Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.

BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

[11C]PBR28 PET imaging is sensitive to neuroinflammation in the aged rat.

Neuroinflammation in the aging rat brain was investigated using [(11)C]PBR28 microPET (positron emission tomography) imaging. Normal rats were studied alongside LRRK2 p.G2019S transgenic rats; this mutation increases the risk of Parkinson's disease in humans. Seventy [(11)C]PBR28 PET scans were acquired. Arterial blood sampling enabled tracer kinetic modeling and estimation of VT. In vitro autoradiography was also performed. PBR28 uptake increased with age, without differences between nontransgenic and transgenic rats. In 12 months of aging (4 to 16 months), standard uptake value (SUV) increased by 56% from 0.44 to 0.69 g/mL, whereas VT increased by 91% from 30 to 57 mL/cm(3). Standard uptake value and VT were strongly correlated (r = 0.52, 95% confidence interval (CI) = 0.31 to 0.69, n = 37). The plasma free fraction, fp, was 0.21 ± 0.03 (mean ± standard deviation, n = 53). In vitro binding increased by 19% in 16 months of aging (4 to 20 months). The SUV was less variable across rats than VT; coefficients of variation were 13% (n = 27) and 29% (n = 12). The intraclass correlation coefficient for SUV was 0.53, but was effectively zero for VT. These data show that [(11)C]PBR28 brain uptake increases with age, implying increased microglial activation in the aged brain.

The nature of progression in Parkinson's disease: an application of non-linear, multivariate, longitudinal random effects modelling.

BACKGROUND: To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson's disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. METHODS: Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. RESULTS: The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. CONCLUSIONS: Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.

Does this patient with liver disease have cirrhosis?

CONTEXT: Among adult patients with liver disease, the ability to identify those most likely to have cirrhosis noninvasively is challenging. OBJECTIVE: To identify simple clinical indicators that can exclude or detect cirrhosis in adults with known or suspected liver disease. DATA SOURCES: We searched MEDLINE and EMBASE (1966 to December 2011) and reference lists from retrieved articles, previous reviews, and physical examination textbooks. STUDY SELECTION: We retained 86 studies of adequate quality that evaluated the accuracy of clinical findings for identifying histologically proven cirrhosis. DATA EXTRACTION: Two authors independently abstracted data (sensitivity, specificity, and likelihood ratios [LRs]) and assessed methodological quality. Random-effects meta-analyses were used to calculate summary LRs across studies. RESULTS: Among the 86 studies, 19,533 patients were included in this meta-analysis, among whom 4725 had biopsy-proven cirrhosis (prevalence rate, 24%; 95% CI, 20%-28%). Many physical examination and simple laboratory tests increase the likelihood of cirrhosis, though the presence of ascites (LR, 7.2; 95% CI, 2.9-12), a platelet count <160 x 10(3)/µL (LR, 6.3; 95% CI, 4.3-8.3), spider nevi (LR, 4.3; 95% CI 2.4-6.2), or a combination of simple laboratory tests with the Bonacini cirrhosis discriminant score >7 (LR, 9.4; 95% CI, 2.6-37) are the most frequently studied, reliable, and informative results. For lowering the likelihood of cirrhosis, the most useful findings are a Lok index <0.2 (a score created from the platelet count, serum aspartate aminotransferase and alanine aminotransferase, and prothrombin international normalized ratio; LR, 0.09; 95% CI, 0.03-0.31); a platelet count ≥160 x 10(3)/µL (LR, 0.29; 95% CI, 0.20-0.39); or the absence of hepatomegaly (LR, 0.37; 95% CI, 0.24-0.51). The overall impression of the clinician was not as informative as the individual findings or laboratory combinations. CONCLUSIONS: For identifying cirrhosis, the presence of a variety of clinical findings or abnormalities in a combination of simple laboratory tests that reflect the underlying pathophysiology increase its likelihood. To exclude cirrhosis, combinations of normal laboratory findings are most useful.

Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease.

Parkinson's disease is a relentlessly progressive neurodegenerative disease. Breakdown of compensatory mechanisms influencing putaminal dopamine processing could contribute to the progressive motor symptoms. We studied a cohort of 78 subjects (at baseline) with sporadic Parkinson's disease and 35 healthy controls with multi-tracer positron emission tomography scans to investigate the evolution of adaptive mechanisms influencing striatal dopamine processing in Parkinson's disease progression. Presynaptic dopaminergic integrity was assessed with three radioligands: (i) [(11)C](±)dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [(11)C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[(18)F]fluoro-L-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[(18)F]-fluorodopamine in synaptic vesicles. The subjects with Parkinson's disease and the healthy controls underwent positron emission tomography scans at the initial visit and after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects were utilized to model the longitudinal changes in tracer values in the putamen standardized relative to normal controls. We found evidence for possible upregulation of dopamine synthesis and downregulation of dopamine transporter in the more severely affected putamen in the early stage of Parkinson's disease. The standardized 6-[(18)F]fluoro-L-DOPA and [(11)C]d-threo-methylphenidate values tended to approach [(11)C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [(11)C](±)dihydrotetrabenazine values <25% of normal), when the rates of decline in the positron emission tomography measurements were similar for all the markers. Our data suggest that compensatory mechanisms decline as Parkinson's disease progresses. This breakdown of compensatory strategies in the putamen could contribute to the progression of motor symptoms in advanced disease.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease.

OBJECTIVE: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). METHODS: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [¹¹C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [¹¹C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[¹8F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. RESULTS: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. INTERPRETATION: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms.

Levodopa and pramipexole effects on presynaptic dopamine PET markers and estimated dopamine release.

PURPOSE: Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson's disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [Δ(DA)]. METHODS: Twenty-three unilaterally 6-OHDA lesioned rats underwent an 11C-dihydrotetrabenazine (DTBZ, VMAT2 marker), an 11C-methylphenidate (MP, DAT marker), and a double 11C-raclopride (RAC, D2-type receptor marker) scan. They were assigned to three treatment groups: saline (N=7), pramipexole (N=8), and levodopa (N=8). After 4 weeks of treatment, imaging was repeated. RESULTS: Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on Δ(DA). CONCLUSION: These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level.

Effects of expectation on placebo-induced dopamine release in Parkinson disease.

CONTEXT: Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined. OBJECTIVE: To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD. DESIGN: Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable. SETTING: University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo. MAIN OUTCOME MEASURES: The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report. RESULTS: Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum. CONCLUSIONS: The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patient's prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.

Response to heat pain stimulation in idiopathic Parkinson's disease.

BACKGROUND: Pain is a prominent nonmotor symptom in Parkinson's disease (PD) but has not been well studied. OBJECTIVE: The aim of this study is to assess thermal experience and emotional content, as well as side-to-side sensory differences in PD "off" and "on" dopaminergic therapy following thermal cutaneous stimulation. DESIGN: Cross-sectional design. SETTING: University teaching hospital. METHODS: Twelve PD subjects experiencing motor fluctuations but no pain symptoms and 13 healthy controls participated in the study. Heat pain and emotional content were assessed using a thermode and visual analog scales in medication on and off states in PD and without medication in healthy controls. RESULTS: There were no side to side differences in heat pain intensity or between PD medication on state and PD medication off state. Unexpectedly, PD subjects reported a higher degree of unpleasantness in response to heat pain while on medication compared with the off state. CONCLUSIONS: These results suggest that the perception of heat pain is mediated, at least in part, by nondopaminergic systems in PD, while dopamine might modulate the affective component of pain.

Trials of neuroprotective therapies for Parkinson's disease: problems and limitations.

