Reproductive factors and Parkinson's disease: a multicenter case-control study.

BACKGROUND: The objective of this study was to evaluate the possible association between endogenous and exogenous estrogens and Parkinson's disease (PD). METHODS: The FRAGAMP study is a large Italian multicenter case-control study. PD was diagnosed according to Gelb's criteria. A standardized questionnaire was administered to record demographic, epidemiological, and clinical data. Adjusted ORs and 95% CIs were estimated using multivariate analysis (logistic regression). RESULTS: Two hundred PD women (mean age, 68.0 ± 9.5 years) and 299 control women (mean age, 61.8 ± 9.9 years) were enrolled in the study. Age at menarche, age at menopause, fertile life duration, cumulative duration of pregnancies, hormone replacement therapy, and surgical menopause were not significantly associated with PD. Multivariate analysis showed a significant positive association between use of oral contraceptives and PD, with an adjusted OR of 3.27 (95% CI, 1.24-8.59; P = .01). CONCLUSIONS: Our data suggest that oral contraceptives could increase the risk of PD.

Voluptuary habits and clinical subtypes of Parkinson's disease: the FRAGAMP case-control study.

We evaluated the possible association between smoking, coffee drinking, and alcohol consumption and Parkinson's disease (PD). The FRAGAMP study is a large Italian multicenter case-control study carried out to evaluate the possible role of environmental and genetic factors in PD. Adjusted ORs were estimated using unconditional logistic regression. Smoking, coffee, and alcohol consumption were also considered as surrogate markers of lifestyle and analysis was carried out considering the presence of at least one, two, or three factors. This latter analysis was separately performed considering Tremor-Dominant (TD) and Akinetic-Rigid (AR) patients. Four hundred ninety-two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. Multivariate analysis showed a significant negative association between PD and cigarette smoking (OR 0.51; 95%CI 0.36-0.72), coffee drinking (OR 0.61; 95%CI 0.43-0.87) and wine consumption (OR 0.62; 95%CI 0.44-0.86); a significant trend dose-effect (P < 0.05) has been found for all the factors studied. We have also found a trend dose-effect for the presence of at least one, two or three factors with a greater risk reduction (83%) for the presence of three factors. However, a different strength of association between TD and AR was found with a greater risk reduction for the AR patients. We found a significant inverse association between PD smoking, coffee, and alcohol consumption. When analysis was carried out considering the association of these factors as possible surrogate markers of a peculiar lifestyle the association was stronger for the AR phenotype.

The FRAGAMP study: environmental and genetic factors in Parkinson's disease, methods and clinical features.

The Fattori di Rischio Ambientali e Genetici Associati alla Malattia di Parkinson (FRAGAMP) study is a multicenter case-control study carried out to evaluate the possible role of environmental and genetic factors in Parkinson's disease (PD). Cases and controls were enrolled from five Movement Disorder centers in Central-Southern Italy. PD was diagnosed according to Gelb's criteria while the control groups consisted of the spouses of the enrolled patients or of healthy controls matched by age and area of residence. Cases and controls underwent a standardised questionnaire and a blood sample was taken for molecular analyses. At the end of the study 585 cases and 481 control subjects (287 spouse-controls and 194 generic-controls) were enrolled. Patients had a Hoehn-Yahr score of 2.3 +/- 0.8; 85% of them took levodopa and 47% had motor complications. The FRAGAMP study represents one of the largest case-control studies carried out in Europe to investigate the possible role of environmental and genetic factors in PD.

The arginine growth hormone stimulation test in bradykinetic-rigid parkinsonisms.

The arginine growth hormone (GH) stimulation test differentiates the Parkinsonian variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine GH stimulation test in distinguishing between PSP, MSA-P, and PD. We measured the GH response to arginine in serum samples of 26 MSA-P, 23 PSP, and 26 PD patients, and in 80 healthy controls. We used ANOVA followed by the Bonferroni test to compare GH values and peaks among groups. We used receiver operating characteristic curve analysis to establish the arginine cut-off level that best differentiated between MSA-P, PSP, and PD. The GH peak was significantly lower (P < 0.01) in MSA-P (1.46 +/- 0.29 microg/L) than in both PD (8.74 +/- 0.98 microg/L) and PSP (6.64 +/- 0.82 microg/L) patients, and controls (8.59 +/- 0.44 microg/L). Growth hormone peaked later in PSP patients than in PD patients and controls. At a cut-off level of 4 microg/L, arginine test distinguished MSA-P from PD with a sensitivity of 92% and a specificity of 96%, and MSA-P from PSP with a sensitivity of 78% and a specificity of 96%. The GH response to arginine differentiates MSA-P from PD and PSP with a good diagnostic accuracy. The neuroendocrine response to arginine of PSP patients differed from that of MSA-P patients, but was not identical to that of normal controls and PD patients. Our results suggest that the impairment of the central mechanisms modulating GH release differs between PSP and MSA-P.

