Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Pathological observations of a long spinal cord lesion in a patient with multiple sclerosis.

We report an autopsy case of multiple sclerosis (MS) manifesting as a long spinal cord lesion. The patient was a Japanese woman. At the age of 59 years, she presented with a one-month history of progressive paraplegia, dysesthesia in the lower extremities, and urinary retention. Magnetic resonance imaging revealed a long, hyperintense lesion on T2-weighted images that extended from the inferior portion of the medulla oblongata to the cervical segments of the spinal cord and an isolated lesion at the T6 level. Cerebrospinal fluid (CSF) examination revealed the presence of oligoclonal bands and increased myelin basic protein levels (999 pg/mL). Serum antibody against aquaporin 4 (AQP4) was undetectable in this patient. She was diagnosed as having atypical MS and experienced symptom improvement following immunotherapy with corticosteroids and plasma exchange. She died of pneumonia and renal failure at the age of 62 years. Postmortem examination revealed a long demyelinating lesion that extended from the inferior portion of the medulla oblongata to the sacral segments of the spinal cord. The lesion was comprised of numerous demyelinating plaques with inflammatory cell infiltration. A long spinal cord lesion is usually indicative of neuromyelitis optica spectrum disorder (NMOSD), and there are limited reports of postmortem observations of long spinal cord lesions among patients with anti-AQP4 antibody-seronegative MS. Our findings suggest that the pathomechanisms of such long spinal cord lesion formation differ between anti-AQP4 antibody-seronegative MS and NMOSD.

Longitudinal Change of DAT SPECT in Parkinson's Disease and Multiple System Atrophy.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD.

Multifaceted structural magnetic resonance imaging findings in demented patients with pathologically confirmed TDP-43 proteinopathy.

This short report clarifies the heterogeneity of structural magnetic resonance imaging (MRI) findings in seven demented patients due to pathologically accumulated TAR DNA-binding protein-43 (TDP-43) protein using visual analyses including visual rating scales (i.e., global cortical atrophy and medial temporal atrophy scales). In addition to the well-known frontotemporal lobar atrophy, structural MRI has revealed multifaceted imaging findings including asymmetric atrophy of the frontoparietal lobe and cerebral peduncle, midbrain atrophy, and localized or diffuse white matter T2 hyperintensity. Understanding of these multifaceted neuroimaging findings is important for the precise antemortem diagnosis of TDP-43 proteinopathy.

An autopsied case of MM1-type sporadic Creutzfeldt-Jakob disease with pathology of Wernicke encephalopathy.

An 83-year-old Japanese man presented with gait disturbance followed by rapidly-progressive cognitive impairment. Magnetic resonance diffusion-weighted images showed extensive hyperintense regions in the cerebral cortex. Four weeks after symptom onset, myoclonus appeared, and the patient developed difficulty swallowing; intravenous peripheral continuous infusions without vitamin supplementation were administered during the last two months of the patient's life. The patient reached the akinetic mutism state and died 12 weeks after symptom onset due to sepsis. The brain weighed 940 g and showed general cerebral atrophy. Extensive spongiform change were observed in the cerebral cortex, striatum, thalamus, and cerebellar cortex, but gliosis was generally mild. Numerous newly-developed hemorrhage foci were observed in the mammillary body, the areas adjacent to the third and fourth ventricles, and the periaqueduct of the midbrain; however, proliferation of capillaries and endothelium and collections of macrophages were relatively inconspicuous. These findings suggested comorbidity with the acute stage of Wernicke encephalopathy (WE). Immunostaining showed extensive diffuse synaptic-type prion protein deposition in the gray matter. According to the neuropathological, genetic, and molecular findings, the present case was finally diagnosed as MM1-type sporadic Creutzfeldt-Jakob disease (CJD) with WE. We should remain alert to the diagnosis of WE when CJD is suspected, and it is necessary to consider the complications of both diseases. This report emphasizes the importance of pathological investigations for the diagnosis of CJD, WE, and the coexistence of both.

An autopsied case of MV2K + C-type sporadic Creutzfeldt-Jakob disease presenting with widespread cerebral cortical involvement and Kuru plaques.