Since the initial results of the DATATOP study, considerable effort has been devoted over the past 20 years to test neuroprotective therapies for Parkinson's disease (PD). Two trials (CALM-PD-CIT and REAL-PET studies) used neuroimaging dopamine changes as a surrogate marker for PD progression, and concluded that pramipexole and ropinirole could have a neuroprotective effect compared to levodopa. However, it should be recognized that all the presynaptic dopamine markers currently available for SPECT and PET studies are potentially subject to regulatory changes. Consequently, the results of these two trials can also be interpreted in terms of drug-related differences in dopamine regulation. More recently, the delayed-start design was applied to test whether rasagiline could have a neuroprotective effect in PD (ADAGIO study). Unfortunately, a major limitation of the delayed-start design is that, whenever the active treatment has a symptomatic effect, the blinding can be broken. This can lead to unequally-distributed placebo responses during phase 2, and is also a potential source of raters' biases. None of the trials on neuroprotective therapies for PD has yet provided solid evidence for neuroprotection.

Proportion of injured drivers presenting to a tertiary care emergency department who engage in future impaired driving activities.

OBJECTIVE: We determined the rate of, and predictive factors for, subsequent impaired driving activity (IDA) by injured drivers treated in a Canadian tertiary care emergency department (ED) following a motor vehicle crash (MVC). METHODS: We retrospectively identified all drivers injured in a MVC who presented to our tertiary care, urban ED (1999-2003) and had their blood alcohol content (BAC) measured. Injured drivers were categorized by BAC: group 1, BAC = 0; group 2, 0 < BAC < or = 17.3 mM (80 mg/dL, legal limit); and group 3, BAC > 17.3 mM. IDA was defined as any of the following: a conviction for impaired driving; a 24-h or 90-day license suspension for impaired driving; involvement in alcohol-related MVC. Time to IDA following the index event between groups was compared with Kaplan-Meier survival analyses. Effects of covariates on time to IDA were analyzed using Cox proportional hazards models. RESULTS: During the study period, 1489 injured drivers met study criteria: 1171 in group 1, 51 in group 2, and 267 in group 3. During an average follow-up of 52.4 months, 82 (30.7%) group 3 drivers engaged in subsequent IDA, compared with 80 (6.8%) group 1 drivers (p < 0.0001). Youth, male gender, history of previous IDA, and the number of previous IDA events were all associated with a significant increase in subsequent IDA. A history of IDA was the strongest predictor of future IDA in group 1 (440% increase risk) and in group 3 (80% increased risk). The magnitude of BAC elevation above the legal limit was not predictive of future IDA. CONCLUSIONS: A high portion of injured impaired drivers who present to hospital engage in repeat IDA following discharge. Besides impairment at time of hospital visit, the best predictor of future IDA is a history of IDA prior to the index event.

Dopamine transporter PET in normal aging: dopamine transporter decline and its possible role in preservation of motor function.

OBJECTIVES: To determine the impact of age-related decline in dopamine transporter (DAT) expression on motor function in the elderly. METHODS: About 33 normal individuals of a wide age range were scanned with PET employing d-threo-[(11)C]-methylphenidate (MP, a marker of DAT) and [(11)C]-dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [(11)C]-MP and motor performance. RESULTS: Age ranged from 27- to 77-year old (mean +/- SD, 54.75 +/- 14.14). There was no age-related decline in binding potentials (BP) for [(11)C]-DTBZ. In contrast, [(11)C]-MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = -0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = -0.80). A differential effect of [(11)C]-MP on PPB could be observed according to age group. There was a positive relation between the PPB and [(11)C]-MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = -19.53, P = 0.031). CONCLUSIONS: Our findings confirm prior observations of age-related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid-adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly.

Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis.