How many parkinsonian patients are suitable candidates for deep brain stimulation of subthalamic nucleus? Results of a questionnaire.

We used a CAPSIT-based questionnaire to estimate the percentage of parkinsonian patients suitable for subthalamic nucleus (STN) deep brain stimulation (DBS) in a movement disorders clinic. We found that out of 641 consecutive PD patients only 1.6% fulfilled strict STN-DBS criteria. When we applied more flexible criteria, the percentage of eligibility increased to 4.5%. Most patients (60%) were ineligible because they did not satisfy multiple questionnaire items. Items related to disease severity were responsible for the largest number of exclusions. This knowledge will help make decisions on resource allocation in centres wishing to start DBS surgery.

Levetiracetam in tardive dyskinesia.

OBJECTIVES: The aim of this study was to evaluate the effect of levetiracetam on tardive dyskinesia (TD), which is known to be a major limitation of chronic antipsychotic drug therapy, particularly with conventional antipsychotics. METHODS: Sixteen patients suffering from chronic psychosis with TD were enrolled consecutively. Levetiracetam was given in gradually increasing doses, starting with 125 twice a day until the best clinical benefit was achieved (mean dosage, 2,290 mg; range, 1,000-3,000 mg). Tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale at baseline and after 1 month and 3 months of treatment with levetiracetam. RESULTS: Compared with baseline, there was a significant improvement in the Abnormal Involuntary Movement Scale score after 1 month still present after 3 months (P < 0.001). All patients well tolerated levetiracetam, except one who dropped out of the trial after the first 2 weeks owing to excessive drowsiness. CONCLUSIONS: The results of this open-label observational study suggest that levetiracetam is a well-tolerated drug and effectively controls TD.

Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.

OBJECTIVE: This study aimed to compare the efficacy and safety of quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis in a randomized, open-label, blinded-rater, parallel group trial. METHODS: Forty-five patients with Parkinson disease (PD) and psychosis induced by antiparkinsonian drugs were randomly assigned to receive either quetiapine or clozapine. The duration of the trial was 12 weeks. Forty patients, 20 in each treatment group, completed the study. The final dose of quetiapine (mean +/- SD) was 91 +/- 47 mg/d and that of clozapine 26 +/- 12 mg/d. The severity of psychosis was assessed using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale-Severity Subscale (CGI-S). The Unified Parkinson's Disease Rating Scale (UPDRS) III was used to assess motor conditions during the study period. The Abnormal Involuntary Movement Scale (AIMS) was performed to evaluate dyskinesias. RESULTS: Forty patients, 20 on clozapine and 20 on quetiapine, completed the study. The psychopathologic state improved significantly (P < 0.001) from baseline in both treatment groups. No differences were found between clozapine and quetiapine at any assessment time. Motor conditions remained unchanged after clozapine and quetiapine. Dyskinesias decreased significantly (P < 0.05) in both groups. Side effects were mild, generally transient, and well tolerated. CONCLUSIONS: Quetiapine and clozapine appear equally efficacious for treatment of dopaminergic psychosis in patients with PD.

A screening instrument for a Sicilian neuroepidemiological survey in the elderly.

