Kazumichi Yamada

Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism.

Dystonia is a neurological syndrome characterized by sustained muscle contractions that produce repetitive twisting movements or abnormal postures. X‐linked recessive dystonia parkinsonism (XDP; DYT3; Lubag) is an adult‐onset disorder that manifests severe and progressive dystonia with a high frequency of generalization. In search for the anatomical basis for dystonia, we performed postmortem analyses of the functional anatomy of the basal ganglia based on the striatal compartments (ie, the striosomes and the matrix compartment) in XDP. Here, we provide anatomopathological evidence that, in the XDP neostriatum, the matrix compartment is relatively spared in a unique fashion, whereas the striosomes are severely depleted. We also document that there is a differential loss of striatal neuron subclasses in XDP. In view of the three‐pathway basal ganglia model, we postulate that the disproportionate involvement of neostriatal compartments and their efferent projections may underlie the manifestation of dystonia in patients with XDP. This study is the first to our knowledge to show specific basal ganglia pathology that could explain the genesis of dystonia in human heredodegenerative movement disorders, suggesting that dystonia may result from an imbalance in the activity between the striosomal and matrix‐based pathways. Ann Neurol 2005

Immunocytochemical localization of the striatal enriched protein tyrosine phosphatase in the rat striatum: A light and electron microscopic study with a complementary DNA-generated polyclonal antibody

The present study concerns the immunocytochemical localization of the striatal enriched protein tyrosine phosphatase in the rat striatum. A novel molecular biology technique allowed us to produce a complementary DNA-generated polyclonal antibody raised against the non-catalytic domain of the striatal enriched protein tyrosine phosphatase, which selectively recognized the striatal enriched protein tyrosine phosphatase protein with 46,000 mol. wt on western blots. Immunocytochemical analysis with the specific antibody revealed strong striatal enriched protein tyrosine phosphatase immunoreactivity in the striatum. Light microscopy showed striatal striatal enriched protein tyrosine phosphatase-immunopositive neurons to be of medium size (mean diameter of 14.4 microns), and to comprise approximately 80% of the total neuronal population in the striatum. These cells had round, triangular or polygonal cell bodies with relatively little cytoplasm. Nerve fibers stained positively for striatal enriched protein tyrosine phosphatase were also present in the globus pallidus and the substantia nigra, and the nigral labeling on the ipsilateral side almost disappeared subsequent to cerebral hemitransection, suggesting these immunolabeled structures to be striatal projections. Double-immunofluorescence analysis demonstrated separate populations of striatal enriched protein tyrosine phosphatase-positive cells and neurons stained for parvalbumin. Also, ultrastructural study showed that the striatal enriched protein tyrosine phosphatase-positive neurons (n = 50) possessed no nuclear indentations or intranuclear inclusions. Thus, most striatal striatal enriched protein tyrosine phosphatase-positive neurons were thought to be of the medium-sized spinous type. At the light microscopic level, stained striatal neurons exhibited striatal enriched protein tyrosine phosphatase immunolabeling in their somata, dendrites and axonal processes, but not in their nuclei. Electron microscopic observation showed strong striatal enriched protein tyrosine phosphatase-immunoreactivity on the inner surface of the plasmalemma, on the outer surfaces of mitochondria and on microtubules, particularly of dendrites. A heavy deposit of immunoreaction product was also present on postsynaptic densities in labeled dendrites, while a light deposit was seen on the synaptic vesicles of nerve terminals. The characteristic distribution profile of striatal enriched protein tyrosine phosphatase suggested that the enzyme may play a role in a variety of functional properties of striatal neurons, especially in postsynaptic signaling processes and in regulation of microtubular functions. On the basis of the present findings, we propose the following conclusions: (i) a protein tyrosine phosphorylation system regulated by striatal enriched protein tyrosine phosphatase is involved in certain specialized cellular processes (e.g. signal transduction cascades) of medium-sized spinous neurons distinct from those of other neuronal subsets in the striatum; (ii) a striatal medium spiny neuron is characterized by its expression of striatal enriched protein tyrosine phosphatase and, therefore, the enzyme is useful for detection of the distinct subset of striatal cells or for tracing their axonal projection fibers in the basal ganglia.

