A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine-rich repeat kinase 2 mutation carrier.

INTRODUCTION: The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit. METHODS: We studied a patient initially diagnosed with SWEDD (based on (18)F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and (18)F-dopa. RESULTS: The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). (18)F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions. CONCLUSIONS: SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease.

DNAJC13 genetic variants in parkinsonism.

BACKGROUND: A novel mutation (p.N855S) in DNAJC13 has been linked to familial, late-onset Lewy body parkinsonism in a Dutch-German-Russian Mennonite multi-incident kindred. METHODS: DNAJC13 was sequenced in 201 patients with parkinsonism and 194 controls from Canada. Rare (minor allele frequency < 0.01) missense variants identified in patients were genotyped in two Parkinson's disease case-controls cohorts. RESULTS: Eighteen rare missense mutations were identified; four were observed in controls, three were observed in both patients and controls, and eleven were identified only in patients. Subsequent genotyping showed p.E1740Q and p.L2170W to be more frequent in patients, and p.R1516H being more frequent in controls. Additionally, p.P336A, p.V722L, p.N855S, p.R1266Q were seen in one patient each, and p.T1895M was found in two patients. CONCLUSION: Although the contribution of rare genetic variation in DNAJC13 to parkinsonisms remains to be further elucidated, this study suggests that, in addition to p.N855S, other rare variants might affect disease susceptibility.

Parkinson's disease and occupation: differences in associations by case identification method suggest referral bias.

METHODS: We used a population-based sample of 403 Parkinson's disease cases and 405 controls to examine risks by occupation. Results were compared to a previous clinic-based analysis. RESULTS: With censoring of jobs held within 10 years of diagnosis, the following had significantly or strongly increased risks: social science, law and library jobs (OR = 1.8); farming and horticulture jobs (OR = 2.0); gas station jobs (OR = 2.6); and welders (OR = 3.0). The following had significantly decreased risks: management and administration jobs (OR = 0.70); and other health care jobs (OR = 0.44). CONCLUSIONS: These results were consistent with other findings for social science and farming occupations. Risks for teaching, medicine and health occupations were not elevated, unlike our previous clinic-based study. This underscores the value of population-based over clinic-based samples. Occupational studies may be particularly susceptible to referral bias because social networks may spread preferentially via jobs.

Head injuries and Parkinson's disease in a case-control study.

BACKGROUND: Head injury is a hypothesised risk factor for Parkinson's disease, but there is a knowledge gap concerning the potential effect of injury circumstances (eg, work-related injuries) on risk. The objective of this study is to address this gap while addressing issues of recall bias and potential for reverse causation by prediagnosis symptoms. METHODS: We conducted a population based case-control study of Parkinson's disease in British Columbia, Canada (403 cases, 405 controls). Interviews queried injury history; whether injuries occurred at work, in a motor vehicle accident or during sports. Participants were also asked to report their suspicions about the causes of Parkinson's disease to provide an indicator of potential recall bias. Associations were estimated with logistic regression, adjusted for age, sex and smoking history. RESULTS: Associations were strongest for injuries involving concussion (OR: 2.08, 95% CI 1.30 to 3.33) and unconsciousness (OR: 2.64, 95% CI 1.39 to 5.03). Effects remained for injuries that occurred long before diagnosis and after adjustment for suspicion of head injury as a cause of Parkinson's disease. Injuries that occurred at work were consistently associated with stronger ORs, although small numbers meant that estimates were not statistically significant. CONCLUSIONS: This study adds to the body of literature suggesting a link between head injury and Parkinson's disease and indicates further scrutiny of workplace incurred head injuries is warranted.

Occupational exposure to whole-body vibration and Parkinson's disease: results from a population-based case-control study.