MV2-type sporadic Creutzfeldt-Jakob disease (sCJD), which was previously called "Kuru-plaque variant", was gradually revealed to have a wide spectrum and has been classified into three pathological subtypes: MV2K, MV2C and MV2K + C. We herein describe the detailed clinical findings and neuropathologic observations from an autopsied MV2K + C-type Japanese sCJD case with widespread cerebral cortical pathology and Kuru plaques. In the early stages of the disease, the patient exhibited gait disturbance with ataxia and dysarthria as well as gradual appearance of cognitive dysfunction. Diffusion-weighted images (DWI) on MRI revealed extensive cerebral cortical hyperintensity. Pathologic investigation revealed extensive spongiform change in the cerebral cortex, particularly in the deeper layers. Vacuole size varied, and some were confluent. Prion protein (PrP) immunostaining revealed extensive PrP deposition in the cerebral cortex, basal ganglia, thalamus, cerebellum, brainstem and spinal cord. In the cerebral cortex, synaptic-type, Kuru plaque-like, and coarse plaque-type PrP depositions were mainly observed, along with some perivacuolar-type PrP depositions. Kuru plaques and coarse plaque-type PrP depositions also were observed in the cerebellar cortex. PrP gene analysis revealed no mutations, and polymorphic codon 129 exhibited Met/Val heterozygosity. Western blot analysis revealed a mixture of intermediate-type PrPSc and type 2 PrPSc . Based on previous reports regarding MV2-type sCJD and the clinicopathologic findings of the present case, we speculated that it may be possible to clinically distinguish each MV2 subtype. Clinical presentation of the MV2K + C subtype includes predominant cerebral cortical involvement signs with ataxia and DWI hyperintensity of the cerebral cortex on MRI.

The prevalence of dementia in subacute myelo-optico-neuropathy (SMON) patients who underwent medical checkups.

AIM: Subacute myelo-optico-neuropathy (SMON) is a known adverse effect of clioquinol use; however, clioquinol dissolves beta-amyloid aggregation in Alzheimer's disease (AD). Therefore, we investigated the prevalence of dementia in SMON patients and whether past clioquinol use affected the current incidence of AD. METHODS: We included 647 SMON patients (195 men, 452 women; mean age 77.9 years) who had undergone medical checkups including the mini-mental state examination (MMSE) in 2012. Of them, 105 patients scored ≤23 on the MMSE assessment. The presence/absence of dementia and disease backgrounds were obtained by a questionnaire. Then, using the medical checkup database, the correlation between the degree of severity when signs of SMON were at their worst and the concurrent presence or absence of AD at present was analyzed. RESULTS: In patients ≥65 years of age, the estimated prevalence of dementia was approximately 10.9% (95% confidence interval: 7.9%-13.8%). The concurrent presence of AD at present was not correlated with the past degree of SMON severity when the SMON signs were at their worst. CONCLUSIONS: The 10.9% prevalence of dementia in SMON patients was lower than a previously reported 15% prevalence found in the general population. According to these results, we cannot draw a definitive conclusion regarding the preventive effect of clioquinol on AD. Additionally, the lack of association between the onset of AD and past severity of SMON precludes definitive conclusions on the relationship between concurrent presence of AD and past clioquinol use.

Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease.

INTRODUCTION: Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II, and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits; however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal models. METHODS: Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A) or 96 weeks (Group B). RESULTS: In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10 group (n = 14; mean ± SD [-4.2 ± 8.2]), indicating improvement in symptoms. There was a statistically significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 ± 8.9). In Group B, UPDRS increased in the ubiquinol-10 group (n = 14; 3.9 ± 8.0), as well as in the placebo group (n = 8; 5.1 ± 10.3). CONCLUSIONS: This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated.

An autopsied case of adult-onset bulbospinalform Alexander disease with a novel S393R mutation in the GFAP gene.

