker of SBMA and is applicable to early-stage detection.
[Show abstract][Hide abstract] ABSTRACT: Laryngospasm is a sudden onset of transient respiratory difficulty that is perceived as life-threatening by patients with spinal and bulbar muscular atrophy (SBMA). The purpose of the study was to analyze the voice characteristics of SBMA patients with laryngospasm using acoustic voice analysis.
Acoustic measurements were obtained from 39 consecutive Japanese patients with genetically confirmed SBMA. A comparison was made between the acoustic voice profiles of 16 patients with laryngospasm and 23 patients without laryngospasm within 6months before the evaluation. Computerized acoustic analysis was performed for a prolonged vowel (/a:/) using the Multi-Dimensional Voice Program (MDVP).
SBMA patients with laryngospasm had smaller fluctuations of vocal fold vibration and the turbulent noise component, indicating stronger vocal fold closure than in those without laryngospasm. Receiver operating characteristic curve analysis showed that the noise-to-harmonic ratio, which globally measures the noise components of voice, is the most useful acoustic parameter to distinguish laryngospasm (area under the curve=0.767, p=0.007).
The smaller noise component in patients with laryngospasm suggests that the vocal folds of these patients are more adducted during phonation than those of the patients without laryngospasm, even in the absence of laryngospasm. Quantitative laryngeal analysis using the MDVP helps to detect laryngeal dysfunction and provides physiological insight into the pathophysiology of laryngospasm in SBMA.
Journal of the neurological sciences 12/2013; · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe a 54-year-old man with mononeuritis multiplex and reactive lymphoid hyperplasia with increased immunoglobulin G4 (IgG4)-positive cells. Asymmetrical numbness and weakness had advanced stepwise for 6 years. Serum immunoglobulin G, IgG4, and immunoglobulin E levels were elevated, whereas M protein was not detected. Chest and abdominal computed tomography showed generalized lymphadenopathy. Inguinal lymph node biopsy revealed expansion of the interfollicular area with infiltration of IgG4-positive cells, of which the absolute number was greater than 100 per high-power field, and the percentage of IgG4+/immunoglobulin G+ plasma cells was 33%. Sural nerve biopsy disclosed axonal neuropathy with tumefactive lymphoid infiltrate in epineurium, but IgG4-positve plasma cells and fibrosis were not detected. Symptoms and laboratory data were improved with oral glucocorticoid therapy at a dose of 0.6 mg/kg per day. Although the causal mechanisms of neuropathy should be determined in future studies, peripheral nerve involvement may occur in patients with reactive lymphoid hyperplasia with increased IgG4-positive cells.
[Show abstract][Hide abstract] ABSTRACT: Folate deficiency is known to be associated with subacute combined degeneration of the spinal cord; however, reports of long-standing cases are rare. Although neurological deficits due to folate deficiency have been reported to respond to folic acid supplementation, the functional outcomes have not been fully elucidated.
The aim of the study was to evaluate the clinical features and response to folate supplementation in a patient with folate deficiency manifested over 10years as a slowly progressive myelopathy.
We performed comprehensive clinical screening, electrophysiological testing, and posturography before and after folate supplementation.
A 49-year-old man had a slowly progressive gait disturbance for 10years. He had not eaten fresh green vegetables for more than 10years. Neurological examination revealed spastic paraplegia and absence of any vibration sense in the lower limbs accompanied by a positive Romberg's sign. Serum folate level was low, and plasma homocysteine level was elevated. Levels of blood thiamine and serum cobalamin were normal. We diagnosed the patient with myelopathy due to folate deficiency. Folic acid supplementation led to improvement of his symptoms; posturography and walking speed tests showed partial improvement, while the somatosensory-evoked potentials and central motor conduction time remained unchanged.
Folate deficiency should be considered as a differential diagnosis of chronic slowly progressive myelopathy. The present case suggests the importance of early diagnosis and treatment before the adverse neurological manifestations of folate deficiency become irreversible.
Journal of the neurological sciences 10/2013; · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
We evaluated 100 cases, consisting of 20 with PSP, 24 with Parkinson's 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 Parkinson's Disease Rating Scale Part III and the Scale for the Assessment and Rating Scale of Ataxia, and MRI using RESOLVE was conducted.
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.
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.
Parkinsonism & Related Disorders 10/2013; · 4.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To elucidate the effect of liver transplantation (LT) on brain dysfunctions in cirrhotic patients who had no clinical evidence of hepatic encephalopathy (HE), we performed a prospective study of voxel-based diffusion tensor imaging (DTI) and detailed cognitive examination.
We assessed 12 consecutive patients as transplant candidates by DTI, with neurological and cognitive examinations just before and at 6 months after LT.
After LT, cirrhotic patients showed significant improvement in visual reproduction, digit symbol, digit span, Stroop test, and Trail-making test scores, suggesting recovery of frontal-temporal function. As for voxel-based DTI, increased mean diffusivity (MD) and reduced fractional anisotropy (FA) values were found before LT in the frontal and temporal lobes of cirrhotic patients. After LT, the unusual FA and MD values observed in the frontal and temporal lobes preoperatively were significantly reduced.
End-stage cirrhotic patients without clinical evidence of HE showed increased MD and decreased FA values in both frontal and temporal lobes. These parameters improved after LT, in line with cognitive function. MD and FA values might be of value as a biomarker in end-stage cirrhotic patients for investigating brain tissue dysfunctions and evaluating the efficacy of LT.
Clinical neurology and neurosurgery 09/2013; · 1.30 Impact Factor