Mitsuhiro Tsujihata

Lewy body–type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases

Article abstract Heart tissues of patients with PD or incidental Lewy body (LB) disease (ILBD) were examined by light and electron microscopy. LBs and α-synuclein–positive neurites were identified in the hearts from 9 of 11 patients with PD and from 7 of 7 patients with ILBD. LBs were present in both tyrosine hydroxylase-positive and -negative nerve processes, which are nerves of extrinsic sympathetic and intrinsic origin, respectively. These findings provide histologic evidence that the postganglionic sympathetic and intrinsic neurons in the heart are involved in the PD disease process.

Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis

Muscle‐specific tyrosine kinase (MuSK) antibodies are found in some patients with “seronegative” myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)–positive end‐plates compared with AChR antibody–positive end‐plates, and C3 was detected in only two of eight MuSK Ab–positive patients. MuSK antibodies do not appear to cause substantial AChR loss, complement deposition, or morphological damage. Effects on MuSK function need to be explored. Ann Neurol 2005;57:289–293

LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density.

AbstractOsteoporosis is a multifactorial trait with low bone mineral density (BMD). We report results of an association study between BMD and nine candidate genes (TGFB1, TGFBR2, SMAD2, SMAD3, SMAD4, IFNB1, IFNAR1, FOS and LRP5), as well as of a case-control study of osteoporosis. Samples for the former association study included 481 general Japanese women. Among the nine candidate genes examined, only LRP5 showed a significant association with BMD. We identified a strong linkage disequilibrium (LD) block within LRP5. Of five LPR5 single nucleotide polymorphisms (SNPs) that are located in the LD block, three gave relatively significant results: Women with the C/C genotype at the c.2220C>T SNP site had higher adjusted BMD (AdjBMD) value compared to those with C/T and T/T (p=0.022); and likewise, G/G at IVS17-30G>A and C/C women at c.3989C>T showed higher AdjBMD than those with G/A or A/A (p=0.039) and with C/T or T/T (p=0.053), respectively. The case-control study in another series of samples consisting of 126 osteoporotic patients and 131 normal controls also gave a significant difference in allele frequency at c.2220C>T (χ2=6.737, p=0.009). These results suggest that LRP5 is a BMD determinant and also contributes to a risk of osteoporosis.

Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome.

The aim of this study was to clarify whether autoimmunity against P/Q‐type voltage‐gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert‐Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD‐LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q‐type VGCC in these patients and controls for the amount and ratio of autoantibody‐channel complex using an 125I‐ω‐conotoxin MVIIC‐binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q‐type VGCC measured by Scatchard analysis were reduced in PCD‐LEMS patients (63.0 ± 7.0fmol/mg, n = 3), compared with the controls (297.8 ± 38.9fmol/mg, n = 6). The ratio of autoantibody‐VGCC complexes to total P/Q‐type VGCCs measured by immunoprecipitation assay were increased in PCD‐LEMS patients. We analysed cerebellar specimens by autoradiography using 125I‐ω‐conotoxin MVIIC, which specifically binds to P/Q‐type VGCCs. In PCD‐LEMS cerebellum, the toxin binding sites of P/Q‐type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q‐type VGCCs in the normal cerebellum. This suggests that P/Q‐type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD‐LEMS.

Seronegative Lambert-Eaton myasthenic syndrome Study of 110 Japanese patients

The authors characterized the clinical and immunologic features of 110 patients with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated calcium channels (VGCC) antibodies were detected in 85% of the patients (seropositive) but not in the rest (seronegative). Except for the indication that small cell lung carcinoma is less common in seronegative patients, no significant differences were found in the clinical characteristics of patients who had or did not have anti-P/Q-type VGCC antibodies. The results of passive transfer experiments suggest that seronegative LEMS is also an autoantibody-mediated disorder.

14-3-3 Protein, Total Tau and Phosphorylated Tau in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease and Neurodegenerative Disease in Japan

Summary1.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 Alzheimers 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.

Beriberi neuropathy: Morphometric study of sural nerve

Seven biopsied sural nerves from patients with beriberi were morphometrically evaluated. In teased fiber analysis the mean frequency of myelinated fibers showing axonal degeneration and segmental demyelination was 37.5 and 5.3%, respectively. In two cases with frequency of segmental demyelination higher than 5%, segmental demyelination was shown by statistical criteria to have occurred on certain fibers in a clustered fashion. Therefore, the segmental demyelination in beriberi may be secondary to axonal degeneration. Electromyographic findings and slow improvement of muscle weakness were compatible with axonal degeneration of motor fibers. Determinations of fiber densities revealed preferential decrease of the density of large myelinated fibers with the preservation of the density of small myelinated and unmyelinated fibers. The preferential nerve fiber involvement in beriberi was not associated with pain in the lower limbs and this fact is contrary to the expectation of the proponents of the gate control theory.

Diagnostic significance of IgG, C3, and C9 at the limb muscle motor end‐plate in minimal myasthenia gravis

We detected deposits of IgG, C3, and C9 (immune complexes) at the limb muscle motor end-plates (biceps brachii muscle) in 16 of 19 patients who exhibited only ocular signs and symptoms of myasthenia gravis that were improved by intravenous injections of edrophonium chloride. Circulating anti-acetylcholine receptor (anti-AChR) antibodies were negative in 6 of the 16 patients, but the motor end-plate fine structure in the postsynaptic regions was abnormal in all 16. Single-fiber EMG revealed no abnormalities in 8 of 13 patients studied. Our results indicate that the detection of immune complexes at the limb muscle end-plate provides a highly sensitive and confirmative method for diagnosing patients with minimal or atypical myasthenia gravis who have no detectable anti-AChR antibodies in their serum.

Bromocriptine Protects Dopaminergic Neurons from Levodopa-Induced Toxicity by Stimulating D2Receptors

Neuroprotective properties of bromocriptine, a D(2) receptor agonist, were investigated using the in vitro neurotoxicity of levodopa for dopaminergic neurons from rat embryonic ventral mesencephalon. Levodopa, when added to the culture medium, showed toxicity which was specific for dopaminergic neurons. Bromocriptine was found to protect dopaminergic neurons from levodopa toxicity. Another D(2) agonist, 2-(N-phenethyl-N-propyl-amino-5-hydroxytetralin, showed similar protective effects. The neuroprotective effect of bromocriptine was inhibited by supplementation of the culture medium with sulpiride, a D(2) antagonist, or by D(2) receptor knockdown with an antisense oligonucleotide. Dopaminergic neurons treated with levodopa showed an increase in free radicals. These data suggest that neuroprotective properties of bromocriptine seen in this cellular model of neurotoxicity are dependent on dopamine D(2) autoreceptor binding and that levodopa toxicity may be related to increased free radical generation in dopaminergic neurons.

Plasmapheresis in treatment of human T-lymphotropic virus type-I associated myelopathy.

In 11 of 18 patients with human T-lymphotropic virus type-I (HTLV-I) associated myelopathy (HAM) gait, sensory, and/or sphincter disturbance improved with plasmapheresis (4 to 6 sessions in 2 weeks), and the effects were maintained for 2 to 4 weeks. Plasmapheresis lowered the titre of HTLV-I antibody in serum but not in cerebrospinal fluid, and change of HTLV-I antibody titres did not correlate with the effects of plasmapheresis. These results suggest that plasmapheresis is useful treatment, at least in producing a temporary improvement, in patients with HAM, and that some humoral factor(s), but not HTLV-I antibody, may be important in the pathogenesis of HAM.