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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. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. Results Decreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. Discussion The present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP-17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage-gated, shaker-related subfamily, β member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimer's brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains.

Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimer's disease (AD), Parkinson's disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype.

Here we report a Japanese family with amyotrophic lateral sclerosis (ALS) characterized by very rapid progression, high penetrance and an autosomal dominant mode of inheritance. The phenotype includes atrophy of sternocleidomastoideus muscles, bulbar involvement, weakness of neck muscles and proximal muscle atrophy. These clinical symptoms are reminiscent of myopathy. All patients examined had similar clinical symptoms, age at onset and disease duration. The proband was found to have mutation R521C in the FUS/TLS gene, and was diagnosed as having ALS6. Autopsy material was available from the mother of the proband and FUS-immunoreactive neuronal and glial cytoplasmic inclusions were observed in the anterior horn of the spinal cord. While atrophy and weakness of the sternocleidomastoideus muscle is not emphasized in previous reports, this symptom may be a clinical hallmark of ALS6.

Familial amyloid polyneuropathy (FAP: type IV), known as familial amyloidosis of the Finnish type (FAF), is very rare and reported only in a few countries. The gelsolin mutation G654A is most frequent causative gene in FAF family. The clinical phenotype of FAF possesses several neurological characteristics with multiple cranial nerve signs, in addition to a peculiar exanthema of "lichen amyloidosus" and pendulous skin "cutis laxa", and the carpal tunnel syndrome. We report a new Japanese FAF family presenting bilateral atrophies and fasciculations of the facial muscles and tongue. The patients in our family presented with skin changes as "lichen amyloidosus" and "cutis laxa". In this FAF family, lichen amyloidosus appeared under sunlight and high temperatures in the summer season every year. Two patients in our family presented with common clinical features of FAF, except for the above laboratory results. Including previous cases and our family, this clinical phenotype is similar to the gelsolin gene mutation (G654A) in FAF family members.

Rat (r) PDZRhoGEF, initially identified as a glutamate transporter EAAT4-associated protein, is a member of a novel RhoGEF subfamily. The N terminus of the protein contains a PDZ and a proline-rich domain, two motifs known to be involved in protein-protein interactions. By using the yeast two-hybrid approach, we screened for proteins that interact with the N terminus of rPDZRhoGEF. The light chain 2 of microtubule-associated protein 1 (LC2) was the only protein identified from the screen that does not contain a type I PDZ-binding motif at its extreme C terminus (-(S/T)Xphi-COOH, where phi is a hydrophobic amino acid). However, the C terminus does conform to a type II-binding motif (-phiXphi). We report here that rPDZRhoGEF interacts with LC2 via the PDZ domain, and the interaction is abolished by mutations in the carboxylate-binding loop. The specificity of the interaction was confirmed using GST fusion protein pull-down assays and coimmunoprecipitations. Expression of rPDZRhoGEF mutants that are unable to interact with proteins via the carboxylate-binding loop induced changes in cell morphology and actin organization. These mutants alter the activation of RhoGTPases, and coexpression of dominant-negative RhoGTPases prevent the morphological changes. Furthermore, in cells expressing wild type rPDZRhoGEF, drug-induced microtubule depolymerization produces changes in cell morphology that are similar to those induced by rPDZRhoGEF mutants. These results indicate that modulation of the guanine nucleotide exchange activity of rPDZRhoGEF through interaction with microtubule-associated protein light chains may coordinate microtubule integrity and the reorganization of actin cytoskeleton. This coordinated action of the actin and microtubular cytoskeletons is essential for the development and maintenance of neuronal polarity.

Purpose: To evaluate the efficacy of the arched blade for making clear corneal incisions in cataract surgery. Methods: This prospective study comprised 112 eyes of 74 patients scheduled for cataract surgery. Temporal clear corneal incisions were made with either a 3.2-mm conventional flat blade or the arched blade. The choice of knife was randomly assigned. Two surgeons, one with substantial cataract surgery experience and the other with less experience, performed the surgery. Corneal topography and aberration were examined pre- and postoperatively. The degree of surgically induced astigmatism (SIA) and high order aberration was analysed. The self-sealing ability of the wound was also compared between both blades. Results: For the less experienced surgeon, the degree of SIA was significantly higher with the 3.2-mm flat blade than with the 3.2-mm arched blade as measured at any time during postoperative follow-up. For the more experienced surgeon, the degree of high order aberration increased significantly with the 3.2-mm flat blade. The incision's self-sealing ability was significantly better when the wound was made with the arched blade rather than with the flat blade. Conclusion: The arched blade proved to be effective in reducing surgically induced astigmatism and high order aberration in cataract surgery, particularly when used by the less experienced surgeon. Using the arched blade should lead to better wound self-sealing and, therefore, safer surgical results.

Here we report a female patient with elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 71, she developed gait disturbance, followed by memory disturbance 1 year later. She had been treated for hypertension and diabetes mellitus for 19 years. There apparently was low penetrance of disease. Magnetic resonance imaging (MRI) findings showed typical features of CADASIL, and the R607C mutation was detected in exon 11 in NOTCH3. This case strongly indicates that CADASIL should be considered when typical findings are observed on MRI even in cases of elderly onset with multiple cerebrovascular risk factors.