A 50-year-old Japanese man with no apparent family history noticed diplopia. He gradually showed gait disturbance and dysuria. Abducens disorder of eye movement with nystagmus, tongue atrophy with fasciculation, spastic tetraparesis, and sensory disturbance were also observed. MRI showed severe atrophy of the medulla oblongata to the cervical cord ("tadpole appearance"). Tracheotomy and gastrostomy were performed 7 years after onset due to the development of bulbar palsy. Death occurred following respiratory failure after 11 years total disease duration. The brain weighed 1,380 g. The cerebrum, cerebellum, midbrain, and upper pons were preserved from atrophy, but the medulla oblongata to the cervical cord showed severe atrophy. A few Rosenthal fibers were observed in the cerebral white matter, basal ganglia, and cerebellum, whereas numerous Rosenthal fibers were observed in the medulla oblongata to the cervical cord. Myelin loss with relatively preserved axons was extensively observed from the middle of the pons to the spinal cord. The clinicopathological diagnosis was adult-onset bulbospinal-form Alexander disease. Glial fibrillary acidic protein (GFAP) gene analysis revealed a novel mutation of S393R. Expression patterns of S393R mutant GFAP using adrenal carcinoma-derived cells (SW13 cells) showed a decreased number of filamentous structures and abnormal aggregates.

[Case of rapidly progressive syringomyelia due to a spinal hemangioblastoma].

A 35-year-old man came to the hospital showing signs of worsening dysesthesia on his right hand. The dysesthesia started on his right hand and then spread to his forearm in two months. It also appeared on his left hand transiently. Initial MR imaging revealed a high signal intensity lesion at Th1-Th10 with an irregular margin (presyrinx state) below C3 on T2WI. The legion extended up to the medulla oblongata rapidly. Corticosteroid therapy lead to a slight improvement in dysesthesia symptoms but did not last. Immunosuppressant was also ineffective. Further examination using Gd enhanced MR imaging in a neurosurgery clinic in a university hospital revealed a spinal tumor at the Th10 level. A tumor resection was performed and dysesthesia improved. Pathological analysis showed hemangioblastoma. Presyrinx and syrinx above Th1 disappeared after the operation. It is necessary to search the whole spine carefully for the possibility of a tumor in the case of steroid resistant progressive spinal lesions with an unknown origin. And we stress the importance of timely surgical intervention regardless of idiopathic or secondary syringomyelia. We would like to report this clinical course presenting MR imaging and discuss the mechanism of forming syringomyelia based on the hypothesis of the alteration of CSF flow.

[Clinical features and MRI findings in spinocerebellar ataxia type 31 (SCA31) comparing with spinocerebellar ataxia type 6 (SCA6)].

Since the discovery of spinocerebellar ataxia type 31 (SCA31) gene, we identified 6 patients whose SCA type had been unkown for a long period of time as having SCA31 in our hospital and realized that SCA31 is not a rare type of autosomal dominant spinocerebellar ataxia in this region. We examined and compared the clinical details of these six SCA31 patients and the same number of SCA6 patients, finding that some SCA31 patients had hearing loss in common while there are more wide range and complicated signs of extra cerebellum in SCA6 such as pyramidal signs, extrapyramidal signs, dizzy sensations or psychotic, mental problems. There is a significant difference in the number of extracerebellar symptoms between SCA31 and SCA6. There are differences also in MRI findings. Cerebellar atrophy starts from the upper vermis in SCA31, as well as some SCA types, whereas the 4th ventricule becomes enlarged in SCA6 even in the early stage of disease. We suggest that these differences in clinical and MRI findings can be clues for accurate diagnosis before gene analysis.

[At-home music therapy intervention using video phone (Skype) for elderly people with dementia].

There are various nonpharmacological therapies available for elderly people with dementia, and these can improve quality of life and the behavioral and psychological symptoms of dementia (BPSD) that appear throughout the progression of the disease. Since a substantial number of effects have been reported for music therapy, we focused on this nonpharmacological intervention. Generally, musical therapy is provided collectively in facilities. However, the music used in this context may not consider the preferences and music abilities of each person. Therefore, in this study we created made-to-order music CDs that accounted for each participant's musical preferences and abilities. Utilizing the CDs, we conducted an intervention study of music therapy using a video phone (Skype) that elderly people with dementia can use at home. An advantage of conducting music therapy for individuals with dementia using a video phone is that those who have difficulty going to the hospital or participating in dementia-related therapy groups can participate in therapy in a familiar place. The results of this intervention showed that participants demonstrated signs of improvement as measured by the smile degree(Smile scan)and Behavior Pathology in Alzheimer's Disease (BEHAVE-AD) scale.

An autopsy case of MM2-cortical + thalamic-type sporadic Creutzfeldt-Jakob disease.