Mechanical stress producing head injury is associated with Parkinson's disease, suggesting that relations with other physical hazards such as whole-body vibration (WBV) should be tested. In this study, the authors evaluated the relation between occupational exposure to WBV and Parkinson's disease. A population-based case-control study with 403 cases and 405 controls was conducted in British Columbia, Canada, between 2001 and 2008. From detailed occupational histories and published measurements, metrics of occupational WBV exposure were constructed and tested for associations with Parkinson's disease using logistic regression and adjusting for age and sex first, and then also for smoking and history of head injury. While ever being occupationally exposed to WBV was inversely associated with Parkinson's disease (odds ratio = 0.67, 95% confidence interval: 0.48, 0.94), higher intensities had consistently elevated odds ratios, with a statistically significant effect being noted for intermediate intensities when exposures were restricted to the 10 years or more prior to diagnosis. Possible mechanisms of an inverse relation between low levels of WBV exposure and Parkinson's disease could include direct protective effects or correlation with other protective effects such as exercise. Higher intensities of WBV could result in micro-injury, leading to vascular or inflammatory pathology in susceptible neurons.

Association of Parkinson's disease with infections and occupational exposure to possible vectors.

The ultimate causes of idiopathic Parkinson's disease (PD) are not fully known, but environmental and occupational causes are suspected. Postencephalitic parkinsonism has been linked to influenza, and other viral infections have also been suspected to relate to PD. We estimated the relationship between PD and both infections and possible vectors of infection (i.e., animal and human) in a population-based, case-control study in British Columbia, Canada. We recruited 403 cases detected by their use of antiparkinsonian medications and 405 controls from the registrants of the provincial universal health insurance plan. Severe influenza was associated with PD (odds ratio [OR]: 2.01; 95% confidence interval [CI]: 1.16-3.48), although this effect was attenuated when reports were restricted to those occurring 10 or more years before diagnosis. Childhood illnesses were inversely associated with PD, particularly red measles (OR: 0.65; 95% CI: 0.48-0.90). Several animal exposures were associated with PD, with statistically significant effects for cats (OR: 2.06; 95% CI: 1.09-3.92) and cattle (OR: 2.23; 95% CI: 1.22-4.09). Influenza infection may be associated with PD. The inverse relationships with childhood infections may suggest an increased risk with subclinical or asymptomatic childhood infections. Occupational exposure to animals may increase risk through transmission of infections or may indicate exposure to another agent of interest (e.g., bacterial endotoxin).

Public opinions about participating in health research.

OBJECTIVES: Privacy legislation has limited options for recruiting subjects to health studies. Policy changes are motivated by assumptions about public attitudes towards participation, yet surveys of attitudes have rarely been done. We investigated public willingness to participate in health research and how willingness was affected by various factors. METHODS: A survey of adults randomly selected from the telephone directory was conducted in British Columbia, Canada. Mailed self-administered questionnaires asked about willingness to participate in health research and the influence on willingness of the method of subject selection, the organization making the contact, and other factors. RESULTS: There were 1,477 respondents (58% of eligible); 85% were willing to participate in health research at least sometimes. The organization making the contact influenced comfort about participation: 10% of respondents felt uncomfortable if contacted by a university, 12% if by a hospital, 26% if by government, and 55% if by private research firms. Factors most positively influencing choice to participate were future health benefits to society (87%) and oneself (87%), and receiving a copy of the study results (81%). CONCLUSIONS: Participation in health research appears to be viewed favourably by members of the public, and participation may be highest when university or hospital-based researchers are able to contact subjects directly using information from government databases.

Strategy for starting BoNT treatment (written consent, initial dose and subsequent doses, interval, follow-up).

Botulinum toxin (BoNT) has become a therapeutic agent for a large variety of medical conditions. It is a symptomatic treatment and in most cases requires repeat injections at regular intervals. The first session is crucial in establishing rapport between the physician and the patient to ensure a continuity of treatment on a long term basis. Since the clinical practice varies widely across different therapeutic indications and in different clinical settings around the world, a general set of strategic approach is difficult to be formulated. This article will focus on the important issues when starting BoNT treatment in patients with cervical dystonia (CD).

Clustering of Parkinson disease: shared cause or coincidence?

BACKGROUND: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology. OBJECTIVE: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada. DESIGN AND PATIENTS: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the alpha-synuclein, parkin, tau genes, and spinocerebellar ataxia genes (SCA2 and SCA3) were negative. RESULTS: The probabilities of random occurrence (P values) in the 3 clusters were P = 7.9 x 10 (-7)for cluster 1, P = 2.6 x 10 (-7)for cluster 2, and P = 1.5 x 10 (-7)for cluster 3. CONCLUSIONS: Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence.

Upregulation of vasopressin V2 and aquaporin 2 in the inner medullary collecting duct of cardiomyopathic hamsters is attenuated by enalapril treatment.

Previous studies showed that aquaporin 2 (AQP2) is elevated in the kidney of the heart failure rat suggesting that an increased amount of AQP2 contributes to water retention in heart failure. We performed the present study to determine whether angiotensin II play a role in causing an increase in the expression of arginine vasopressin (AVP) V2 and AQP2 mRNA in the kidney of the cardiomyopathic hamster. The expression of AVP V2 and AQP2 mRNA in the inner medullary collecting duct (IMCD) was measured by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) before and after treatment with an angiotensin-converting enzyme inhibitor, enalapril. Our results showed that the expression of AVP V2 (0.53 +/- 0.05 v 1.03 +/- 0.15 amol/microg of total RNA, P <.01) and AQP2 mRNA (0.027 +/- 0.002 v 0.036 +/- 0.002 amol/microg of total RNA, P <.05) in the IMCD of the cardiomyopathic hamster is upregulated. Treating the cardiomyopathic hamster with enalapril for 7 days negated the changes. In situ hybridization experiments confirmed the intensity of the signals for both AVP V2 and AQP2 mRNA was more intense in the IMCD of the cardiomyopathic hamster. Enalapril treatment reduced the signal intensity to a level comparable to the normal hamster. These results suggested that the increases in the expression of AVP V2 and AQP2 mRNA are mediated by angiotensin II.

Angiotensin II upregulates the expression of vasopressin V2 mRNA in the inner medullary collecting duct of the rat.

Previous in vivo studies in cardiomyopathic hamsters suggested that the expression of vasopressin (AVP) V2 mRNA is up- regulated by angiotensin II. The present study was performed to determine whether angiotensin II plays a role in regulating the expression of AVP V2 mRNA and aquaporin-2 (AQP2) mRNA in the inner medullary collecting duct (IMCD) of the male Wistar rat. The expression of AVP V2 mRNA and AQP2 mRNA in the IMCD was measured by competitive reverse-transcriptase polymerase chain reaction (RT-PCR). Six groups of experiments were performed. In the first group, we incubated IMCD with 3 different doses of angiotensin II (10(-11), 10(-9) and 10(-7) mol/L). Angiotensin II caused a significant increase in the AVP V2 mRNA in a dose-dependent manner but its effect on AQP2 mRNA was modest. This effect of angiotensin II was inhibited by angiotensin II receptor antagonist, [Sar1,Ile8]-angiotensin II. To examine the role of PKA in mediating an increase in AVP V2 mRNA expression, we incubated IMCD with 10(-7) and 10(-11) M of angiotensin II in the presence of a specific protein kinase A (PKA) inhibitor, Rp diasteroisomer of adenosine 3'-5'-cylic monophosphothionate (Rp-cAMPS). The angiotensin II-induced upregulation of V2 mRNA was abolished. In the fourth group, we examined the effect of protein kinase C (PKC) inhibition on V2 mRNA expression. The upregulation of V2 mRNA induced by angiotensin II was greatly exaggerated when IMCD was incubated with angiotensin II and RO-31-8220 (PKC inhibitor). In the fifth and sixth groups of studies, we determined the direct effect of PKA and PKC on regulating the expression of V2 mRNA and AQP2 mRNA in the IMCD, respectively. Dibutryl cAMP stimulated an upregulation in the expression of V2 mRNA and AQP2 mRNA, whereas phorbol esters suppressed the expression of V2 mRNA. These results suggested that PKA stimulates and PKC suppresses the expression of V2 mRNA in the IMCD of the kidney.

Attenuation of renal vasopressin V2 receptor upregulation by bosentan, an ETA/ETB receptor antagonist.