Lack of Reelin causes malpositioning of nigral dopaminergic neurons: Evidence from comparison of normal and Relnrl mutant mice

The reeler gene (Relnrl, formerly rl) product Reelin controls neuronal migration and positioning and thereby plays a key role in brain development. Mutation of Reln leads to widespread disruption of laminar cortical regions and ectopia in some brainstem nuclei. In the embryonic striatum of normal mice, a substantial expression of reelin mRNA has been documented; however, the anomalous positioning of neurons in the basal ganglia of reeler mice remains to be studied. We provide first evidence for a potential role of Reelin in the developmental formation of the substantia nigra. In reeler mutant mice lacking Reelin, dopaminergic neurons destined for the substantia nigra fail to migrate laterally and become anomalously clustered just lateral to the ventral tegmental area. Their axons appear to project to striatal patches forming “dopamine islands.” Results from the normal mice show that, at the midembryonic stage, Reelin identified with CR‐50 is highly concentrated in the ventral mesencephalon, where nigral dopaminergic neurons are in progress to migrate laterally to their eventual position of the adult brain. A combination of CR‐50 labeling and anterograde axonal tracing provided evidence that embryonic striatal neurons may supply the ventral portion of the mesencephalon with Reelin through their axonal projections. We hypothesize that Reelin plays a role in the positioning of nigral dopaminergic neurons and that it can act as an environmental cue at a remote site far from its birthplace via a transaxonal delivery system. J. Comp. Neurol. 461:166–173, 2003.

Long term continuous bilateral pallidal stimulation produces stimulation independent relief of cervical dystonia.

Idiopathic cervical dystonia is the most common form of focal dystonia in adults.1,2 It is characterised by involuntary, sustained contractions of the cervical muscles and produces abnormal head movements or postures. Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) is now accepted in the treatment of a wide spectrum of dystonias including cervical dystonia (for a review, see Krauss3), the mechanisms underlying its beneficial effects on dystonia remain unclear. We report a patient in whom continuous long term (22 month) bilateral pallidal stimulation eventually produced stimulation independent relief of cervical dystonia. This 54 year old right handed man had a one year history of involuntary head rotation toward the left. He had no previous exposure to neuroleptics and no family history of dystonia. On admission in June 2000, he manifested severe cervical dystonia with neck pain characterised by left and posterior head turn and tilt (fig 1A). The right sternocleidomastoid muscle was contracted and hypertrophied. His cervical dystonia decreased in the supine position or when performing a sensory trick which consisted of putting his right hand on his chin or neck. On the Toronto western spasmodic torticollis rating scale (TWSTRS), his total severity score (TSS) was 25 (maximum = 35), and his total disability score (TDS) was 21 (maximum = 30). Figure 1  (A) Photograph taken before implantation of the deep brain stimulation (DBS) electrodes. Note severe cervical dystonia characterised by left and …

Combination of thalamic Vim stimulation and GPi pallidotomy synergistically abolishes Holmes’ tremor

The recent report of Kim et al ,1 who demonstrated that stereotactic surgical ablation of the thalamic nucleus ventrointermedius (Vim) markedly improved Holmes’ tremor in a patient with midbrain tumour, corroborated our earlier findings.2 In their patient, Vim thalamotomy alleviated tremor in both the distal and proximal segments of the upper extremity.1 However, controversy continues to surround the advisability of using this procedure for proximal tremors because the placement of larger lesions carries increased risks and the somatotopy of the proximal or truncal muscles remains obscure in the human Vim.3–5 Here we present a patient with a pontine haemorrhage in whom the combination of thalamic Vim deep brain stimulation (DBS) and globus pallidus internus (GPi) pallidotomy abolished Holmes’ tremor. This 53 year old right-handed man with a history of essential hypertension suddenly developed right hemiparesis and cerebellar ataxia in February 2000. He was admitted to a hospital where radiological examinations showed a left upper brainstem haemorrhage (fig 1A). His neurological state gradually improved. However, in October 2001 a coarse, slowly progressive tremor arose in his right upper extremity. It was severely disabling and he could not use his right arm. He was admitted to our hospital in December 2001. Figure 1  (A) Computed tomography (CT) scan showing a haematoma in the pontine tegmentum. (B, C) Axial views of T2-weighted magnetic resonance images at chronic stage (22 months after onset) demonstrating a haemosiderin ring around the lesion in the pontine tegmentum (B, arrow) and a high signal intensity area in the left …

Multiple cerebral arterial occlusions in a young patient with Sjögren's syndrome: case report.

We describe a case of a young patient with multiple occlusions of major cerebral arteries and Sjögrens syndrome. This 17-year-old female patient experienced repeated transient ischemic attacks of right hemiparesis, speech disturbance, and unconsciousness. Angiography revealed progressive occlusion of the bilateral carotid and vertebral arteries. Examinations, including a serological test, a rose bengal test, Ga scintigraphy, and a biopsy of the parotid gland, indicated Sjögrens syndrome. The patient was successfully managed with bypass surgery. Patients with Sjögrens syndrome may experience progressive occlusion of the major cerebral arteries resembling that of moyamoya disease.