A 59-year-old Japanese man presented with depressed mood, insomnia, abnormal behavior and dementia. Visual and gait disturbance with ataxia also developed. Diffusion-weighted MRI showed widespread regions of hyperintensity in the bilateral cerebral cortex. The patient died at 62 after a progressive clinical course of 32 months. Myoclonus, periodic sharp-wave complexes on EEG, and akinetic mutism state were not observed. Neuropathologic examination showed widespread cerebral neocortical involvement with both large confluent vacuole-type, alongside fine vacuole-type spongiform changes. Mild spongiform degeneration was observed in the striatum and lateral thalamus. Severe neuron loss with hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus was present. Cerebral white matter showed diffuse myelin pallor indicating panencephalopathic-type pathology. In the cerebellar cortex, severe Purkinje neuron loss was observed, but no spongiform degeneration in the molecular layer or neuron loss in the granular cell layer. PrP immunostaining showed widespread perivacuolar-type PrP, irregular plaque-like PrP, and synaptic-type PrP depositions in the cerebral neocortex. Mild PrP deposition was observed in the striatum, lateral thalamus and brainstem, whereas PrP deposition was not apparent in the medial thalamus and inferior olivary nucleus. PrP gene analysis showed no mutations, and methionine homozygosity was observed at codon 129. Western blot analysis of protease-resistant PrP showed type 2 PrP pattern. MRI and cerebral neocortical pathology suggested MM2-cortical-type sporadic Creutzfeldt-Jakob disease (sCJD), whereas the clinical course and pathology of the medial thalamus and inferior olivary nucleus suggested MM2-thalamic-type sCJD. We believe this was a combination of MM2-cortical-type and MM2-thalamic-type sCJD, which explains the broad spectrum of MM2-type sCJD findings and symptoms.

[A patient with myelitis of varicella-zoster without skin lesions--diagnostic value of virus antibody index in CSF].

A previously healthy 55-year-old woman developed abnormal sensation on the right occipital region. It expanded for the following three weeks. On admission, examination revealed abnormal and decreased sensation in touch and pinprick at right C2 to C6 dermatome without skin lesion. There was no muscle weakness. Deep tendon reflexes were more active in the right than in the left. MRI demonstrated a lesion of isointensity on T1-weighted, hyperintensity on T2-weighted, which was enhanced with contrast material on gadolinium-enhanced T1-weighted image at the upper cervical spinal cord corresponding to C2. Laboratory studies showed no immunosuppression and autoantibodies. The antibody index to varicella-zoster virus (VZV) was elevated in the cerebrospinal fluid (CSF). This finding prompted us to a diagnosis of myelitis of zoster sine herpete. VZV is thought to be a causative agent in cases of CNS infections of unknown etiology such as myelitis, even in the absence of skin manifestations. Amplification of VZV DNA by PCR in the CSF and the detection of an intrathecal production of anti-VZV antibodies have important diagnostic value, although their presence depends on the timing of the CSF sampling. The percentage of PCR-positive cases drops after seven or ten days, whereas that of specific antibodies-positive cases elevates. Because VZV myelitis are usually protracted, PCR does not always provide an exquisite sensitivity. Thus, the evaluation of antibody index provides the evidence of intrathecal production of anti-VZV antibodies. That is expressed as CSF antibody titer/serum antibody titer/CSF IgG/serum IgG. This quotient superior to 1.5 or 2.0 suggests CNS synthesis. As the sample of our patient was taken relatively late, this value was diagnostic. We would like to emphasize the importance of making precise diagnosis and adequate initial treatment in patients with myelitis of unknown etiology even if there is no skin lesions.

[Prognosis of patients with progressive supranuclear palsy].

Survival and prognosis were investigated in 45 patients with progressive supranuclear palsy (including 10 autopsy cases) from April, 1991 to March, 2003 in Higashi Nagoya National Hospital. The subjects were 28 males, and 17 females. Mean age at onset was 64.9 years old (45-79 years old), and median survival time was 6 years. Age at onset, sex and clinical group due to NINDS-SPSP criteria ("probable" vs "possible") were not related to survival time. Among the symptoms and signs at onset, only dysphagia was related to prognosis. Dysphagia within the first year from onset reduced survival time (p < 0.0001).

Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.