Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Plasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI). METHODS: The study was a multicenter, randomized, double-blind, placebo-controlled trial of 24weeks. Participants were 328 patients aged 60 to 85years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945. FINDINGS: Of 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20≤MMSE-J≤23) and MCI (24≤MMSE-J≤27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P=0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77years in the treatment group, and the between-group differences were statistically significant in females (P=0.017) and in those aged below 77years (P=0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group. INTERPRETATION: Oral administration of scallop-derived purified Pls may improve cognitive functions of mild AD. FUNDING: The Japanese Plasmalogen Society.

Timed Up and Go test, atrophy of medial temporal areas and cognitive functions in community-dwelling older adults with normal cognition and mild cognitive impairment.

AIM: This study aimed to ascertain if performance on the Timed Up and Go (TUG) test is associated with indicators of brain volume and cognitive functions among community-dwelling older adults with normal cognition or mild cognitive impairment. METHODS: Participants were 80 community-dwelling older adults aged 65-89years (44 men, 36 women), including 20 with mild cognitive impairment. Participants completed the TUG and a battery of cognitive assessments, including the Mini-Mental State Examination (MMSE), the Logical Memory I and II (LM-I, LM-II) subtests of the Wechsler Memory Scale-Revised; and the Trail Making Test A and B (TMT-A, TMT-B). Bilateral, right- and left-side medial temporal area atrophy as well as whole gray and white matter indices were determined with the Voxel-based Specific Regional Analysis System for Alzheimer's Disease. We divided participants into three groups based on TUG performance: "better" (≤6.9s); "normal" (7-10s); and "poor" (≥10.1s). RESULTS: Worse TMT-A and TMT-B performance showed significant independent associations with worse TUG performance (P<0.05, P<0.01 for trend, respectively). After adjusting for covariates, severe atrophy of bilateral, right-, and left-side medial temporal areas were significantly independently associated with worse TUG performance (P<0.05 for trend). However, no significant associations were found between MMSE, LM-I, LM-II, whole gray and white matter indices, and TUG performance. CONCLUSIONS: Worse TUG performance is related to poor performance on TMT-A and TMT-B, and is independently associated with severe medial temporal area atrophy in community-dwelling older adults.

A Randomized Controlled Trial of Subcutaneous Apomorphine for Parkinson Disease: A Repeat Dose and Pharmacokinetic Study.

OBJECTIVES: This study is the first controlled trial to evaluate the efficacy and safety of subcutaneous apomorphine in Japanese patients with advanced Parkinson disease. METHODS: A phase II, multicenter, randomized, double-blind, parallel-group trial was undertaken in 16 patients with advanced Parkinson disease with wearing-off phenomenon to compare subcutaneous apomorphine versus placebo. The maintenance dose of apomorphine (1-6 mg per dose), determined individually for each patient by titration, was additionally administered 3 times at 2-hour intervals in the multiple-dose phase in which pharmacokinetics was evaluated. RESULTS: The mean (SD) maintenance apomorphine dose was 3.4 (1.4) mg (range, 2-6 mg). The change in the Unified Parkinson's Disease Rating Scale motor score 20 minutes after maintenance dose administration was significantly greater in the apomorphine group than in the placebo group (least squares mean, -24.0 vs -4.1, P = 0.021). Apomorphine treatment resulted in an "on" state approximately 20 minutes after dose administration, lasting for approximately 60 minutes. Apomorphine was rapidly absorbed, with the maximum plasma concentration (Cmax) reached in 0.367 to 0.383 hour. It was quickly eliminated with a half-life of 0.520 to 0.793 hour, suggesting no accumulation during multiple-dose phase. The Cmax of apomorphine at effective dose was presumed to be approximately 20 ng/mL. Apomorphine was well tolerated. CONCLUSIONS: Subcutaneous apomorphine is expected to provide a new treatment option in Japan as a rescue therapy. Two-hour interval injections did not cause reduced responses, and effective blood concentration was presumed to be approximately 20 ng/mL similar, to the previous study conducted at North America.

Predictors of the emergence of apathy after bilateral stimulation of the subthalamic nucleus in patients with Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a valid therapeutic tool that ameliorates motor symptoms in patients with Parkinson's disease (PD). However, apathy is one of the neuropsychiatric complications that may occur after STN-DBS surgery, and this may adversely influence the quality of life of patients despite significant motor improvement. OBJECTIVE: This study aimed to elucidate preoperative predictive factors for the presence of postoperative apathy in patients treated with STN-DBS. METHODS: Twenty-five consecutive PD patients receiving bilateral STN-DBS were recruited. The assessment instruments include modified Hoehn & Yahr stages, Unified Parkinson's Disease Rating Scale motor (part III) and dyskinesia (part IVa) scores, Parkinson's Disease Questionnaire-39 scores, Self-Rating Depression Scale scores, and Apathy Scale scores. Predictive factors for postoperative apathy were assessed. RESULTS: While STN-DBS resulted in a significant improvement in motor symptoms, six patients (24%) developed significant apathy after surgery. In multiple logistic regression analyses, preoperative severity of dyskinesia was found to be an independent predictor for the acute phase of postoperative apathy with STN-DBS (odds ratio = 89.993, p = 0.003). CONCLUSIONS: This study suggests that preoperative dyskinesia may predict postoperative apathy in the acute phase in patients with PD treated with STN-DBS. The pathogenesis of postoperative apathy remains unknown, but in patients with severe dyskinesia before STN-DBS, attention should be given to monitoring for postoperative apathy.

Prediction of outcomes in MCI with (123)I-IMP-CBF SPECT: a multicenter prospective cohort study.

OBJECTIVE: The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of (123)I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and (123)I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline (123)I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. RESULTS: Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). CONCLUSIONS: (123)I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.

MDR1 C3435T polymorphism and interaction with environmental factors in risk of Parkinson's disease: a case-control study in Japan.

It has been suggested that P-glycoprotein (P-gp), the product of multidrug resistance 1 (MDR1) gene, regulates the brain entry of various xenobiotics. Impaired function of P-gp may be associated with an increased risk of Parkinson's disease (PD). The aim of this study was to investigate the impact of a MDR1 C3435T polymorphism on PD risk alone or in combination with environmental factors. A total of 238 patients with PD and 368 controls were genotyped for the MDR1 C3435T polymorphism. Subjects with the TT genotype of the C3435T polymorphism showed a nonsignificantly increased risk of PD [odds ratio (OR)=1.49, 95% confidence interval (CI)=0.85-2.25] compared with those with the CC genotype. A gene-environment interaction was suggested, with a combination of at least one T allele and ever drinking conferring significantly higher risk (OR=1.83, 95% CI=1.07-3.15, p=0.029), compared with the CC genotype and never drinking. No significant interaction of smoking or occupational pesticide use with the C3435T polymorphism was observed. Our results suggest that the C3435T polymorphism may not play an important role in PD susceptibility in Japanese. Evidence of an interaction between the C3435T polymorphism and alcohol consumption was suggested.

[Primary central nervous system lymphoma: a case report and evaluation of the diagnostic value of IL-10 level in the cerebrospinal fluid].

We report a case of primary central nervous system lymphoma (PCNSL) that presented with visual disturbance. A 76-year-old man developed decreased bilateral visual acuity. He was diagnosed with bilateral retrobulbar neuritis by an ophthalmologist. Treatment with high-dose corticosteroids was initiated and resulted in mild improvement of visual acuity. However, the patient gradually became apathetic and bradykinetic, experiencing difficulty performing the activities of daily living; he was admitted to our hospital because of this progressive illness. Neurological examination revealed bradyphrenia and bradykinesia with frontal lobe release signs, disorientation, and ideomotor apraxia. Magnetic resonance imaging showed abnormal signals in the bilateral basal ganglia and thalamus. Cerebrospinal fluid (CSF) examination revealed no pleocytosis and slightly elevated protein levels: ß2-microglobulin level was mildly increased, and IL-10 level in the CSF was markedly elevated. These findings suggested a diagnosis of PCNSL, and a brain biopsy specimen was obtained from the left caudate head. Pathological findings indicated diffuse large B-cell lymphoma. Nonspecific neurological manifestations and radiological findings can make the diagnosis of PCNSL difficult and result in delayed diagnosis. Visual impairment has been suggested as a feature of PCNSL, and an elevated IL-10 level in the CSF may be a useful marker for diagnosing PCNSL.

Refractory acute disseminated encephalomyelitis with anti-galactocerebroside antibody.

Acute disseminated encephalomyelitis causes multifocal demyelination in the central nerve system. Although this disease generally responds well to steroid therapy, it is occasionally steroid-resistant, leading to poor outcomes. Serological markers of prognosis are currently unavailable. We measured anti-glycolipid antibodies in 25 consecutive patients with acute disseminated encephalomyelitis, and found that four patients were positive for anti-galactocerebroside antibodies. All four patients had a poor response to steroids. We summarize clinical information on these four patients and three similar patients reported previously. This is the first report to describe concomitant involvement of the central nerve system and peripheral nervous system in anti-galactocerebroside antibody-associated acute disseminated encephalomyelitis, consistent with the location of galactocerebroside, and to document a dramatic response to repeated intravenous immunoglobulin therapy after unsuccessful steroid treatment in one patient.

Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a Japanese population.

Several genome-wide association studies and case-control studies have investigated the relationships between single nucleotide polymorphisms (SNPs) in the BST1 gene and Parkinson's disease (PD), but the results have been inconsistent. We examined the relationships between SNPs rs11931532, rs12645693, and rs11724635 and the risk of sporadic PD in Japan. Included were 229 cases within 6years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. SNPs rs11931532 and rs12645693 were not significantly related to sporadic PD. Compared with a reference group of subjects with the CC genotype of SNP rs11724635, those with the AA genotype had a marginally significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95% CI: 0.95-2.61, P=0.08). No significant interactions were found between BST1 SNP rs11724635 and smoking or caffeine intake with respect to sporadic PD. The current study failed to detect significant relationships between BST1 SNPs rs11931532, rs12645693, and rs11724635 and sporadic PD; however, the relationship between SNP rs11724635 and sporadic PD was of borderline significance. We do not find evidence for interactions between smoking or caffeine intake and SNP rs11724635 affecting sporadic PD.

[Reversible posterior leukoencephalopathy syndrome (RPLS) associated with Wegener's granulomatosis: a case report and review of the literature].

Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by sudden onset of headaches, visual disorders, decreased consciousness, and convulsion associated with brain edema occurring in the occipital lobe. Several different causes including malignant hypertension, eclampsia, renal failure, and use of immunosuppressants have been reported in patients with RPLS. Our patient was a 45-year-old man who presented with fever, arthralgia, and melena approximately 1 year previously and received the diagnosis of Wegener's granulomatosis. Following steroid therapy his symptoms ameliorated; however, during the course of the illness he developed tension-type headache, nausea and vomiting, and bilateral loss of visual acuity. On admission, his visual acuity was markedly decreased without any abnormal findings in the optic fundus. There was no neurological deficit except the visual symptoms. Imaging of the head revealed multiple lesions in the white and gray matter of the bilateral occipital lobe and cerebellar hemisphere, which proved vasogenic edematous lesions by the hyperintense signals in T(2) weighted, FLAIR, and diffusion weighted images, suggesting the diagnosis of RPLS. Treatment with antihypertensive drug and glycerol was initiated and the patient made a full clinical recovery within a few days. The pathogenesis of RPLS is not fully understood. Our case was not on any immunosuppressant therapy at the time of onset of RPLS, and his hypertension was mild and transient without renal failure. It is possible that RPLS in our patient might be a manifestation related to Wegener's granulomatosis-mediated vascular endothelial injury.

Changes in phospholipid composition of erythrocyte membrane in Alzheimer's disease.

BACKGROUND: There are several reports indicating a decrease of ethanolamine plasmalogen (pl-PE) in brain tissues and in serum of patients with Alzheimer's disease (AD). The present study aimed to examine the composition of erythrocyte phospholipids including pl-PE in patients with AD. METHOD: A high-performance liquid chromatography (HPLC) method that can separate intact plasmalogens and all other phospholipid classes by a single chromatographic run was used. RESULTS: The ratios of pl-PE, phosphatidylethanolamine (PE) and phosphatidylserine (PS) to sphingomyelin were low as compared to those of the age-matched controls. CONCLUSION: These changes in erythrocyte phospholipids may reflect changes induced by oxidative stress, indicating the presence of high oxidative stress in the peripheral blood of AD patients.

UCHL1 S18Y variant is a risk factor for Parkinson's disease in Japan.

BACKGROUND: A recent meta-analysis on the UCHL1 S18Y variant and Parkinson's disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan. METHODS: Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake. RESULTS: Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 - 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD. CONCLUSIONS: This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake.

Multicentre population-based dementia prevalence survey in Japan: a preliminary report.

Community-based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimer's disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5-year age strata between 65 and 99 years was 5.8-77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011-2012.

Anti-cholinergics for axial symptoms in Parkinson's disease after subthalamic stimulation.

OBJECTIVE: We studied the effect of anti-cholinergic therapy on axial symptoms that show a tendency to worsen over time after deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson's disease (PD). PATIENTS AND METHODS: We conducted a prospective study of 20 consecutive patients treated with the anti-cholinergic agent trihexyphenidyl after bilateral STN-DBS and assessed the effect of anti-cholinergic therapy on parkinsonism 1 month after its initiation using the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: After a mean post-operative follow-up period of 22.3 months, the scores of axial symptoms on UPDRS part II (ADL score) and part III (motor score) deteriorated by 87% and 54% (baseline), respectively, compared with the pre-operative scores (P < 0.001 for both comparisons). After adding trihexyphenidyl to dopaminergic medication with stimulation, the scores of axial symptoms on UPDRS part II and part III improved from baseline by 33% and 39%, respectively (P < 0.001 for both comparisons). CONCLUSIONS: Our findings demonstrated that the anti-cholinergic agent trihexyphenidyl shows positive effect for a patient population developing deterioration of axial symptoms after STN-DBS. The results in the present study may provide insights into the mechanism of emergence or progression of axial symptoms in patients with PD after STN-DBS.

[Primary clivus diffuse large B cell lymphoma presenting with posterior neck pain and bilateral abducens nerve palsy].

Bilateral abducens nerve palsy is an unusual clinical presentation, which could be caused by stroke, aneurysm, trauma and malignant neoplasm. We describe here a patient with bilateral abducens nerve palsy caused by large B cell lymphoma originated from clivus. An 83-year-old woman admitted to our hospital because of diplopia and severe posterior neck pain. Her diplopia developed one month before and progressed to her admission. Neurological examination revealed bilateral abducens nerve palsy. Brain MRI with enhancement lesion in the clivus, suggesting that bilateral petroclival segment of the abducens nerves were affected by the lesion. Biopsied was performed via a transsphenoidal approach, and histological diagnosis was made as diffuse large B cell lymphoma. She received oral corticosteroid administration combined with radiation therapy. After initiation of the treatment, posterior neck pain was resolved and tumor size was reduced in the repeated brain MRI. However, diplopia and bilateral abducens nerve palsy were still unresolved. Although malignant lymphoma originated at the clivus is uncommon, according to a presenting case as well as previously reported cases, lymphoma can present as an isolated involvement in the clivus associated with headache, and bilateral abducens nerve palsy. It is suggested that the clivus tumor affected the petroclival segment of abducent nerve in our case.

Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients.

Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-ß increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD.

SNCA polymorphisms, smoking, and sporadic Parkinson's disease in Japanese.

