Kazuo Iwasa

Decreased β-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration

Several previous studies have identified biochemical markers for Alzheimers disease (AD): cerebrospinal fluid (CSF)-beta-amyloid peptide42 (CSF-Abeta42), CSF-total tau protein (CSF-tau) and CSF-phosphorylated tau protein (CSF-ptau). Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) as well as AD are diseases with tauopathies. CSF-Abeta42, CSF-tau, and CSF-ptau have not been rigorously investigated in PSP and CBD. In the present study, we assessed CSF-Abeta42, CSF-tau, and CSF-ptau as biochemical markers for PSP and CBD, compared with AD. The subjects consisted of 18 cases of PSP, 9 cases with CBD, 69 cases with AD, and 43 control subjects. Genotyping or phenotyping of apolipoprotein E (apoE) was also performed. CSF-Abeta42 levels were significantly decreased in patients with PSP and CBD as well as in AD patients. The ratio of CSF-ptau to CSF-Abeta42 provided high diagnostic accuracy to distinguish both PSP from AD, and CBD from AD. ApoE genotype/phenotype was not associated with CSF-Abeta42 levels in all groups. We concluded that CSF-Abeta42 levels are reduced in PSP and CBD as well as in AD.

Consumption of Green Tea, but Not Black Tea or Coffee, Is Associated with Reduced Risk of Cognitive Decline

Our objective was to determine whether the consumption of green tea, coffee, or black tea influences the incidence of dementia and mild cognitive impairment (MCI) in older people. We conducted a population-based prospective study with Japanese residents aged >60 years from Nakajima, Japan (the Nakajima Project). Participants received an evaluation of cognitive function and blood tests. The consumption of green tea, coffee, and black tea was also evaluated at baseline. Of 723 participants with normal cognitive function at a baseline survey (2007–2008), 490 completed the follow up survey in 2011–2013. The incidence of dementia during the follow-up period (mean ± SD: 4.9±0.9 years) was 5.3%, and that of MCI was 13.1%. The multiple-adjusted odds ratio for the incidence of overall cognitive decline (dementia or MCI) was 0.32 (95% CI: 0.16–0.64) among individuals who consumed green tea every day and 0.47 (95% CI: 0.25–0.86) among those who consumed green tea 1–6 days per week compared with individuals who did not consume green tea at all. The multiple-adjusted odds ratio for the incidence of dementia was 0.26 (95% CI: 0.06–1.06) among individuals who consumed green tea every day compared with those who did not consume green tea at all. No association was found between coffee or black tea consumption and the incidence of dementia or MCI. Our results indicate that green tea consumption is significantly associated with reduced risk of cognitive decline, even after adjustment for possible confounding factors.

Antibodies to synthetic peptides of the alA subunit of the voltage‐gated calcium channel in Lambert‐Eaton myasthenic syndrome

To search for antigenic sites in the molecular structure of alA subunit of the voltage-gated calcium channel (VGCC) (P/Q-type) in the Lambert-Eaton myasthenic syndrome (LEMS), we studied by immunoprecipitation assay serum samples from 30 LEMS patients (16 with small cell lung carcinoma (SCLC), 20 disease controls (10 with SCLC without LEMS and 10 with myasthenia gravis), and 15 healthy controls. Synthetic peptide antigens corresponded to the extracellular region (S5-S6 linker region) of each of the four domains forming the al subunit of P/Q-type VGCC. In addition, we studied serum samples for anti-P/Q-type VGCC antibodies by using w-conotoxin MVIIC-labeled extract of human cerebellum as an antigen. Among sera of 30 LEMS patients, nine samples (30%) (six with SCLC) were positive for antibodies to the domain IV S5-S6 linker peptide, and six samples (20%) (five with SCLC) were positive for antibodies to the domain II S5-S6 linker peptide. Only two of 15 antipeptide-positive sera were positive for both antibodies. Titers for antibodies to domain IV, as well as those for antibodies to domain II, correlated with those of anti-P/Q-type VGCC (human cerebellum extract) antibodies. The antipeptide antibody was present in only one of 20 disease controls, a patient with SCLC without LEMS. Our observations suggest two potential epitopes of LEMS antibodies.

A Comparison of the Diagnostic Sensitivity of MRI, CBF-SPECT, FDG-PET and Cerebrospinal Fluid Biomarkers for Detecting Alzheimer's Disease in a Memory Clinic

