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In this report we describe a 72-year-old woman who had cytomegalovirus infection-related Guillain-Barré syndrome (GBS) associated with multiple immunoglobulin M (IgM) anti-ganglioside antibodies. She became tetraplegic with respiratory failure, but recovered completely after intravenous immunoglobulin therapy and plasmapheresis. The serum contained high-titer IgM antibody activities to several gangliosides with disialosyl residues (GD1b, GD3, GT1b, GQ1b, and GT1a) and GD1a. These antibodies are often found in sera from patients with chronic sensory ataxic neuropathy, but they occur rarely in GBS. Muscle Nerve 38: 1630-1633, 2008. [ABSTRACT FROM AUTHOR]

An atom-economical sequential-flow synthesis of donepezil, a widely prescribed drug for Alzheimer's disease, was accomplished using inexpensive, commercially available precursors. This achievement was made possible by reconfiguring the synthetic route to include only heterogeneous catalytic addition and condensation reactions, with a particular emphasis on skeletal transformation and bond formation through hydrogenation processes. Notably, water was the sole byproduct in this synthesis. A crucial aspect of this work was the development of appropriate continuous-flow processes to achieve a one-flow synthesis. This was accomplished by implementing in-line treatments of the main reaction stream to eliminate inhibitory factors that could affect catalyst performance in the hydrogenation steps., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Quaternary ammonium hydroxide resins are widely recognized for their effectiveness as immobilized bases and are frequently utilized as commodity chemicals for anion-exchange applications. However, despite their accessibility, chemically controlling their properties has proven challenging, hindering research and development efforts toward their use as solid base catalysts. This study investigates the synthetic factors that are crucial for achieving high functional performance in polystyrene resins. Using commercially available resin as a benchmark and the continuous-flow Henry reaction as a model system, we explore and evaluate newly synthesized resin catalysts to maximize their basic catalytic activity.

Continuous-flow synthesis of baclofen precursor (2) was achieved using achiral and chiral heterogeneous catalysts in high yield with high enantioselectivity. The key steps are chiral calcium-catalyzed asymmetric 1,4-addition of a malonate to a nitroalkene and chemoselective reduction of a nitro compound to the corresponding amino compound by using molecular hydrogen. A dimethylpolysilane (DMPS)-modified platinum catalyst supported on activated carbon (AC) and calcium phosphate (CP) has been developed that has remarkable activity for the selective hydrogenation of nitro compounds., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation., Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch ( n = 11) or donepezil ( n = 11) for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased), cognitive function, and blood biochemical variables, including various hormones., Results: Rivastigmine treatment significantly improved appetite (from 1.6 ± 0.5 to 2.6 ± 0.7), whereas donepezil treatment did not (from 2.0 ± 0.0 to 1.8 ± 0.4). Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 ± 60.5 to 246.8 ± 78.5 IU/L) and increased the cortisol level (from 11.86 ± 3.12 to 14.61 ± 3.29 μg/dL) and the acyl/des-acyl ghrelin ratio (from 4.03 ± 2.96 to 5.28 ± 2.72). The levels of leptin, insulin, total ghrel-in, and cognitive function were not significantly affected by either treatment., Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss.

Background: Freezing of gait (FOG) has been linked to increased numbers of steps taken while walking. We tested the hypothesis that an increased number of steps associated with FOG might predict the exacerbation of the severity of Parkinson's disease (PD)., Methods: We prospectively studied 26 patients. Clinical assessments were performed and balance was evaluated in 30 patients with Hoehn-Yahr stage III PD 6 years previously. Gait parameters were analyzed with the use of an originally designed, suddenly narrowed path. PD-related independent variables, balance investigation-related variables, and gait-independent-related variables were analyzed by multiple logistic regression analysis., Results: The Hoehn-Yahr stage increased in 14 patients and was unchanged in 12 patients. The 36-item Short-Form Health Survey score (OR 1.079, p = 0.041, 95% CI 1.003-1.161) and the number of steps on the suddenly narrow path (OR 1.605, p = 0.047, 95% CI 1.006-2.56) were related to an increase in the Hoehn-Yahr stage. The number of steps was significantly higher on the suddenly narrowed path (11.3 ± 3.6) than on a straightly narrowed path (10.1 ± 3.2) at the time of final follow-up in the 26 patients (p < 0.001)., Conclusions: An increased number of steps associated with FOG, which was elicited by the suddenly narrowed path, might be one predictor of an upgrade of stage in patients with Hoehn-Yahr stage III PD., (© 2018 S. Karger AG, Basel.)

A continuous-flow synthesis of β-nitroolefins by using heterogeneous base catalysts has been developed. Although the use of an excess amount of nitro-donor such as nitromethane is required in conventional methods, nearly equimolar amounts of nitro-donors and carbonyl compounds are sufficient for high-yielding production of nitroolefins. Catalysts for this flow protocol are inexpensive and abundant, and high durability and high productivity were also realized by using an appropriate second support., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: The 2010 revisions to the McDonald criteria for the diagnosis of multiple sclerosis (MS) were recently published. One objective of the revision was to simplify the MRI criteria. The MRI criteria do not specify magnetic field strength. We studied whether there was any difference in diagnosis between brain 3.0-T and 1.5-T MRI according to the 2010 revisions of the McDonald criteria., Patients and Methods: We prospectively studied brain 3.0-T and 1.5-T MRI in 22 patients with MS. 1.5-T MRI was performed 24h after 3.0-T MRI, and the scanning protocol included contiguous axial sections of T2-weighted images (T2WI), T1WI, and enhanced T1WI. These two different MRI and neurological assessments were scheduled to be repeated 3 and 6 months after study entry., Results: The regions where MS lesions were better visualized on 3.0-T MRI tended to be in deep white matter on T2WI. Dissemination of lesions in space and time was similar for 3.0-T and 1.5-T MRI., Conclusion: Our study found no difference between brain 3.0-T and 1.5-T MRI. There was no apparent impact of brain 3.0-T MRI on the diagnosis of MS according to the 2010 version of the MRI criteria., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Considerable attention has focused on the prevention of dementia in terms of non-genetic risk factors, including midlife obesity, especially visceral obesity associated with hyperglycemia, hypertension, and hypercholesterolemia. Accumulating evidence has indicated that the increased insulin resistance in relation to visceral fat accumulation is potential risk of Alzheimer's disease (AD) and vascular dementia. Reducing the accumulating visceral fat may contribute to reduce the risk of on set and progression of AD and vascular dementia. Treatment with renin-angiotensin system blockers in hypertension might slow the rate of cognitive decline in patients with AD by modulating insulin resistance.

Background: Accumulating evidence indicates an association of Alzheimer's disease (AD) with the metabolic syndrome (MetS), characterized by visceral fat accumulation with insulin resistance and altered secretion of adipocytokines such as adiponectin and leptin. The renin-angiotensin system (RAS) regulates blood pressure and insulin resistance. Recent studies suggest that the RAS plays crucial roles in cognitive functions and that adipocytokines exert neuroprotective activity in the brain. We investigated whether RAS blockers (RASB) affect adipocytokines and cognitive function in patients with AD., Methods: We studied 78 patients with a diagnosis of probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition and 106 nondemented control subjects who visited our clinic with a main complaint of headache or dizziness. We examined retrospectively the effects of RASB on adipocytokines and cognitive decline in patients with AD who were divided into three groups: hypertension treated with RASB (HT-RASB; n = 17), hypertension treated with other antihypertensive drugs (HT-other; n = 34), and no hypertension (non-HT; n = 27)., Results: The HT-RASB group had a significantly higher serum leptin level and a relatively larger visceral fat area than the other groups, because of the bias toward patients with MetS in this group. The HT-RASB group also had a significantly lower immunoreactive insulin level, a relatively low homeostasis model assessment as an index of insulin resistance, and a relatively high serum adiponectin level among the three groups. Cognitive decline, estimated on the basis of the mean annual decline using the Hasegawa Dementia Scale score was significantly low in the HT-RASB group., Conclusion: Treatment with RASB might modulate serum adipocytokines and glucose homeostasis, potentially slowing cognitive decline in patients with AD., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Chiral bis-phosphoric acid 1 was designed to identify a new class of structural features in chiral Brønsted acid catalysts. X-ray diffraction analysis revealed the single atropisomer 1, bearing S axial chirality at 3,3'-biaryl substituents on (R)-binaphthyl and intramolecular hydrogen bonding between the two phosphoric acid moieties. The newly designed bis-phosphoric acid 1 was evaluated in the Diels-Alder reaction of α,β-unsaturated aldehydes 4 with 1-N-acylamino-1,3-butadienes 3. After systematic variation of the catalyst substituents, as well as the N-acyl substituents of 1,3-butadiene, the use of an N-Cbz amidodiene 3a in the presence of bis-phosphoric acid 1e with a 2,4,6-tri-isopropylphenyl group was found to be optimal to yield the 1S,6R enantiomeric product 5aa in a Diels-Alder reaction of acrolein (4a). Application of this method to substituted substrates was found to be an efficient approach to the enantioselective synthesis of 3- and 3,6-substituted cyclic formylcarbamates 5. The specific character as well as the utility of 1e was further established by comparing its enantioselectivity, absolute stereochemistry, and catalytic efficiency with those of mono-phosphoric acid 2., (© 2011 American Chemical Society)

