Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease.

Introduction: Symptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies.

Methods: The data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies.

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.

Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness.

HLA-DRB1*14 and DQB1*05 are associated with Japanese anti-MuSK antibody-positive myasthenia gravis patients.

Background: Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients.

Methods: We included 58 MG patients with anti-acetylcholine receptor antibody (AChR+MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK+MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers.

Does Anticholinergic Activity Affect Neuropathology? Implication of Neuroinflammation in Alzheimer's Disease.

One characteristic neuropathological feature of Alzheimer's disease (AD) is profound neuronal loss in the nucleus basalis of Meynert, the major source of cholinergic innervation of the cerebral cortex. Clinically, anticholinergic activity causes a decline in cognitive function and increases the risk of dementia, thus possibly enhancing AD pathologies and neurodegeneration. Until now there has been insufficient human neuropathological data to support this conclusion.

[Cognitive Function and Calcium. Suppression of neurotoxicity by an anti-dementia drug managing calcium influx].

Although drugs affecting N-methyl-D-aspartate (NMDA) receptors are being largely expected for anti-dementia drugs, memantine has been solely approved. As memantine has moderate affinity to NMDA receptors, memantine display efficacy of neuro-protection and learning promotion. In clinical trials, memantine showed suppression of progression of symptoms with dementia including improvement and suppression of aggressiveness and behavioral disturbance.

Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression.

The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD.

Immunohistochemical analysis of tau phosphorylation and astroglial activation with enhanced leptin receptor expression in diet-induced obesity mouse hippocampus.

Accumulating evidence indicates that obesity is an independent risk factor for developing Alzheimer disease (AD). Recent studies have shown that diet-induced obesity (DIO) enhances AD-related pathologies in transgenic mouse models of the disease. DIO increases amyloid β (Aβ) deposition in amyloidogenic transgenic mice and enhances tau phosphorylation in tau transgenic mice.

[Neuroimaging studies of diabetes and risk of Alzheimer's disease].

Several evidences from longitudinal epidemiological studies have demonstrated that diabetes significantly increases the risk of Alzheimer's disease (AD). The underlying pathophysiologies that link diabetes and development of AD are, recurrent hypoglycemia, antioxidative stress due to hyperglycemia, atherosclerosis and vascular lesions, and abnormal insulin signaling in the brain. Emerging evidences from neuroimaging studies of diabetic patients can shed light on the pathomechanisms linking diabetes with AD.

Therapeutic strategies for tau mediated neurodegeneration.

Based on the amyloid hypothesis, controlling β-amyloid protein (Aβ) accumulation is supposed to suppress downstream pathological events, tau accumulation, neurodegeneration and cognitive decline. However, in recent clinical trials, Aβ removal or reducing Aβ production has shown limited efficacy. Moreover, while active immunisation with Aβ resulted in the clearance of Aβ, it did not prevent tau pathology or neurodegeneration.

Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: an immunohistochemical study.

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), suggesting abnormally increased excitability of motor axons. Previous nerve excitability studies have shown reduced axonal potassium currents in ALS patients that may contribute to the hyperexcitability and thereby generation of fasciculations. To clarify changes in axonal ion channel expression in motor axons of ALS, we performed immunohistochemistry of potassium and sodium channels in the C7 and L5 ventral/dorsal roots obtained from five autopsy cases of sporadic ALS.

Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model.

Anticholinergics, and drugs with anticholinergic properties, are widely and frequently prescribed, especially to the elderly. It is well known that these drugs decrease cognitive function and increase the risk of dementia. Although the mechanism of anticholinergic drug-induced cognitive impairment has been assumed to be functionally reduced acetylcholine (ACh) neurotransmission, some data have indicated that anticholinergics might enhance the pathology of Alzheimer's disease.

Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model.

Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19).

Flexion-induced cervical myelopathy associated with fewer elastic fibers and thickening in the posterior dura mater.

Two patients with a condition clinically resembling juvenile muscular atrophy of distal upper extremity (Hirayama disease) showed forward protrusive movement of the posterior cervical dura matter during neck flexion. The dura displacement was characteristically limited in an approximately central portion of the posterior dura, which is different from Hirayama disease, which exhibits whole posterior dura displacement. Interestingly, the restricted dura in these patients showed thickening with reduced elastic fibers, indicating that the decreased stretchability of the posterior dura had caused motor dominant cervical myelopathy.

[Neurodegeneration and inflammation: analysis of a FTDP-17 model mouse].

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age.

Neuromyelitis optica and anti-aquaporin-4 antibodies measured by an enzyme-linked immunosorbent assay.

NMO-IgG, a disease-specific autoantibody for neuromyelitis optica, recognizes aquaporin-4 (AQP4) and has been examined by indirect immunofluorescence assay. We developed an enzyme-linked immunosorbent assay (ELISA) to detect anti-AQP4 antibodies by establishing methods for expression in a baculovirus system and purification of recombinant AQP4 as antigen. Elevated anti-AQP4 antibody titers in serum were found in 15 (71%) of 21 patients with neuromyelitis optica, 4.

Astrocytic tau pathology positively correlates with neurofibrillary tangle density in progressive supranuclear palsy.

Tufted astrocytes (TAs) are considered reliable, specific markers for the neuropathologic diagnosis of progressive supranuclear palsy (PSP). It is known that neurofibrillary tangles (NFTs) may relate directly to neurodegeneration, but the role of glial tau pathology is not well determined. To examine the hypothesis that TAs are as pathogenic as NFTs and that both might have a common accumulation, we evaluated the topographic relationship between TAs and NFTs in 12 cases of PSP.

Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age.

Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model.

Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP.

Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies.

Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter.

Low-dose tacrolimus treatment in thymectomised and steroid-dependent myasthenia gravis.

Objectives: The effects of tacrolimus, a new immunosuppressive drug, which inhibits calcineurin pathway and also might enhance corticosteroid (CS) receptor-mediated gene expressions, on clinical outcome and biochemical data were evaluated in thymectomised and steroid-dependent myasthenia gravis (MG) patients.

Patients And Methods: We administrated low-dose tacrolimus (3 mg/day orally) to 17 steroid-dependent thymectomised MG patients. They were followed for 4 to 58 months, average 19.

Increased ability of peripheral blood lymphocytes to degrade laminin in multiple sclerosis.

T lymphocytes and macrophages probably play a role in the pathogenesis of multiple sclerosis (MS), and migration of these cells into the central nervous system is facilitated by disruption of the capillary basement membrane. Laminin is a major extracellular matrix of the basement membrane. To investigate whether ability of lymphocytes to degrade laminin correlates with disease activity in MS, we conducted a prospective study in consecutive 24 MS patients.

Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy.

Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenic tau gene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds.

Reduction of detyrosinated microtubules and Golgi fragmentation are linked to tau-induced degeneration in astrocytes.

Several human neurodegenerative diseases are associated with abnormal accumulations of aggregated tau proteins and glial degeneration in astrocytes, but the mechanism whereby tau proteins cause astrocytic degeneration is unclear. Here, we analyzed the biological consequences of overexpressing the longest human tau isoform in primary cultures of rat astrocytes using adenoviral-mediated gene transfer. Significantly, we found specific decreases in stable detyrosinated [glutamate (Glu)] microtubules (MTs) with concomitant increases in tubulin biosynthesis and the accumulation of acetylated, tyrosinated, alpha- and beta-tubulin.