Several case-control studies and genome-wide association studies have examined the relationships between single nucleotide polymorphisms (SNPs) in the SNCA gene and Parkinson's disease (PD), and have provided inconsistent results. We investigated the relationships between SNPs rs356229, rs356219, rs356220, rs7684318, and rs2736990 and the risk of sporadic PD in Japan using data from a multicenter hospital-based case-control study. Included were 229 cases within 6 years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. Based on the recessive model, compared with subjects with the CC or CT genotype of SNP rs356220, those with the TT genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.42 (95% CI: 1.002-2.02). In the additive model, SNP rs2736990 was significantly related to the risk of sporadic PD: the adjusted OR was 1.30 (95% CI: 1.002-1.68). There were no significant relationships between SNP rs356229, rs356219, or rs7684318 and the risk of sporadic PD in any genetic model. The additive interactions between SNPs rs356219 and rs356220 and smoking with respect to sporadic PD were significant although the multiplicative interactions were not significant. This study suggests that SNCA SNPs rs356220 and rs2736990 are significantly associated with the risk of sporadic PD in Japanese. We also present new evidence for biological interactions between SNPs rs356219 and rs356220 and smoking that affect sporadic PD.

Mitsugumin 29 is transcriptionally induced in senile plaque-associated astrocytes.

Astrocytes associated with beta-amyloid (Aß)-deposited senile plaques are a common neuropathological feature of Alzheimer's disease (AD). There is little doubt that the association of Aß with the major component in the central nervous system cells significantly influences disease progression, however, the molecular mechanisms by which Aß contributes to the astrocyte-mediated neuropathological changes have not been well established. In an effort to identify astrocyte-derived molecules that may be closely associated with exacerbation of AD, we identified a novel Aß-induced rat gene, whose mouse counterpart, mitsugumin 29 (MG29), is known to be involved in intracellular Ca²âº homeostasis in skeletal muscle. To evaluate the roles of human MG29 in AD, we investigated its expression in AD brain. In non-AD brains, MG29 mRNA has been detected in neurons, but not in quiescent astrocytes. On the contrary, in AD brains, MG29 is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Human MG29-transfected cells express the protein in the endoplasmic reticulum and the level of expression is involved in Ca²âº-dependent exocytosis mechanisms. Increased MG29 expression in senile plaques-associated activated astrocytes suggests that intracellular Ca²âº turnovers may be changed in these astrocytes. This might be related in sustained Ca²âº-dependent exocytosis of various transmitters including glutamate, leading to the acceleration of neurodegeneration in the lesion observed in AD.

Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population.

BACKGROUND: Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. METHODS: We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. RESULTS: Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. CONCLUSIONS: The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.

Occupational risk factors for Parkinson's disease: a case-control study in Japan.

BACKGROUND: The evidence for associations between occupational factors and the risk of Parkinson's disease (PD) is inconsistent. We assessed the risk of PD associated with various occupational factors in Japan. METHODS: We examined 249 cases within 6 years of onset of PD. Control subjects were 369 inpatients and outpatients without neurodegenerative disease. Information on occupational factors was obtained from a self-administered questionnaire. Relative risks of PD were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) based on logistic regression. Adjustments were made for gender, age, region of residence, educational level, and pack-years of smoking. RESULTS: Working in a professional or technical occupation tended to be inversely related to the risk of PD: adjusted OR was 0.59 (95% CI: 0.32-1.06, P = 0.08). According to a stratified analysis by gender, the decreased risk of PD for persons in professional or technical occupations was statistically significant only for men. Adjusted ORs for a professional or technical occupation among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed (P = 0.048 for homogeneity of OR). In contrast, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively. No statistical significance was seen in data concerning exposure to occupational agents and the risk of PD, although roughly a 2-fold increase in OR was observed for workers exposed to stone or sand. CONCLUSION: The results of our study suggest that occupational factors do not play a substantial etiologic role in this population. However, among men, professional or technical occupations may decrease the risk of PD.