Background and Purpose: Features of tumefactive demyelinating lesion (TDL) on magnetic resonance imaging (MRI) can facilitate the differential diagnosis of TDL and neoplastic lesions, but vary considerably among patients. The larger TDL grows, the more difficult it becomes to differentiate TDL from neoplastic lesions. The purpose of this study was to elucidate typical MRI features in 12 patients with large TDL (>30 mm in diameter)., Methods: We identified 12 patients with large TDL (six men, six women; age range 17-64 years, median age 27 years) and studied the clinical histories and the results of laboratory and various radiological studies in these patients. All cases of clinically definite multiple sclerosis were diagnosed in accordance with McDonald's revised criteria., Results: Common MRI features of large TDLs included variable degrees of mass effect (71%) and edema (100%), a T2 hypointense rim (79%), venular enhancement (57%), and peripheral restriction on diffusion-weighted images (50%). Ring enhancement (38%), open-ring enhancement (31%), or decreased N-acetylaspartate ratios on magnetic resonance spectroscopy (22%) were less frequently observed. Brain angiography demonstrated venous dilatations on and around the TDL., Conclusions: The diagnosis of large TDL is challenging. Our findings suggest that multiple venous dilatations on and around TDLs on angiography can facilitate diagnosis., (Copyright © 2010 by the American Society of Neuroimaging.)

Background: It is difficult to predict the risk of falling, especially in patients with good motor ability, and the mechanisms underlying the relation between gait patterns and falling in Parkinson's disease (PD) remain unclear. We investigated factors related to falling, including walking speed and time, in patients with Hoehn-Yahr stage III PD., Methods: We performed clinical assessments and evaluated balance in 30 patients with PD. Information on falling was obtained from questionnaires and personal interviews. Gait patterns were analyzed with the use of an originally designed, suddenly narrowed path., Results: Gait velocity was slower in fallers than in non-fallers (p = 0.047). Unified Parkinson's Disease Rating Scale part II (UPDRS part II) score, fear of falling, and gait velocity were significantly related to falling on analysis with a single logistic model. When a multiple logistic model was used, the UPDRS part II score was significantly related to falling (OR: 1.48, p = 0.037, 95% CI: 1.02-2.16)., Conclusions: Patients with Hoehn-Yahr stage III PD showed slow gait velocity attributed to fear of falling before arrival at a narrowed entrance or while walking on a narrowed path. The UPDRS part II score is significantly related to the risk of future falls., (Copyright © 2011 S. Karger AG, Basel.)

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C gamma (PKC gamma). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with increased kinase activity. Notably, one patient with a severe phenotype is the first homozygote for the mutation causing SCA14. We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (APTX), a DNA repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant PKC gamma, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin alpha, a nuclear import adaptor. Decreased nuclear APTX increased oxidative stress-induced DNA damage and cell death. Phosphorylation-resistant APTX, kinase inhibitors, and antioxidants may be therapeutic options for SCA14.

Objectives: Sleep attacks (SAs) in Parkinson's disease (PD) are rare, but clinically important because they significantly impair the daily lives of patients. Causes of SAs include long-term activation of dopaminergic (especially D3) receptors. Recent studies suggest that SAs in PD may be related to impairment of hypothalamic orexin neurons, similar to narcolepsy. Whether orexin is associated with long-term activation of dopaminergic receptors remains uncertain., Patients and Methods: We measured levels of orexin in samples of spinal cerebrospinal fluid (CSF) from 25 patients with PD, including 9 with excessive daytime sleepiness and 4 with SAs. Furthermore, in the four patients with SAs, the selective dopamine D1/D2 agonist pergolide was substituted for the causative drugs with D3 stimulatory activity, and CSF-orexin levels were measured before and after switching treatment., Results: In the 25 patients with PD, including the 4 patients with SAs, lower CSF-orexin levels were associated with a longer disease duration, which has been linked to a higher incidence of SAs. Switching treatment to pergolide significantly increased CSF-orexin levels and completely resolved SAs in the four patients with PD., Conclusion: Despite the small number of patients studied, our results suggest that orexin transmission is most likely involved in SAs in PD and that abrogation of D3 receptor stimulation may increase orexin and thereby inhibit SAs.

Autosomal dominant cerebellar ataxia (ADCA) includes heterogeneous neurodegenerative diseases with or without various neurological signs and symptoms. Ishikawa et al reported a new type of ADCA, named chromosome16q22.1 linked ADCA (16q-ADCA), attributed to a heterozygous C→T substitution in the 5' non-coding region of puratrophin-1 gene. We searched for this mutation in168 patients from 129 families with ADCA and found it in six patients. The patients generally showed late onset pure cerebellar ataxia similar to previous reports but two had mild axonal neuropathy and orthostatic hypotension (OH). Our results suggest that 16q-ADCA shows a broader clinical presentation than previously thought.

Triple A syndrome is an autosomal recessive neurological disease, mimicking motor neuron disease, and is caused by mutant ALADIN, a nuclear-pore complex component. We recently discovered that the pathogenesis involved impaired nuclear import of DNA repair proteins, including DNA ligase I and the cerebellar ataxia causative protein aprataxin. Such impairment was overcome by fusing classical nuclear localization signal (NLS) and 137-aa downstream sequence of XRCC1, designated stretched NLS (stNLS). We report here that the minimum essential sequence of stNLS (mstNLS) is residues 239-276, downsized by more than 100 aa. mstNLS enabled efficient nuclear import of DNA repair proteins in patient fibroblasts, functioned under oxidative stress, and reduced oxidative-stress-induced cell death, more effectively than stNLS. The stress-tolerability of mstNLS was also exerted in control fibroblasts and neuroblastoma cells. These findings may help develop treatments for currently intractable triple A syndrome and other oxidative-stress-related neurological diseases, and contribute to nuclear compartmentalization study.

Objectives: Most abnormalities on magnetic resonance imaging (MRI) in limbic encephalitis involve the medial temporal lobes and are associated with memory impairment. Recent neuroimaging studies have shown that not only the medial temporal lobes, but also the prefrontal lobes, contribute to cognitive functions., Methods: We describe a case of limbic encephalitis with abnormalities in the medial temporal lobes on MRI and decreased accumulation of radionuclide in the prefrontal regions on SPECT., Results: The patient had persistent retrograde amnesia, particularly affecting remotely acquired memories including public events and autobiographical memories., Conclusion: Disruption of the prefrontal-medial temporal circuitry by intense inflammation may have initiated the metabolic changes in the prefrontal cortices, which may exacerbate amnesia.

We describe the findings on single photon emission computed tomography (SPECT) in a patient who had genetically definite megalencephalic leukoencephalopathy with subcortical cysts. Technetium-99m-ethyl cysteinate dimer SPECT revealed hypoperfusion in the cerebral white matter, which had shown high signal intensity on magnetic resonance imaging (MRI) T2 images. Hypoperfusion was also unexpectedly found in the frontal cortices, which showed no abnormalities on MRI. This frontal abnormality corresponded clinically to a low score on the frontal assessment battery. Decreased GABA receptor density as suggested by (123)I-Iomazenil SPECT provided further evidence of cortical neuron dysfunction. Although confirmation must await future larger-scale SPECT and functional studies, our findings suggest that SPECT can be used to non-invasively monitor in vivo cortical function in this disease.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is caused by mutations in the gene encoding aprataxin (APTX). Although several in vitro findings proposed that impaired enzymatic activities of APTX are responsible for EAOH/AOA1, potential instability of mutant proteins has also been suggested as the pathogenesis based on in vivo finding that mutant proteins are almost undetectable in EAOH/AOA1 tissues or cells. The present study aimed to experimentally prove instability of mutant proteins in neuronal cells, the cell type preferentially affected by this disease. Results of pulse-chase experiments demonstrated that all of the disease-associated mutants had extremely shorter half-lives than the WT. We further found that mutants were targeted for rapid proteasome-mediated degradation. These results help establish pathogenic and physiological protein characteristics of APTX in neuronal cells.

