Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.

AIMS: Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. METHODS: Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. RESULTS: (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident. CONCLUSIONS: There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.

Mediastinal neurilemmoma complicated with spinal subarachnoid hemorrhage.

A 28-year-old woman suffered severe back pain and headache during exercising on three occasions during the prior two-month period. On admission, the physical examination revealed symptoms of meningeal irritation, nuchal rigidity, severe headache, continuous nausea, and vomiting. Cerebral computed tomography of the intracranial subarachnoidal space revealed no subarachnoid hemorrhage. Her cerebrospinal fluid was bloody. Spinal magnetic resonance imaging identified a posterior mediastinal tumor adherent to the left side of the 5th thoracic vertebra and an abnormally expanded blood vessel near the mediastinal tumor. In addition, a high signal intensity lesion appeared to be present on the surface of the spinal cord. A mediastinal neoplasm was removed through standard thoracotomy. During surgery, marked enlargement was noted in some veins (hemiazygos and 5th intercostal veins) which apparently had been constricted by the mediastinal tumor. Surgical and radiological findings suggested a relationship between the constricted venous return due to the tumor and the patient's spinal subarachnoid hemorrhage.

Efficacy of a low-dose subcutaneous lisuride infusion in Parkinson's disease.

Five parkinsonian patients with motor fluctuations and dyskinesia after long-term treatment with levodopa were treated with subcutaneous lisuride infusion (0.24-0.42 mg/day) together with oral levodopa for a mean period of 27 (range 13-36) months. All 5 patients showed marked initial improvement in mobility. Mild psychiatric side effects were observed in three patients; however, these side effects disappeared with reduction in the dosage of lisuride to 0.06 mg per day without a significant increase in motor fluctuations. A low dose of subcutaneous lisuride infusion with oral levodopa is an effective treatment for fluctuations of motor performance in parkinsonian patients without adverse psychiatric effects.

Modality specific naming and gesture disturbances: a case with optic aphasia, bilateral tactile aphasia, optic apraxia and tactile apraxia.

This study reports a patient who manifested optic aphasia, tactile aphasia, optic apraxia, and tactile apraxia following an operation for epidural left parietal haematoma. He could neither name nor pantomime the use of objects presented visually or tactually, but correctly performed semantic association tasks, thus demonstrating preserved recognition. He could name and pantomime the use of auditorily presented objects. Experimental results disproved that pantomime disorders were secondary to naming disorders, and suggested that modality specific aphasia and modality specific apraxia are independent clinical syndromes. CT scans showed injury to the posterior callosal radiations, the white matter of the angular gyrus, and the medial portion of the occipital lobe in the left hemisphere. We suggest that modality specific aphasia and modality specific apraxia can be explained by assuming a common semantic memory store.

Haplotype analysis in gelsolin-related amyloidosis reveals independent origin of identical mutation (G654A) of gelsolin in Finland and Japan.

Familial amyloidosis, Finnish type (FAF) (gelsolin-related amyloidosis) is an autosomal dominant form of systemic amyloidosis characterized by corneal lattice dystrophy and peripheral polyneuropathy. The accumulating protein in FAF consists of fragments of gelsolin, an actin-modulating protein. The gelsolin mutation G654A has been found in both Finnish and Japanese patients. To study the origin of the gelsolin mutation in these patients we performed haplotype analysis in 10 Finnish and 2 Japanese FAF families. Poymorphic DNA markers GSN, D9S103, AFMa061xd9, and AFMa139xb9 revealed a uniform disease haplotype in all the disease-associated chromosomes of the Finnish FAF families, which was different from the one observed in the Japanese families. The present results and the previously detected gelsolin mutation G654T in Czech and Danish FAF patients suggest that nucleotide 654 may represent a mutation hot spot in the gelsolin gene. The DNA markers studied here will be useful in future genealogical analyses of FAF.

[Familial amyloid polyneuropathy type IV (Finnish type)--a clinicopathological study].

Familial amyloid polyneuropathy type IV (Finnish type, FAP IV) is one form of hereditary generalized amyloidosis with autosomal dominant trait and is characterized clinically by a triad of corneal lattice dystrophy, caudal cranial neuropathy and various skin changes. The vast majority of the families with this disorder originated from Finland. We carried out a clinicopathological study of a large FAP IV kindred recently found in Japan. This family consisted of 73 members in 5 generations with 17 affected individuals and 7 of them (ages 45 to 73) were examined in detail. All patients showed typical clinical manifestations, lacking significant peripheral neuropathy in the limbs. However, autonomic dysfunctions including orthostatic fainting and dysuria were seen in 2 patients. Congophilic amyloid deposits were commonly observed in an aspiration biopsy of abdominal fat tissues, and noradrenergic nerve fibers of the rectal mucosa were reduced in one patient with autonomic symptoms. DNA analysis using PCR revealed a single base change (G to A) at nucleotide position 654 of the gelsolin gene in 7 patients and one asymptomatic individual. The clinical pictures and gene abnormality in this Japanese family are very similar to those reported in Finland. Moreover, this study added that autonomic nerves might be involved in FAP IV patients at the advanced stage.

Tactile agnosia and tactile aphasia: symptomatological and anatomical differences.

Two patients with tactile naming disorders are reported. Case 1 (right hand tactile agnosia due to bilateral cerebral infarction) differentiated tactile qualities of objects normally, but could neither name nor categorize the objects. Case 2 (bilateral tactile aphasia after operation of an epidural left parietal haematoma) had as severe a tactile naming disturbance as Case 1, but could categorize objects normally, demonstrating that tactile recognition was preserved. Case 1 may be the first case of tactile agnosia clearly differentiated from tactile aphasia. CT scans of Case 1 revealed lesions in the left angular gyrus, and in the right parietal, temporal, and occipital lobes. Case 2 had lesions in the left angular gyrus and of posterior callosal radiations. Our findings suggest that tactile agnosia appears when the somatosensory association cortex is disconnected by a subcortical lesion of the angular gyrus from the semantic memory store located in the inferior temporal lobe, while tactile aphasia represents a tactual-verbal disconnection.

Gastrointestinal amyloid deposition in familial amyloid polyneuropathy.

We found degeneration of enteric nerve plexuses in two patients with type I familial amyloid polyneuropathy. Amyloid deposition was more severe in the wall of the stomach than in the rectum. Hypomotility of the upper gastrointestinal tract, resulting from both amyloid deposition in the stomach and upper bowel and degeneration of the intrinsic autonomic nerves, may be responsible for anorexia, nausea, and vomiting. Diarrhea and constipation may be caused by degeneration of the enteric nerve plexuses. Gastric biopsy is valuable and safe in the diagnosis to type I familial amyloid polyneuropathy.