Neuronal induction of 72-kDa heat shock protein following methamphetamine-induced hyperthermia in the mouse hippocampus

By means of an immunohistochemical technique, we examined the neuronal induction of 72-kDa heat shock protein (HSP72) in response to methamphetamine-induced hyperthermia in the mouse hippocampus. Strong HSP72 immunoreactivity (ir) was found in the neurons of hippocampus proper, particularly in the CA1/2 and medical CA3 subfields, at 10 h after drug injection. By 18 h, those neurons still revealed HSP72-ir, while neurons of the dentate gyrus also appeared positive for HSP72. At this stage, intense HSP72-ir was first detected in non-neuronal cells, i.e. glial and vascular endothelial cells. At 24 h, no apparent HSP72-ir was found in the hippocampal neurons, while only non-neuronal cells still revealed immunoreactivity for HSP72. In addition, no morphological evidence of cell degeneration or loss was noted in the CA1 sector or other hippocampal regions at 5 days after hyperthermic insult. In conclusion, (1) methamphetamine-induced hyperthermia per se is a stressful stimulant causing neuronal induction of HSP72 in the hippocampus neurons, particularly of CA1/2 and medial CA3 sectors, but does not prove fatal to the cells; (2) there is a cell type-specific difference in response to hyperthermic insult by inducing HSP72 and the timing of the induction response in the hippocampal formation; and (3) the animals that underwent drug-induced hyperthermia may be useful as an experimental model for the study of the protective mechanism of heat shock proteins against subsequent harmful stimuli.

Lateral Asymmetry and Spatial Difference of Iron Deposition in the Substantia Nigra of Patients with Parkinson Disease Measured with Quantitative Susceptibility Mapping

The authors evaluated 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls who underwent 3T MR imaging with a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility maps they measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both cerebral hemispheres. Susceptibility in the middle part, the posterior part, and the whole substantia nigra was significantly higher in the more and the less affected hemibrains of patients with Parkinson disease than in the healthy controls. Also, susceptibility was significantly higher in the posterior substantia nigra of the more affected hemibrain. BACKGROUND AND PURPOSE: Quantitative susceptibility mapping is useful for assessing iron deposition in the substantia nigra of patients with Parkinson disease. We aimed to determine whether quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference in iron deposits in the substantia nigra of patients with Parkinson disease. MATERIALS AND METHODS: Our study population comprised 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls. They underwent 3T MR imaging by using a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility mapping, we measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both hemibrains. To identify the more and less affected hemibrains in patients with Parkinson disease, we assessed the severity of movement symptoms for each hemibrain by using the Unified Parkinsons Disease Rating Scale. RESULTS: In the posterior substantia nigra of patients with Parkinson disease, the mean susceptibility value was significantly higher in the more than the less affected hemibrain substantia nigra (P < .05). This value was significantly higher in both the more and less affected hemibrains of patients with Parkinson disease than in controls (P < .05). Asymmetry of the mean susceptibility values was significantly greater for patients than controls (P < .05). Receiver operating characteristic analysis showed that quantitative susceptibility mapping of the posterior substantia nigra in the more affected hemibrain provided the highest power for discriminating patients with Parkinson disease from the controls. CONCLUSIONS: Quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease.

Effect of bilateral subthalamic nucleus stimulation on levodopa-unresponsive axial symptoms in Parkinson’s disease

SummaryBackground. The levodopa responsiveness of motor, particularly axial symptoms is a good predictor of the effectiveness of subthalamic nucleus (STN) stimulation in patients with Parkinson’s disease (PD). However, many Japanese PD patients are intolerant of higher doses of antiparkinsonian drugs and some aspects of their axial symptoms may remain unresponsive to treatment. We retrospectively investigated the effects of bilateral STN stimulation on the axial signs unresponsive to levodopa in Japanese patients with PD.Methods. We enrolled 29 consecutive patients into this study. Six independent axial symptoms, i.e. falling, freezing, gait, standing, posture, and postural instability, were scored on the Unified Parkinson’s Disease Rating Scale (UPDRS), before and 3 months after bilateral STN stimulation and differences were statistically analysed.Findings. Postoperatively, the mean levodopa dosage was decreased by 27%. The preoperative responsiveness to antiparkinsonian drugs with respect to freezing, gait, posture, and postural instability were positively correlated with postoperative off-medication improvement (p < 0.05). For each individual axial symptom, some patients showed an excellent response to STN stimulation, despite preoperative unresponsiveness to levodopa. These selected patients were not always treated with lower doses of antiparkinsonian drugs preoperatively, but they had milder preoperative scores on the UPDRS with respect to daily activities and overall axial function.Conclusions. The axial symptoms of PD unresponsive to levodopa were ameliorated by bilateral STN stimulation in patients manifesting a milder degree of preoperative axial signs. Our findings suggest that STN stimulation exerted a definite but limited effect on levodopa-unresponsive axial features, pointing to the need to identify different target structures that control axial functions via non-dopaminergic systems.

Impact of bilateral pallidal stimulation on DYT1-generalized dystonia in Japanese patients

Early‐onset generalized dystonia attributable to a DYT1 gene mutation is a hyperkinetic movement disorder that responds poorly to pharmacotherapy. In this video brief, we show that continuous bilateral stimulation of the globus pallidus internus produced sustained and marked improvements in the motor symptoms and functional disabilities of Japanese patients with DYT1‐generalized dystonia.