Background/Aim: Magnetic resonance imaging (MRI), cerebral blood flow single photon emission computed tomography (CBF-SPECT), fluorodeoxyglucose-positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) biomarkers are used for the diagnosis of Alzheimer’s disease (AD). We aimed to reveal the relative sensitivity of these tools in a memory clinic setting. Methods: In 207 patients with probable AD in our memory clinic, medial temporal lobe atrophy on MRI, hypoperfusion/hypometabolism of the parietotemporal lobe and posterior cingulate gyrus in ethylcysteinate dimer-CBF-SPECT/FDG-PET, and abnormalities of CSF amyloid β-protein 1–42, total tau and phosphorylated tau were evaluated as findings characteristic of AD. Results: The AD findings were observed in 77.4% of all AD patients with MRI, 81.6% with CBF-SPECT, 93.1% with FDG-PET and 94.0% with CSF biomarkers. At the stage of Clinical Dementia Rating (CDR) 0.5, CSF biomarkers were the most sensitive (90.0%); at the stage of CDR 1, FDG-PET (96.7%) and CSF biomarkers (95.5%) were highly sensitive. At the stage of CDR 2, all tools showed high positive percentages. Conclusion: The diagnosis of AD was most often supported by CSF biomarkers and FDG-PET at the early stage of dementia (CDR 1) and by CSF biomarkers at the earlier stage (CDR 0.5).

Antibodies to Calcium Channel and synaptotagmin in Lambert-Eaton Myasthenic syndrome

In the Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease that is often associated with lung cancer and characterized by reduced quantal release of acetylcholine from the motor nerve terminal, our studies to search for the target of LEMS antibodies have brought the voltage-gated calcium channel (VGCC) into relief. Among multiple types of VGCCs, the P/Q-type was highly recognized by LEMS antibodies. Using synthetic peptides or recombinant proteins as antigens, the study specified the S5-S6 linker regions in 3 of 4 domains as immunodominant sites in the molecular structure of P/Q-type VGCC alpha1 subunit. Synaptotagmin, one of the functionally VGCC-associated synaptic proteins, was also found to be an immunogen in the pathogenesis of LEMS.

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti‐RyR peptide antibody. The rat serum contained anti‐RyR antibodies, but no anti‐acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation–contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti‐RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.

Calcium channel peptide can cause an autoimmune-mediated model of Lambert–Eaton myasthenic syndrome in rats

The Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission characterized by the reduced quantal release of acetylcholine from the motor nerve terminal, wherein the P/Q-type of voltage-gated calcium channel (VGCC) and is attacked by a majority of LEMS antibodies. Using the molecular structure of the alpha1 subunit (consisting of 4 domains) of the P/Q-type VGCC as a reference, we synthesized the extracellular region (S5-S6 linker) of the domain III, known as the segment which plays an important role in channel functions. Six of the ten Lewis rats immunized with this synthetic peptide conjugated with carrier protein showed moderate weakness (grade 1 in a 3-graded scale, for myasthenic weakness in experimental animals) and a reduction in acetylcholine quantum content of end-plate potentials. Antipeptide antibodies raised in test rats reacted with omega-conotoxin MVIIC-sensitive cerebellar extract (P/Q-type VGCC) and the domain III peptide inhibited the binding of rat antibodies to VGCCs. Our findings suggest the identification of one of the potential epitopes of LEMS antibodies.

Cerebrospinal fluid of Alzheimer patients promotes β-amyloid fibril formation in vitro

Cerebral deposition of amyloid beta-peptide (Abeta) is an invariant feature of Alzheimers disease (AD). To answer why soluble Abeta does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro, by using fluorescence spectroscopy with thioflavin T and electron microscopy. Although the CSF obtained from both groups inhibited the formation of both fAbeta(1-40) and fAbeta(1-42), the CSF from non-AD patients inhibited the formation of fAbetas more strongly than that from AD patients. In AD patients, the final levels of fAbetas formation showed a significant negative correlation with the Abeta(1-42) level in CSF. These results indicate that fAbeta deposition in the brain of AD may be enhanced by the decrease of specific inhibitory factors and/or by the increase of specific accelerating factors in CSF.

Clinical efficacy and cytokine network-modulating effects of tacrolimus in myasthenia gravis

To clarify the long-term efficacy, safety and the cytokine network-modulating effects of tacrolimus in myasthenia gravis, medical records of 86 newly diagnosed consecutive patients and nine steroid-dependent patients were retrospectively reviewed, and peripheral blood mononuclear cells (PBMC) were cultured for the cytokine profile. Steroid reduction effects were observed by using tacrolimus, and no serious adverse effects were observed. The culture study showed reduced IL-12, IL-17, IFN-gamma, GM-CSF, TNF-alpha and MIP-1beta, and elevated IL-10 in the PBMC from patients who received tacrolimus, which suggests inhibition of T cells and macrophages, and enhancement of type 1 regulatory T cells.

Recombinant calcium channel is recognized by Lambert–Eaton myasthenic syndrome antibodies

Article abstract The authors studied sera from 36 patients with Lambert–Eaton myasthenic syndrome (LEMS) by immunoblots using the recombinant protein derived from the DNA sequence encoding for the domain III S5-S6 linker of the P/Q-type voltage-gated calcium channel α1 subunit. The results of 18 patients were positive for antibodies to this recombinant protein. The results of 2 of 10 patients with lung cancer without LEMS were also positive.