We describe a successful outcome of long-term interferon beta-1b therapy in a patient who had multiple sclerosis (MS) with positive serum autoantibody to muscle acetylcholine receptor (AChR-Ab). Because of the reported possible causative linkage between interferon beta-1b and myasthenia gravis (MG), the presence of the pathogenic antibody complicated therapeutic strategies. We carefully observed the patient for further 6 months before the treatment, excluding symptomatic MG. The interferon beta-1b therapy then provided a clinical benefit. Hopefully this report will allow MS patients in similar situations to make more rapid, unprejudiced judgments than our patients.

Objective: Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive form of cerebellar ataxia. The causative protein for EAOH/AOA1, aprataxin (APTX), interacts with X-ray repair cross-complementing 1 (XRCC1), a scaffold DNA repair protein for single-strand breaks (SSBs). The goal of this study was to prove the functional involvement of APTX in SSB repair (SSBR)., Methods: We visualized the SSBR process with a recently developed laser irradiation system that allows real-time observation of SSBR proteins and with a local ultraviolet-irradiation system using a XPA-UVDE cell line that repairs DNA lesions exclusively via SSBR. APTX was knocked down using small interference RNA in the cells. Oxidative stress-induced DNA damage and cell death were assessed in EAOH fibroblasts and cerebellum., Results: Our systems showed the XRCC1-dependent recruitment of APTX to SSBs. SSBR was impaired in APTX-knocked-down cells. Oxidative stress in EAOH fibroblasts readily induced SSBs and cell death, which were blocked by antioxidants. Accumulated oxidative DNA damage was confirmed in EAOH cerebellum., Interpretation: This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.

Background and Purpose: Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia. Techniques for the quantitative assessment of neurodegenerative lesions remain to be established in this disease. We attempted to quantify global and region-specific neurodegeneration in DRPLA using analysis of apparent diffusion coefficient (ADC) maps., Methods: Diffusion-weighted images (b = 1000 s/mm(2)) by echo-planar sequences were obtained with the use of a 1.5T clinical scanner. Whole-brain histogram and region of interest (ROI) analyses of ADC values as well as conventional MR imaging studies were performed in 6 patients with genetically confirmed DRPLA., Results: Histograms demonstrated significantly higher mean ADC values in the patients than in age- and sex-matched control subjects (P < .01). ROI analysis revealed that the patients had significantly higher ADC values in the cerebellum and globus pallidus, preferentially affected regions (P < .05), but not in the thalamus, the region relatively spared in this disease. ADC values in the white matter were higher only in patients with adult-onset disease. Histogram analyses could more sensitively identify abnormalities than ROI analyses, because the former avoided errors associated with setting ROIs and thus had smaller P values on statistical analysis than the latter., Conclusions: Histogram ADC analyses were more sensitive for the detection of neurodegeneration in DRPLA than ROI analyses, whereas ROI analyses revealed regional alterations reflecting the distribution of pathologic changes. Thus, histogram and ROI analyses complement each other and may permit the sensitive, quantitative evaluation of neurodegeneration in DRPLA, especially that involving the globus pallidus showing normal T2 signals.

Japanese encephalitis (JE) virus is a mosquito-borne virus belonging to the flavivirus family, including the West Nile and St Louis encephalitis viruses endemic to North America. JE virus is prevalent in East Asian countries and can cause acute lethal encephalitis. Although vaccination programs have decreased the incidence of JE in Japan, the cases that do occur are often fatal or associated with considerable clinical sequelae. We report, for the first time to our knowledge, a patient who had repetitive bouts of hyperthermia in the summertime after recovery from acute JE. An insulin challenge test revealed only marginal increases in the levels of beta-endorphin and growth hormone, indicating partial medial hypothalamic dysfunction. Magnetic resonance imaging showed T2 hyperintensity in both thalamic paraventricular subcortical regions, known to project to the hypothalamic paraventricular nucleus. We thus attributed the episodes of hyperthermia to secondary hypothalamic impairment with thalamic lesions.

Triple A syndrome is an autosomal recessive neuroendocrinological disease caused by mutations in a gene that encodes 546 amino acid residues. The encoded protein is the nucleoporin ALADIN, a component of nuclear pore complex (NPC). We identified a mutant ALADIN(I482S) that fails to target NPC and investigated the consequences of mistargeting using cultured fibroblasts (I482Sf) from a patient with triple A syndrome. ALADIN(I482S) affected a karyopherin-alpha/beta-mediated import pathway and decreased nuclear accumulations of aprataxin (APTX), a repair protein for DNA single-strand breaks (SSBs), and of DNA ligase I in I482Sf. This decrease was restored by wild-type ALADIN. ALADIN(I482S) had no effect on imports of M9/kap-beta2, BIB/kap-beta3, histone H1/importin 7, the ubiquitin conjugating enzyme UbcM2/importin 11, or the spliceosome protein U1A, indicating that ALADIN(I482S) selectively impaired transport of discrete import complexes through NPC. Cell survival assay showed hypersensitivity of I482Sf to l-buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent. BSO decreased nuclear APTX and ligase I levels in I482Sf and normal control fibroblasts, but increased SSBs only in I482Sf. These observations implied that I482Sf are hypersensitive to BSO and no longer sufficiently repair SSBs. Consistent with this notion, I482Sf transfected with both APTX and ligase I had increased resistance to BSO, whereas I482Sf transfected with LacZ vector remained hypersensitive to BSO. We propose that oxidative stress aggravates nuclear import failure, which is already compromised in patient cells. Consequent DNA damage, beyond the limited capacity of DNA repair proteins, i.e., APTX and ligase I, may participate in triggering cell death.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurological disorder caused by a CAG repeat expansion in the DRPLA gene encoding polyglutamine (polyQ). Although previous experimental studies have demonstrated that histone deacetylase (HDAC) inhibitors are therapeutically active, known HDAC inhibitors have considerable adverse effects clinically. To identify new HDAC inhibitors for the treatment of DRPLA, we evaluated a new series of HDAC inhibitors, N-hydroxycarboxamides, with our drug screening system, which uses neuronal PC12 cells stably transfected with a part of the DRPLA gene. We found that two of four N-hydroxycarboxamides significantly reduced polyQ-induced cell death. The essential structure of these compounds is a hydroxamic acid residue, which is shared with trichostatin A, a known HDAC inhibitor. Although our study showed mild neuroprotective effects, further structural modification of compounds that retain this residue may decrease cytotoxicity and increase protective activity against polyQ toxicity.

We investigated three genotypes (AA, AT, and TT) produced by signal peptide polymorphism of the alpha-1-antichymotrypsin (ACT) gene in 105 patients with multiple system atrophy (MSA) and age-matched controls. The frequency of ACT-AA genotype was significantly higher in patients with MSA (20.0%) than in controls (10.5%). The onset of MSA was significantly earlier and the disease progressed significantly faster in patients with ACT-AA genotype than in those with non-ACT-AA genotypes. The ACT concentration in cerebrospinal fluid was increased in patients with ACT-AA. To our knowledge, this is the first study to show that the ACT-AA genotype is a risk factor and modulating factor for MSA. Our findings suggest the involvement of ACT-relating inflammatory process in the pathogenesis of MSA.

The etiology of Parkinson's disease (PD) remains unclear; however, generation of reactive oxygen species during oxidation of dopamine (DA) could be one of the factors leading to selective loss of nigral dopaminergic neurons in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake and partition DA from neuronal cytoplasm into synaptic vesicles. Therefore, alterations of VMAT2 function may cause cytoplasmic accumulation of free DA, toxic to dopaminergic neurons. Upstream of a putative promoter region of the VMAT2 gene, there exist polymorphic sequences consisting of two microsatellites, (CA)n and (GA)n. We performed a case-control study of this polymorphic region to determine whether the VMAT2 gene is related to PD. We found six genotypes; however, there was no significant difference in the allele frequencies between patients with PD and control subjects. Our data suggest that the polymorphic region of the VMAT2 gene studied here is not closely related to PD.

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS.

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis induced by various types of Alzheimer's disease-related insults. We have previously indicated that HN increases cellular ATP levels and speculated that this peptide may rescue energy-deficient cells in mitochondrial disorders. Here, we report, for the first time, increased HN expression in skeletal muscles from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). HN was strongly positive in all ragged-red fibers (RRFs) and some non-RRFs, and most of them were type 1 fibers generally requiring higher energy than type 2 fibers. HN in these fibers was localized in mitochondria. HN expression was also increased in small arteries that strongly reacted for succinate dehydrogenase. Our experiments on muscular TE671 cells indicated the possibility that synthesized HN increases cellular ATP levels by directly acting on mitochondria. From these in vivo and in vitro findings, we propose that HN expression might be induced in response to the energy crisis within affected fibers and vessels in MELAS muscles and further be a possible therapeutic candidate for MELAS.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal-dominant neurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.

Purpose: To quantify impairment of the basal ganglia (globus pallidus and thalamus) in adult-onset dentatorubral-pallidoluysian atrophy (DRPLA)., Methods: Five patients with genetically definite adult-onset DRPLA (aged 51 to 65 years, mean 55.6 years) and 5 age- and sex-matched healthy controls underwent conventional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) of the brain in the voxels predominantly containing the globus pallidus or the thalamus., Results: Conventional MRI studies showed apparently normal intensities in the globus pallidus and thalamus. MRS showed that the choline (Cho)/creatine (Cr) ratio for the patients' globus pallidus, the region preferentially affected in DRPLA, was significantly higher than that in the controls (p<0.05). The N-acetylaspartate (NAA)/Cr ratio for the globus pallidus and the Cho/Cr and NAA/Cr ratios for the thalamus, the region relatively spared in this disease, did not differ significantly between the patients and controls., Conclusions: MRS may sensitively and specifically detect biochemical alterations in susceptible regions of patients with adult-onset DRPLA.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is an autosomal recessive form of cerebellar ataxia that occurs most commonly in Japan but is also frequently seen in Europe. This disease is caused by mutations in the aprataxin gene, but the functions of the gene product and the pathogenic mechanism remain unclear. The present study provides experimental evidence that the histidine triad (HIT) domain in aprataxin has enzymatic activity that is negatively regulated by the intramolecular interaction of the N-terminal domain. Furthermore, the reduction in HIT activity seen in all the disease-causing mutants tested, and the correlation between the reduced activity and the severe phenotype, support that aprataxin's physiological function is associated with its catalytic activity. Our findings suggest that the clinical phenotypes are caused by a loss of aprataxin function, attributable largely to diminished HIT activity but partially to a reduction in the levels of gene products.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is one of the most common forms of autosomal recessive cerebellar ataxia. We identified six new alternative transcripts produced by the aprataxin gene responsible for EAOH. Total eight transcripts encoded truncated proteins that were located within the nucleus or cytoplasm and showed different binding abilities to wild-type (WT) aprataxin. Thus, the alternative splicing increases the molecular diversity of aprataxin and the expression profiles of these transcripts in various tissues may be related to the tissue-specific phenotypes.

The neurotoxicity of amyloid beta (Abeta) is widely believed to play a seminal role in neurodegeneration in Alzheimer's disease. We examined the effect of Chrysamine G (CG) on such neurotoxicity using the specific measurement of surviving neurons. CG was found to reduce the neurodegeneration induced by both the active short fragment of Abeta(25-35) and full-sized Abeta(1-40). In this study, we synthesized a new chemical compound from a monovalent structure of CG (hCG), with a lower affinity for Abeta, and compared its activity with that of CG. Both CG and hCG were found to be equally efficacious in reducing Abeta-induced neuronal death at a concentration of 0.1-1 microM, indicating that the mechanism of action for CG was not due to its chelating activity, but rather due to its anti-oxidant activity., (Copyright 2002 Elsevier Science Ireland Ltd.)

A 15-year-old boy developed ataxic gait, diplopia and hoarseness. Within 3 days after the onset, he had additional symptoms of dysphagia and dysarthria. He was admitted to our hospital 7 days after the onset of the disease. On admission, he had total ophthalmoplegia, ataxia, areflexia, facial diplegia, bulbar palsy and weakness of the neck and upper arms. Serum anti-GQ 1 b and anti-GT 1 a antibodies were significantly elevated. A diagnosis of Fisher syndrome associated with pharyngeal-cervical-brachial weakness was made. He was placed on a high dose of intravenous immunoglobins (12.5 g/day x 2 days) and had steroid pulse therapy (methylprednisolone 1 g x 3 days), which resulted in an almost complete recovery. There have been no reports of Fisher syndrome associated with brachio-pharyngeal-palsy. As in the case of the pharyngeal-cervical-brachial variant of Guillain Barré syndrome, anti-GT 1 a antibodies may be associated with Fisher syndrome with pharyngeal-cervical-brachial weakness.