14-3-3 protein, total tau and phosphorylated tau in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease and neurodegenerative disease in Japan.

1. Sporadic Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and fatal disease. Patients with CJD usually become akinetic mutism within approximately 6 months. In addition, clinical signs and symptoms at early stage of sporadic CJD may not be easy to distinguish from other neurodegenerative diseases by neurological findings. However, diagnostic biochemical parameters including 14-3-3 protein, S100, neuron-specific enorase in cerebrospinal fluid (CSF) have been used as diagnostic markers, elevated titers of these markers can also be observed in CSF in other neurodegenerative diseases. Therefore, we examined other biochemical markers to discriminate CJD from other neurodegenerative diseases in CSF. 2. We analyzed CSF samples derived from 100 patients with various neurodegenerative disorders by Western blot of 14-3-3 protein, quantification of total tau (t-tau) protein, and phosphorylated tau (p-tau) protein. All patients with CJD in this study showed positive 14-3-3 protein and elevated t-tau protein (>1000 pg/mL) in CSF. We also detected positive 14-3-3 protein bands in two patients in non-CJD group (patients with dementia of Alzheimer's type; DAT) and also detected elevated t-tau protein in three patients in non-CJD group. Elevated t-tau protein levels were observed in two patients with DAT and in one patient with cerevrovascular disease in acute phase. 3. To distinguish patients with CJD from non-CJD patients with elevated t-tau protein in CSF, we compared the ratio of p-tau and t-tau proteins. The p-/t-tau ratio was dramatically and significantly higher in DAT patients rather than in CJD patients. 4.Therefore, we concluded that the assay of t-tau protein may be useful as 1st screening and the ratio of p-tau protein/t-tau protein would be useful as 2nd screening to discriminate CJD from other neurodegenerative diseases.

Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification.

Mutation of Cu/Zn superoxide dismutase (SOD1) contributes to a portion of the cases of familial amyotrophic lateral sclerosis (FALS). We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene. To investigate the cellular consequences of this mutation, we produced transgenic mice that expressed normal and mutated copies of human SOD1: wild-type SOD1 (W), wild-type SOD1 with a FLAG epitope at C-terminal (WF), mutated SOD1 with the 2-bp deletion (D), and SOD1 with the 2-bp deletion with FLAG (DF). The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD1 (W and WF) mice did not. Homozygotes of D and DF lines showed the ALS symptoms at an earlier age and died earlier than the heterozygotes. By Northern blot analysis, the mRNAs for all human SOD1s were confirmed in these lines. All the human SOD1 proteins, except the D mutant, were detectable by immunoblot. The D protein was only confirmed when it was concentrated by immunoprecipitation. Neuropathologically, loss of spinal motor neurons and reactive gliosis were common features in the symptomatic lines. The remaining motor neurons in these mice also exhibited eosinophilic inclusions. The biochemical and pathological characteristics of these mice are quite similar to those of human FALS patients with same mutation. This intriguing model will provide an important source of information of the pathogenesis of FALS.

[Reversible MRI findings of posterior column of the spinal cord in a patient with acute autonomic and sensory neuropathy].

We report serial spinal MRI T2 findings in a patient with acute autonomic and sensory neuropathy (AASN). A 20-year-old woman was admitted to our hospital with progressive sensory disturbance in her extremities and orthostatic syncope after her symptoms of upper respiratory infection. Neurological examination demonstrated reduced tendon reflexes, hypalgesia, paresthesia, reduced position sensation in distal dominant extremities (predominant in lower legs) and wide variety of autonomic dysfunction (severe orthostatic hypotension, anhidrosis, urinary disturbance, coughing attack, constipation and appetite loss). She was diagnosed as having AASN. Although high dose intravenous immunoglobulin therapy successfully prevented the symptom progression, her sensory disturbance and autonomic dysfunction were prolonged and showed only slow improvement. Spinal MRI on acute phase was normal. On chronic phase (11 month after the onset), spinal MRI T2 weighted images demonstrated high intensity lesion in the posterior column successive from upper cervical to lower thoracic spinal cord. Those abnormal findings were attenuated in concordance with her symptom improvement and finally disappeared when she became to walk stably without assist.

[A case report of syphilitic meningitis with right oculomotor nerve palsy].

A 63-year-old man presented with acute-onset right ptosis and diplopia. The patient reported having engaged in unspecified sexual activities during his third decade and was found to have positive syphilitic serological findings at the age of 56 years. No clinical symptoms were noted at this time. On admission, he showed only right oculomotor nerve palsy. The patient's intelligence, gait and sensory functions were normal. Laboratory analysis revealed positive syphilitic serological findings and examination of the cerebrospinal fluid (CSF) further revealed pleocytosis, a higher IgG index and positive syphilitic reactions. A computed tomographic scan and other imaging studies were diagnostically nonspecific. We made a diagnosis of right oculomotor nerve palsy due to syphilitic meningitis. We treated the syphilitic meningitis with intravenous injections of penicillin G (24 million units per day for 21 days). Jarisch-Herxheimer reaction and other side effects were not apparent. We first made a thorough examination of the CSF to rule out diagnosis of meningitis, and pursued methylprednisolone pulse therapy (MPP, 1 g/day for 3 days) to treat the oculomotor nerve palsy. The ptosis and diplopia showed signs of improvement following the second MPP therapy session. The present case suggests that neurosyphilis is an important differential diagnosis for presentations of unspecific oculomotor nerve palsy and that MPP therapy may prove an effective treatment for it, even where there has been the long clinical onset.

An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan.

We identify the prevalence and genetic features of Charcot-Marie-Tooth disease (CMT) in Yonago and Sakaiminato, western Japan. From information in registered records and questionnaires, definite or candidate CMT patients were examined. Eleven families with 19 patients (7 female and 12 male) were identified and the prevalence was 10.8 per 100,000 in April 2000. Eleven patients in 6 families showed a Thr124Met mutation of the MPZ gene, in 2 families duplication of the PMP22 gene was suggested and no abnormalities were found in 2 families. To identify the occurrence of mildly affected CMT, the exhaustive region-matched and family study was necessary.

Double-blind crossover study of branched-chain amino acid therapy in patients with spinocerebellar degeneration.

To determine whether treatment with branched-chain amino acids (BCAA) can improve the condition of patients with ataxia, a double-blind crossover study of BCAA therapy was performed in 16 patients with spinocerebellar degeneration (SCD). The patients were treated with BCAA in oral doses of 1.5, 3.0, or 6.0 g or with placebo daily for 4 weeks in each study phase. The order of treatment phases (placebo or BCAA) was assigned randomly. An International Cooperative Ataxia Rating Scale (ICARS) was used to quantify the severity of symptoms of SCD. The mean ICARS score improved significantly with BCAA treatment compared with the mean pretreatment score (p<0.01). In addition, the improvement in the mean global ICARS score was significant in the middle-dose group compared with that in the placebo group (p<0.02). The estimated improvement in kinetic functions compared with pretreatment (p<0.01) was significant after treatment with BCAA, 1.5 and 3.0 g. All of the responders manifested predominantly cerebellar symptoms, especially those with spinocerebellar ataxia type 6 (SCA6). Thus, treatment with BCAA may be effective in patients with the cerebellar form of SCD.

[A young adult case of spontaneous basilar artery dissection].

We reported a case of basilar artery dissection in a 20-year-old man suffering sudden onset of consciousness disturbance. Brain CT revealed a cerebral infarction of the whole territories of vertebro-basilar artery and his 3DCT showed the occlusion at the base of basilar artery. Autopsy revealed that the subintimal dissection was found at the base of basilar artery and the dissection was spreaded to the distal of bilateral posterior cerebral arteries. The characteristics of his vertebro-basilar artery were small in diameter, thin media and thickened intima. According to these findings, we supposed this rare case of basilar dissection occurred all at once based on a functional abnormality in his small vertebro-basilar arterial wall.