The effects of chronic subthalamic stimulation on nonmotor symptoms in advanced Parkinson's disease, revealed by an online questionnaire program.

BACKGROUND: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson's disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. METHODS: We developed an online PC-based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. RESULTS: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. CONCLUSION: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.

Vitamin D receptor gene polymorphisms, smoking, and risk of sporadic Parkinson's disease in Japan.

Epidemiological evidence on the relationships between the vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), and rs2228570 (FokI) and Parkinson's disease (PD) is inconsistent. We investigated these relationships in 229 sporadic PD patients within six years of onset in Japan. Controls were 357 patients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. A significant inverse association was found between SNP rs2228570 and the risk of sporadic PD under the additive but not the co-dominant or dominant model (P=0.048); however, this fell below significance after adjustment for multiple comparisons (adjusted P=0.46). No significant relationships were found between SNPs rs731236, rs7975232, or rs1544410 and the risk of sporadic PD in any genetic model. VDR haplotypes inferred in the current study were not associated with sporadic PD. Compared with subjects with the GA or AA genotype of SNP rs2228570 who had ever smoked, those with the GG genotype who had never smoked had a 3.78-fold increased risk of sporadic PD; however, no significant interaction was observed. VDR SNP rs2228570 may be associated with sporadic PD in Japan. Smoking did not significantly modify the relationship between SNP rs2228570 and sporadic PD.

PARK16 polymorphisms, interaction with smoking, and sporadic Parkinson's disease in Japan.

Epidemiological evidence on the relationships between PARK16 single nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) is inconsistent. We examined this issue in Japan. Included were 229 cases within six years of PD onset. Controls were 356 patients without neurodegenerative disease. Compared with subjects with the AA genotype of SNP rs823128, those with the AG genotype, but not the GG genotype, had a significantly reduced risk of sporadic PD. Compared with the AA genotype of SNP rs947211, both the AG genotype and the GG genotype were significantly related to an increased risk of sporadic PD. Using subjects with the AA genotype of SNP rs823156 as a reference group, there were significant inverse relationships under the additive and dominant models. No significant relationships were found between SNPs rs16856139 or rs11240572 and sporadic PD. The CAAAC, the TGAGA, and the CAGAC haplotypes were significantly related to sporadic PD. The additive interaction between SNP rs823128 and smoking affecting sporadic PD was significant, although the multiplicative interaction was not significant. The PARK16 SNPs rs823128, rs947211, and rs823156 and the CAAAC, TGAGA, and CAGAC haplotypes may be significantly associated with sporadic PD in Japan. New evidence of an additive interaction between SNP rs823156 and smoking is suggested.

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.

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.

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.

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.

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.

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.

Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.

Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.

Intake of Japanese and Chinese teas reduces risk of Parkinson's disease.

Studies that have addressed the association between the intake of coffee or caffeine and Parkinson's disease (PD) were conducted mainly in Western countries. Little is known about this relationship in an Asian population. Therefore, we performed an assessment of the association of the intake of coffee, other caffeine-containing beverages, and caffeine with the risk of PD in Japan. The study involved 249 PD cases and 368 control subjects. Information on dietary factors was obtained through a self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, educational level, pack-years of smoking, body mass index, the dietary glycemic index, and intake of cholesterol, vitamin E, ß-carotene, vitamin B(6,) alcohol, and iron. Intake of coffee, black tea, and Japanese and Chinese teas was significantly inversely associated with the risk of PD: the adjusted odds ratios in comparison of the highest with the lowest quartile were 0.52, 0.58, and 0.59, respectively (95% confidence intervals = 0.30-0.90, 0.35-0.97, and 0.35-0.995, respectively). A clear inverse dose-response relationship between total caffeine intake and PD risk was observed. We confirmed that the intake of coffee and caffeine reduced the risk of PD. Furthermore, this is the first study to show a significant inverse relationship between the intake of Japanese and Chinese teas and the risk of PD.

Apomorphine treatment in Alzheimer mice promoting amyloid-ß degradation.

OBJECTIVE: Intracellular amyloid ß-protein (Aß) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. METHODS: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aß degradation, activity of Aß-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. RESULTS: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aß, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aß, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells. INTERPRETATION: 3xTg-AD mice show intraneuronal Aß accumulation and memory disturbances before extracellular Aß deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aß and p-tau levels by APO treatment strongly suggest that intraneuronal Aß is an important therapeutic target and APO will be a novel drug for AD.

Alcohol drinking and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study. METHODS: From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors. RESULTS: Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk. CONCLUSIONS: We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.

LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson's disease: a case-control study in Japan.

Previous case-control studies in Japanese and ethnic Chinese populations reported that the LRRK2 Gly2385Arg variant is a risk factor for Parkinson's disease (PD). We aimed to validate the previous findings and investigate whether cigarette smoking influences the relationship between the Gly2385Arg variant and PD. Included were 229 cases within 6years of onset of sporadic PD. Controls were 358 inpatients and outpatients without a neurodegenerative disease. The frequency of the heterozygous genotype was 13.1% of cases and 6.4% of controls: adjusted OR for the GA genotype was 2.06 (95% CI: 1.15-3.69). Compared with subjects with the GG genotype who had ever smoked, those with the GA genotype who had never smoked had a 5.8-fold increased risk of sporadic PD. The multiplicative interaction between the SNP and smoking was not statistically significant. With respect to the additive interaction, the estimated attributable proportion due to interaction (AP), but not relative excess risk due to interaction or the synergy index, was statistically significant (AP=0.50, 95% CI: 0.05-0.94), suggesting the presence of a biological interaction. The present study confirms that the LRRK2 Gly2385Arg variant is a risk factor for sporadic PD. In addition, we provide new evidence for the biological interaction between the polymorphism and smoking with regard to the risk of sporadic PD.

Case-control study of risk of Parkinson's disease in relation to hypertension, hypercholesterolemia, and diabetes in Japan.

This case-control study investigated the associations of a history of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of Parkinson's disease (PD) in Japan. Included were 249 cases within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Data on the vascular risk factors and confounders were obtained from a self-administered questionnaire. The vascular risk factors were defined based on drug treatment. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, leisure-time exercise, body mass index, dietary intake of energy, cholesterol, vitamin E, alcohol, and coffee and the dietary glycemic index. The proportions of hypertension, hypercholesterolemia, and diabetes mellitus prior to the onset of PD were 23.7%, 9.6%, and 4.0%, respectively, in cases. Hypertension, hypercholesterolemia, and diabetes mellitus were significantly associated with a decreased risk of PD: the adjusted ORs were 0.43 (95% CI: 0.29-0.64), 0.58 (95% CI: 0.33-0.97), and 0.38 (95% CI: 0.17-0.79), respectively. No significant differences were observed in the association of vascular risk factors with the risk of PD between men and women. We found evidence of significant inverse associations of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of PD in Japan. Further well-designed investigations of the association of vascular risk factors with the risk of PD are needed, particularly large-scale prospective studies in Asia.

Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.

Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors.

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-beta protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a beta-secretase inhibitor or gamma-secretase inhibitor significantly attenuated the effects of the PS1 mutants on caspase-3/7 activation and recovered cell viability. Our present data suggest that these PS1 mutants accelerate the activation of initiator caspases and promote apoptosis, which may be associated, at least in part, with amyloid-beta production.

Subthalamic nucleus stimulation does not cause deterioration of preexisting hallucinations in Parkinson's disease patients.

BACKGROUND: Among the neuropsychiatric symptoms in Parkinson's disease (PD) patients, hallucination can result from the disease itself or medical treatment. Hallucination associated with subthalamic nucleus stimulation (STN-DBS) has been reported; however, it is still unclear whether PD patients with a history of hallucination are appropriate candidates for STN-DBS or not. AIMS: We investigated the effect of STN-DBS on preexisting hallucination associated with advanced PD. METHODS: Eighteen STN-DBS patients were investigated retrospectively. The severity of hallucination was assessed by the thought disorder score on the Unified Parkinson's Disease Rating Scale (UPDRS, part 1-item 2) in the patients' interviews; the score 6 months after the initiation of STN-DBS was compared with the highest score throughout the preoperative history and the score 2 weeks before surgery. RESULTS: Hoehn-Yahr stage and motor score (UPDRS part 3) were significantly improved following STN-DBS. Six months after the initiation of STN-DBS, the severity of hallucination, assessed by thought disorder score, did not increase, but rather decreased compared with the preoperative level (p < 0.05 by McNemar's test). The daily levodopa equivalent dose was increased in 2 patients without the development of hallucination. On the other hand, anti-parkinsonian drugs were totally withdrawn in 1 patient, but without improvement of hallucination. CONCLUSIONS: Our findings indicate that STN-DBS surgery does not always lead to deterioration of preexisting hallucination in PD. In advanced PD, hallucination involves a multifactorial pathogenesis and a history of hallucination is not a contraindication to STN-DBS surgery.

Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.