We evaluated the sensitivity and specificity of a screening instrument developed for use in a two-phase neuroepidemiological survey in Sicily. The Sicilian Epidemiological Dementia Study (SEDES) project will evaluate the prevalence and incidence of dementia, parkinsonisms and essential tremor in four Sicilian municipalities. It is a two-phase door-to-door survey. To identify subjects with possible neurological disorders, in this study, we developed a screening instrument including a symptoms questionnaire and simple physical tasks for parkinsonisms and essential tremor. The Mini-Mental State Examination (MMSE) was chosen for screening dementia. The symptoms questionnaire and simple tasks developed to identify possible patients with parkinsonism and essential tremor, was tested in a hospital setting. To evaluate sensitivity, we selected 20 patients with essential tremor and 40 with Parkinson's disease (20 with Stages I-II and 20 with Stages III-V) [Neurology 17 (1967) 427]. To evaluate specificity we also selected 20 healthy subjects. The screening instrument was administered in a hospital setting by trained interviewers. Sensitivity of the screening instrument (questionnaire plus simple tasks) was 100% for essential tremor and parkinsonisms regardless of the stage. Specificity of the instrument was 90% (95% CI 66.9-98.2); the predictive positive value was 90.9%, while the negative predictive value was 100%. Even if validity was assessed in a hospital setting, the high sensitivity and specificity obtained suggest that the instrument could be an appropriate screening tool for parkinsonisms and essential tremor in a two-phase neuroepidemiological survey.

Multiple system atrophy is distinguished from idiopathic Parkinson's disease by the arginine growth hormone stimulation test.

OBJECTIVE: Multiple system atrophy (MSA) may be difficult to distinguish from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine growth hormone (GH) stimulation test in distinguishing between MSA and PD in large populations of patients. METHODS: We measured the GH response to arginine in 69 MSA (43 MSAp [parkinsonism as the main motor feature] and 26 MSAc [cerebellar features predominated]) patients, 35 PD patients, and 90 healthy control subjects. We used receiver-operating curve analysis to establish the arginine cutoff value that best differentiated between MSA and PD. RESULTS: The GH response to arginine was significantly lower (p < 0.01) in MSA than in either PD patients or control subjects. At a cutoff level of 4 microg/L, arginine distinguished MSAp from PD with a sensitivity and specificity of 91% and MSAc from PD with a sensitivity of 96% and specificity of 91%. The arginine test had a positive predictive value for MSA of 95%. The GH response to arginine was not affected by disease duration or severity, MSA motor subtype, pyramidal signs, response to dopaminergic therapy, or magnetic resonance imaging findings. INTERPRETATION: The GH response to arginine differentiates MSA from PD with a high diagnostic accuracy. The results suggest an impairment of cholinergic central systems modulating GH release in MSA.

Tumor diagnosis preceding Parkinson's disease: a case-control study.

Lower cancer risk in Parkinson's disease (PD) patients compared to the general population has been reported. However, most of the studies were based on death certificates. We designed a case-control study to estimate the association of tumor preceding PD onset and PD. PD patients were matched by age and gender to PD-free individuals, randomly selected from the municipalities of residence of cases. Occurrence of tumors preceding PD onset was assessed through a structured questionnaire. Neoplasms were categorized as benign, malignant, or of uncertain classification, and endocrine-related or not. Odds ratios (OR) were calculated using conditional logistic regression and adjusted for tumor categories and risk factors. We included 222 PD patients. Frequency of cancer was 6.8% for cases, 12.6% for controls. PD patients had a decreased risk for neoplasms (adjusted OR, 0.4; 95% confidence interval [CI], 0.2-0.7). Risk was reduced only for women (adjusted OR, 0.3; 95% CI, 0.1-0.7). PD patients had a decreased risk both for malignant (adjusted OR, 0.6; 95% CI, 0.1-2.5) and nonmalignant neoplasms (adjusted OR, 0.3; 95% CI, 0.1-0.7). Still, risk was decreased for endocrine-related tumors (adjusted OR, 0.3; 95% CI, 0.1-0.9) and non-endocrine-related tumors (adjusted OR, 0.4; 95% CI, 0.1-0.9). Our study confirms the inverse association between PD and neoplasms reported in previous epidemiologic studies.

Effect of levodopa on interleukin-15 and RANTES circulating levels in patients affected by Parkinson's disease.

Parkinson's disease (PD) is an extra-pyramidal neurodegenerative disorder, in which alterations of the immune system are involved. Interleukin (IL)-15 stimulates cellular immune response and induces growth and differentiation of various immune cells. RANTES, promoting leukocyte infiltration to sites of inflammation, mediates the trafficking and homing of immune cells. To clarify the potential effect of levodopa on the immunological network of PD, we analyzed IL-15 and RANTES serum levels in PD patients, treated or not with levodopa, and in healthy donors. Levodopa-treated patients showed significantly higher IL-15 and RANTES circulating levels with respect to healthy controls and higher, although not significantly, levels with respect to untreated patients. So, we hypothesize that the immunological alterations found in PD may be linked, at least in part, to levodopa therapy.