To clarify the clinical, neuropathological, and molecular characteristics of spinocerebellar ataxia type 6 (SCA6), two unrelated Japanese families with SCA6 were studied. A clinical feature of the two families was late onset "pure" cerebellar ataxia. Pathologically, three SCA6 brains consistently showed Purkinje cell dominant cortical cerebellar degeneration. Morphometric analysis showed that loss of the cerebellar granule cells and inferior olivary neurons were very mild compared with the severity of Purkinje cell loss. There was no obvious ubiquitin immunoreactive nuclear inclusions. All affected patients had identical expanded alleles, and the expansion was also homogeneously distributed throughout the brain without mosaicism. The present study showed that SCA6 is characterised by Purkinje cell dominant cortical cerebellar degeneration, highly stable transmission of the CAG repeat expansion, and lack of ubiquitin immunoreactive nuclear inclusions.

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

We observed abundant membranous cytoplasmic bodies in several remaining anterior horn neurons in two patients with sporadic amyotrophic lateral sclerosis (ALS). These bodies were rare in the neurons of the frontal cortex and of the rectum examined in one case. The link between membranous cytoplasmic bodies and ALS is vague; however, pathogenesis of ALS is unknown and there are few reports on the lysosomal system in ALS. Therefore, further study is needed in order to evaluate abnormalities in the lysosomal system to clarify the degenerative processes in ALS.

Morphological features of neurons in human inferior olivary nuclei were studied in 6 autopsied patients with dentato-olivary pathway lesions, who had survived for between 6 days and 15 months. Central chromatolysis-like neuronal enlargements were already present in the acute cases. Electron microscopy revealed round, homogeneous and electron-dense granules, varying in diameter from 0.15 micron to 2.5 microns, occurring frequently within the rough endoplasmic reticulum (ER) in the chromatolytic neurons of all 6 patients. No similar granules were observed in 6 controls. The vacuoles were due to dilatation of the rough ER, and often contained floccular materials. Neurofilamentous hyperplasia in the neurons was more frequently seen in the chronic cases. These findings suggest that the fundamental changes in the neurons in olivary hypertrophy occur within the rough ER.

To evaluate the efficacy of the arched blade for making clear corneal incisions in cataract surgery.This prospective study comprised 112 eyes of 74 patients scheduled for cataract surgery. Temporal clear corneal incisions were made with either a 3.2-mm conventional flat blade or the arched blade. The choice of knife was randomly assigned. Two surgeons, one with substantial cataract surgery experience and the other with less experience, performed the surgery. Corneal topography and aberration were examined pre- and postoperatively. The degree of surgically induced astigmatism (SIA) and high order aberration was analysed. The self-sealing ability of the wound was also compared between both blades.For the less experienced surgeon, the degree of SIA was significantly higher with the 3.2-mm flat blade than with the 3.2-mm arched blade as measured at any time during postoperative follow-up. For the more experienced surgeon, the degree of high order aberration increased significantly with the 3.2-mm flat blade. The incision's self-sealing ability was significantly better when the wound was made with the arched blade rather than with the flat blade.The arched blade proved to be effective in reducing surgically induced astigmatism and high order aberration in cataract surgery, particularly when used by the less experienced surgeon. Using the arched blade should lead to better wound self-sealing and, therefore, safer surgical results.

45 and 47, respectively. His parents were not consanguineous and there is no previous history of similar neurological diseases in the family. Examination of the optic fundi showed no abnormal findings. He had no numbness, paresthesia, muscle weakness, muscle atrophy, abnormal involuntary movements or ataxia. Superficial sensation was normal, but vibratory sense was very slightly impaired in the lower limbs. The deep tendon reflexes were normal in the upper limbs. The patellar tendon reflexes were bilaterally increased, and the bilateral Achilles tendon reflexes were mildly diminished. The plantar responses were bilaterally extensor, but no spasticity was observed. Brain MRI revealed severe symmetrical white matter hyperintensities in the periventricular area on T2-weighted images and cerebral atrophy. Results from nerve conduction studies Dear Sir, Metachromatic leukodystrophy (MLD, MIM 250100) is an autosomal recessive hereditary disease characterized by neurological symptoms such as cognitive and behavioral abnormalities, ataxia and seizures [1] . MLD results from deficiency of arylsulfatase A (ASA), resulting in sulfatide accumulation in the central and peripheral nervous system [1] . A number of mutations in the ASA gene associated with decreased activity of ASA have been reported in patients with MLD [1] . Here we report a male patient with adult-onset MLD who is compound heterozygous for a novel nonsense mutation (C38X) (TGC ] TGA) and a known missense mutation (T409I) (ACT ] ATT) [2, 3] . Of note, this patient showed severely decreased nerve conduction velocities without obvious external clinical signs of neuropathy, normally a characteristic feature of MLD. The absence of clear external signs contributed to initial misdiagnosis. The 33-year-old male developed irritability and disorientation and visited a hospital department of psychiatry. There he was diagnosed with schizophrenia and, although he continued to take medications Received: November 21, 2007 Accepted: January 28, 2008 Published online: October 3, 2008

Background: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.Objectives: To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.Design, Setting, and Participants: We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.Results: The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families ( of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).Conclusions: The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.