Circulating endothelin (ET) levels are elevated in heart failure and positively correlated with severity of heart failure. Recent studies demonstrated arginine vasopressin (AVP) V2 mRNA expression was upregulated in the inner medullary collecting duct (IMCD) of cardiomyopathic hamsters (CM). The goal of the present studies was to determine if ET-1 is involved in upregulating the expression of AVP V2 mRNA in the IMCD of CM by using a mixed ETA/ETB receptor antagonist bosentan. Our results showed plasma ET-1 levels increased in CM hamsters and related with the severity of heart failure. The competitive reverse-transcriptase polymerase chain reaction (RT-PCR) method was used to quantify the expression of AVP V2 and aquaporin 2 (AQP2) mRNA in the IMCD. AVP V2 mRNA expression was elevated in placebo-treated CM hamsters and decreased significantly with 14 days of bosentan treatment. Similar results were seen with AQP2 mRNA. The effect of bosentan in normalizing the expression of AVP V2 and AQP2 mRNA in the IMCD of CM was confirmed by in situ hybridization studies. Bosentan treatments reduced the intensitites of the signals in the IMCD of CM hamsters to that seen in normal hamsters. This study demonstrated that AVP V2 and AQP2 mRNA are upregulated in CM hamsters and these upregulations are attenuated by bosentan treatment, suggesting that ET-1 plays a role in upregulating the expression of AVP V2 mRNA in CM hamsters.

Regulation of aquaporin-4 in a traumatic brain injury model in rats.

OBJECT: Aquaporin-4 (AQP4) plays a significant role in the regulation of brain water homeostasis. In this study the authors investigated the regulation of AQP4 following a focal cortical contusion injury in rats. METHODS: Thirty-three adult male Wistar rats received a focal cortical contusion of the parietal cortex. An additional nine rats underwent a craniectomy, but no trauma was inflicted (sham injury). Animals were killed 1, 4, and 24 hours later. The rat brains were examined for water content by comparing the wet and dry weights of each hemisphere. Aquaporin-4 messenger (m)RNA was measured by reverse transcription-polymerase chain reaction. A ratio of AQP4 mRNA expression in the lesioned hemisphere compared with that in the contralateral control hemisphere was calculated for each animal at the injury site (parietal cortex) and at sites adjacent to (occipital cortex) and distant from the injury (frontal pole cortex). Brain edema was significantly increased at the injury site. The expression of AQP4 mRNA was significantly increased at the injury site, significantly decreased adjacent to the injury site, and not significantly different at a site distant from the injury. The magnitude of AQP4 mRNA upregulation at the injured parietal cortex correlated with the degree of downregulation in the adjacent occipital cortex. CONCLUSIONS: Data from this study demonstrate that an upregulation of AQP4 occurs at the site of traumatic brain injury and that a downregulation of this molecule occurs adjacent to the site of injury. Understanding the physiology of AQP4 and its regulation following brain injury may allow for the development of novel treatments for cerebral edema that accompanies head injury.

Pesticide exposure and risk of Parkinson's disease--a population-based case-control study evaluating the potential for recall bias.

OBJECTIVE: The aim of this study was to investigate whether pesticide exposure was associated with Parkinson's disease in a population-based case-control study in British Columbia, Canada. METHODS: Patients reimbursed for anti-parkinsonian agents were identified and screened for eligibility as cases. Controls were selected from the universal health insurance database, frequency-matched to the case sample on birth year, gender, and geographic region. A total of 403 cases and 405 controls were interviewed about their job, medical and personal habits histories, and beliefs about disease risk factors. Among those reporting pesticide exposure, an occupational hygiene review selected participants exposed "beyond background" (ie, above the level expected in the general population). Unconditional logistic regression was used to estimate associations for different pesticide categories. RESULTS: Of the cases, 74 (18%) self-reported pesticide exposure and 37 (9%) were judged to be exposed beyond background. Self-reported exposure was associated with increased risk [odds ratio (OR) 1.76, 95% confidence interval (95% CI) 1.15-2.70], however the risk estimate was reduced following the hygiene review when restricted to those considered exposed (OR, 1.51, 95% CI, 0.85-2.69). When agricultural work was added to the model, the risk for hygiene-reviewed pesticide exposure was not elevated (OR 0.83, 95% CI 0.43-1.61), but agricultural work was (OR 2.47, 95% CI 1.18-5.15). More than twice as many cases as controls thought chemicals cause Parkinson's disease. Discussion This study provides little support for pesticide exposure as a cause of Parkinson's disease. The observed pattern of step-wise decreases in risk estimates might indicate differential recall by case status. The relationship to agricultural jobs suggests that farming exposures--other than pesticides--should be considered as risk factors for Parkinson's disease.