Ischaemic stroke in young people: a prospective and long-term follow-up study.

BACKGROUND: A few studies have comprehensively assessed the epidemiology, aetiology, prognosis, and secondary prevention of ischaemic stroke in young adults. To gain further information on this field, we have prospectively studied a hospital-based series of young adults with a first-ever episode of cerebral ischaemia (CI). METHODS: Sixty consecutive patients aged 17-45 with ischaemic stroke (55 patients) or transient ischaemic attack within 24 h before hospital admission were recruited and investigated by a standardized rigorous protocol. The patients were followed up for >or=1 year after hospital discharge. Arbitrary doses of aspirin 100 mg/d or ticlopidine 250 mg b.i.d. in case of intolerance to aspirin were given for the secondary prevention. Adjusted-dose oral anticoagulation (INR target 2.5) was used in the presence of cardioembolism or hypercoagulable states. Endpoints included the residual disability, rated by modified Rankin Scale (RS) and Barthel Index (BI), and poststroke recurrence. RESULTS: CI was associated with two or more risk factors in 61.6% of patients. Cigarette smoking was more frequently associated with male gender (p < 0.05) and migraine history with female sex (p < 0.05). The atherothrombotic diagnostic subtype and the subtype from 'other cause' predominated significantly among patients >or=35 years old (p < 0.05) and <35 years (p < 0.025), respectively. The 'other cause' subset was more frequent in female gender (p < 0.05). Transoesophageal echocardiography (TEE) detected potential cardiac sources of emboli (PCSE) at an extent 3 times higher (p < 0.0001) than transthoracic echocardiography. Congenital heart defects were nearly threefold more frequent than acquired ones, with a prevalence of patent foramen ovale. At a mean of 6.1 +/- 2.6 years (confidence interval 5.4 to 6.8), follow-up data were available for only 54 patients, since five patients were lost and one died in the acute phase. Poststroke recurrence rate was low (7.4%) and no event was fatal. General handicap was severe to moderately severe (RS>3) in 11% of the patients, slight to moderate (1>or=RSor=95), 38.9% partially dependent (BI 60 to 86), and 11.1% fully dependent (BI <60). Thirty-seven (68.5%) patients returned to work, although adjustments (other job or part-time employment) were necessary for 10 out of them (27%). CONCLUSIONS: The present study, though limited by the relatively small number of subjects, suggests that the overall prognosis of ischaemic stroke in young adults is good. We strongly recommend TEE in all patients with ischaemic stroke as an essential tool to increase the detection of PCSE and make the therapeutic approach more efficient.

Accuracy of death certificates for amyotrophic lateral sclerosis varies significantly from north to south of Italy: implications for mortality studies.

OBJECTIVE: To evaluate the accuracy of death certificates (DCs) for amyotrophic lateral sclerosis (ALS) in different parts of Italy. Studies based on DC diagnosis for ALS have shown a reduced mortality comparing northern with southern Italy. These data are in contrast with results from other surveys on the incidence of ALS performed in Italy and other countries. METHODS: Archives of neurological clinics from northern (Milano, Monza, Pavia, and Bologna) and southern Italy including islands (Napoli, Sassari, Palermo, and Messina) were searched for patients discharged with a diagnosis of ALS in the period 1970-1995. Subjects affected by definite/probable ALS according to the Scottish Motor Neuron Disease Research Group diagnostic criteria were included. DCs were obtained from the vital statistic bureau. True positive rates (TPRs) and 95% confidence intervals (CIs) for proportions were calculated for northern and southern Italy separately. Multiple logistic regression analysis was performed according to gender, age at onset, age and year of death, and interval between onset and death. RESULTS: We found 651 patients affected by definite/probable ALS; 573 of them had died by December 31, 1996. DCs were available for 566 subjects (411 from northern Italy and 155 from southern Italy). TPR was 66.7% (95% CI 61.9-71.2) for northern Italy and 51.6% (95% CI 43.5-59.7) for southern Italy (chi(2) = 10.9, p = 0.001). Logistic regression analysis showed an association between a lower accuracy of DCs and the interval between onset of symptoms and death. TPR calculations considering different death periods (1970-1982 and 1983-1996) showed comparable rates of accuracy over time. CONCLUSIONS: Mortality statistics based on official death records do not accurately reflect interregional mortality for ALS in Italy.

Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus.