Tamaki Kimura

A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease.

Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinsons disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinsons disease.

Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter.

To determine the role of norepinephrine transporter in reuptake of L‐DOPA‐derived extracellular DA in the DA‐denervated Parkinsonian striatum, we examined extracellular DA levels in the striatum of 6‐hydroxyDA‐lesioned rats that received L‐DOPA (50 mg/kg with 12.5 mg/kg of benserazide) and L‐DOPA plus desipramine (25 mg/kg), a selective norepinephrine reuptake inhibitor, using in vivo microdialysis. The pretreatment with desipramine increased levels of extracellular DA derived from administrated L‐DOPA in the DA‐denervated striatum. This study provides evidence that L‐DOPA‐derived DA is taken up by the norepinephrine transporter, instead of the dopamine transporter, in the striatum with dopaminergic denervation. This result suggests that the norepinephrine transporter could be a promising target in the treatment for Parkinsons disease. Synapse 62:632–635, 2008.

Morphologic changes of dendritic spines of striatal neurons in the levodopa-induced dyskinesia model.

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa‐induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa‐induced dyskinesia model, we used 6‐hydroxydopamine‐lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa‐induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa‐induced dyskinesia.

Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis.

To elucidate the relevance of metabotropic glutamate receptors (mGluRs) to the selective vulnerability of motor neurons in the spinal cord in patients with amyotrophic lateral sclerosis (ALS), we investigated the distribution of mRNAs coding mGluR1-5 in the normal human spinal cord. The mRNAs for mGluR1, 4 and 5 were observed in the spinal gray matter, whereas mGluR2 mRNA was absent in the spinal cord and mGluR3 mRNA was displayed only on glial cells in the white matter. Signals for mGluR1 and mGluR5 were enriched in the dorsal horn, while mGluR4 mRNA was abundant in the ventral horn. Since agonists to group I mGluRs (mGluR 1 and 5) have been demonstrated to have neuroprotective effects on spinal motor neurons, less expression of mRNAs coding mGluR1 and mGluR5 in the ventral horn than in the dorsal horn may be implicated in the selective susceptibility of spinal motor neurons in ALS.

Giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

We describe an unusual case of myasthenia gravis. Our patient had been diagnosed as having myasthenia gravis with thymoma at the age of 64 years, and died of acute respiratory failure at the age of 80 years. Post mortem examination revealed CD8‐positive lymphocytic infiltration with numerous giant cells in the skeletal muscles and myocardium. Immunohistochemical and ultrastructural studies revealed that there were two types of giant cells: histiocytic and myocytic in origin. Furthermore, both types of giant cells were immunopositive for proteins implicated in the late endosome and lysosome‐protease systems, suggesting that endocytosis may be the key mechanism in the formation of giant cells. The present case, together with a few similar cases reported previously, may represent a particular subset of polymyositis, that is, giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

Hypertrophy of medial globus pallidus and substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA: Implication for L-DOPA-induced dyskinesia in Parkinson's disease

The medial globus pallidus plays a crucial role in generation of L‐DOPA‐induced dyskinesia in patients with Parkinsons disease. The 6‐hydroxydopamine‐lesioned rat exhibiting behavioral sensitization to L‐DOPA is one useful animal model for examining L‐DOPA‐induced dyskinesia. To determine neuropathological abnormality responsible  for  behavioral  sensitization,  the  medial  globus pallidus and the substantia nigra reticulata in 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA were examined. Intermittent L‐DOPA treatment induced hypertrophy of the lesioned‐side of medial globus pallidus and substantia nigra reticulata of 6‐hydroxydopamine‐lesioned rats with behavioral sensitization to L‐DOPA. Additionally, coadministration of a 5‐HT1A receptor agonist, 8‐hydroxy‐2(di‐n‐propylamino)tetralin with L‐DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L‐DOPA in 6‐hydroxydopamine‐lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L‐DOPA‐induced dyskinesia in patients with Parkinsons disease.

Drebrin immunoreactivity in the striatum of a rat model of levodopa-induced dyskinesia.

Levodopa‐induced dyskinesia has been suggested to result from maladaptive plasticity at corticostriatal synapses. Synaptic plasticity is based upon morphologic changes of dendritic spines. To elucidate whether the morphologic changes of spines occur in the striatum of rat models of levodopa‐induced dyskinesia, we examined immunoreactivity of drebrin, an actin‐binding protein localized in dendritic spines of excitatory synapses, using 6‐hydroxydopamine‐lesioned rats repeatedly treated with levodopa. The cross‐sectional area of drebrin‐immunoreactive organelles, putative spines, in the dopamine‐denervated striatum of the levodopa‐induced dyskinesia model was greater than that of the Parkinsons disease model. Immunoelectron microscopic examinations confirmed that drebrin‐immunoreactive spines became enlarged in the dopamine‐denervated striatum of the levodopa‐induced dyskinesia model, but not in the Parkinsons disease model. These results suggest that the development of levodopa‐induced dyskinesia is associated with enlargement of dendritic spines at corticostriatal excitatory synapses.

Venous Cerebral Infarction in a Patient With Peripheral Hemodialysis Shunt and Occlusion of the Left Brachiocephalic Vein

Intracranial venous congestion is a rare condition in hemodialysis patients with central venous occlusion. We report a patient with cerebral venous infarction resulting from high reflex flow into the cranium induced by an arteriovenous hemodialysis shunt in the arm and occlusion of the brachiocephalic vein. This case illustrates that abnormal extracranial venous circulation should be considered when cerebral venous congestion is assumed to produce neurologic symptoms in patients with an arteriovenous shunt.

Cerebral venous thrombosis with dural arteriovenous fistulas and antiphospholipid syndrome: a case report

Dear Editor, Dural arteriovenous fistulas (DAVF) and antiphospholipid syndrome (APS) are important risk factors for cerebral venous thrombosis (CTV). We describe a young patient presenting with CVT with DAVF and APS. However, the combination of the DAVF and APS has not been reported in patients with CVT. A 38-year-old man visited our outpatient clinic because of abnormal behavior. He had no mental retardation. Two weeks before the visit, he drove into a closed ski slope and crashed his car. When he was found, he had been in the car for 2 days in the ski slope. He was confused and then transferred to a local hospital. Examinations including head CT scan showed no abnormality. His daily behavior initially appeared to be normal after the episode. However, he began to demonstrate abnormal activities such as pouring water onto salad and became unable to do easy arithmetic. He did not complain of headache and fever. He showed no nuchal rigidity on admission. He was disoriented and had bradyphrenia. Mini-mental state examination was 22/30 in which he had severe loss of recent memory. The Rey–Osterrieth figure test revealed severe verbal and visual memory deficits along with inattention. He had no abnormality in cranial nerves. D-dimer was normal and b2GPI-dependent IgG antiphospholipid antibody was 54 U/ml (\3.5 U/ml). Brain MRI revealed abnormal high signals in the bilateral thalamus (Fig. 1). Brain MR venography (MRV) revealed thrombosis in the straight sinus. Digital subtraction angiography showed DAVF from marginal tentorial arteries of bilateral internal carotid arteries, bilateral occipital arteries, tentorial branches of bilateral median meningeal arteries, and right lateral posterior choroidal artery. These DAVF flowed into the vein of Galen, and the blood flow of the DAVF regurgitated into bilateral internal cerebral veins. The vein of Galen and the straight sinus were occluded. The patient was diagnosed as CVT with multiple DAVF and APS. Anticoagulant therapy was started from the day of admission, but he fell into stupor. Three times of transarterial embolisation (TAE) were performed on the DAVF and then the DAVF was surgically resected. The specimen showed arteriovenous shunting between dural arteries and veins with multilayered elastic tissue in venous walls. After the operation, attention and verbal memory on the Rey–Osterrieth figure test remarkably improved. A followup brain MRI showed a decrease in the area of abnormal intensity (Fig. 1). He was discharged without aid. We described a patient with CVT, in which cognitive disorder was a prominent symptom due to venous infarction of the bilateral thalamus by the occlusion of the straight sinus. The patient had DAVF draining into the vein of Galen. Additionally APS was found in our patient. APS is also one of the major risk factors of CVT [1]. DAVF and CVT have been closely related to each other. However, it remains to be elucidated whether DAVF is the Y. Miki (&) M. Tomiyama A. Arai T. Kimura C. Suzuki J. Nunomura M. Baba Department of Neurology, Aomori Prefectural Central Hospital, Higashi Tsukurimichi 2-1-1, Aomori, Japan e-mail: yasuomiki@hotmail.com

A novel mutation in the arylsulfatase A gene associated with adult-onset metachromatic leukodystrophy without clinical evidence of neuropathy.

! 45 and 47, respectively. His parents were not consanguineous and there is no previous history of similar neurological diseases in the family. Examination of the optic fundi showed no abnormal findings. He had no numbness, paresthesia, muscle weakness, muscle atrophy, abnormal involuntary movements or ataxia. Superficial sensation was normal, but vibratory sense was very slightly impaired in the lower limbs. The deep tendon reflexes were normal in the upper limbs. The patellar tendon reflexes were bilaterally increased, and the bilateral Achilles tendon reflexes were mildly diminished. The plantar responses were bilaterally extensor, but no spasticity was observed. Brain MRI revealed severe symmetrical white matter hyperintensities in the periventricular area on T2-weighted images and cerebral atrophy. Results from nerve conduction studies Dear Sir, Metachromatic leukodystrophy (MLD, MIM 250100) is an autosomal recessive hereditary disease characterized by neurological symptoms such as cognitive and behavioral abnormalities, ataxia and seizures [1] . MLD results from deficiency of arylsulfatase A (ASA), resulting in sulfatide accumulation in the central and peripheral nervous system [1] . A number of mutations in the ASA gene associated with decreased activity of ASA have been reported in patients with MLD [1] . Here we report a male patient with adult-onset MLD who is compound heterozygous for a novel nonsense mutation (C38X) (TGC ] TGA) and a known missense mutation (T409I) (ACT ] ATT) [2, 3] . Of note, this patient showed severely decreased nerve conduction velocities without obvious external clinical signs of neuropathy, normally a characteristic feature of MLD. The absence of clear external signs contributed to initial misdiagnosis. The 33-year-old male developed irritability and disorientation and visited a hospital department of psychiatry. There he was diagnosed with schizophrenia and, although he continued to take medications Received: November 21, 2007 Accepted: January 28, 2008 Published online: October 3, 2008