INTRODUCTION: The purpose of this study was to perform a systematic review and meta-analysis of exogenous surfactant administration to assess whether this therapy may be useful in adult patients with acute respiratory distress syndrome. METHODS: We performed a computerized literature search from 1966 to December 2005 to identify randomized clinical trials. The primary outcome measure was mortality 28-30 days after randomization. Secondary outcome measures included a change in oxygenation (PaO2:FiO2 ratio), the number of ventilation-free days, and the mean duration of ventilation. Meta-analysis was performed using the inverse variance method. RESULTS: Two hundred and fifty-one articles were identified. Five studies met our inclusion criteria. Treatment with pulmonary surfactant was not associated with reduced mortality compared with the control group (odds ratio 0.97; 95% confidence interval (CI) 0.73, 1.30). Subgroup analysis revealed no difference between surfactant containing surface protein or not - the pooled odds ratio for mortality was 0.87 (95% CI 0.48, 1.58) for trials using surface protein and the odds ratio was 1.08 (95% CI 0.72, 1.64) for trials without surface protein. The mean difference in change in the PaO2:FiO2 ratio was not significant (P = 0.11). There was a trend for improved oxygenation in the surfactant group (pooled mean change 13.18 mmHg, standard error 8.23 mmHg; 95% CI -2.95, 29.32). The number of ventilation-free days and the mean duration of ventilation could not undergo pooled analysis due to a lack of sufficient data. CONCLUSION: Exogenous surfactant may improve oxygenation but has not been shown to improve mortality. Currently, exogenous surfactant cannot be considered an effective adjunctive therapy in acute respiratory distress syndrome.

Does this dyspneic patient in the emergency department have congestive heart failure?

CONTEXT: Dyspnea is a common complaint in the emergency department where physicians must accurately make a rapid diagnosis. OBJECTIVE: To assess the usefulness of history, symptoms, and signs along with routine diagnostic studies (chest radiograph, electrocardiogram, and serum B-type natriuretic peptide [BNP]) that differentiate heart failure from other causes of dyspnea in the emergency department. DATA SOURCES: We searched MEDLINE (1966-July 2005) and the reference lists from retrieved articles, previous reviews, and physical examination textbooks. STUDY SELECTION: We retained 22 studies of various findings for diagnosing heart failure in adult patients presenting with dyspnea to the emergency department. DATA EXTRACTION: Two authors independently abstracted data (sensitivity, specificity, and likelihood ratios [LRs]) and assessed methodological quality. DATA SYNTHESIS: Many features increased the probability of heart failure, with the best feature for each category being the presence of (1) past history of heart failure (positive LR = 5.8; 95% confidence interval [CI], 4.1-8.0); (2) the symptom of paroxysmal nocturnal dyspnea (positive LR = 2.6; 95% CI, 1.5-4.5); (3) the sign of the third heart sound (S(3)) gallop (positive LR = 11; 95% CI, 4.9-25.0); (4) the chest radiograph showing pulmonary venous congestion (positive LR = 12.0; 95% CI, 6.8-21.0); and (5) electrocardiogram showing atrial fibrillation (positive LR = 3.8; 95% CI, 1.7-8.8). The features that best decreased the probability of heart failure were the absence of (1) past history of heart failure (negative LR = 0.45; 95% CI, 0.38-0.53); (2) the symptom of dyspnea on exertion (negative LR = 0.48; 95% CI, 0.35-0.67); (3) rales (negative LR = 0.51; 95% CI, 0.37-0.70); (4) the chest radiograph showing cardiomegaly (negative LR = 0.33; 95% CI, 0.23-0.48); and (5) any electrocardiogram abnormality (negative LR = 0.64; 95% CI, 0.47-0.88). A low serum BNP proved to be the most useful test (serum B-type natriuretic peptide <100 pg/mL; negative LR = 0.11; 95% CI, 0.07-0.16). CONCLUSIONS: For dyspneic adult emergency department patients, a directed history, physical examination, chest radiograph, and electrocardiography should be performed. If the suspicion of heart failure remains, obtaining a serum BNP level may be helpful, especially for excluding heart failure.

Medical student selection: choice of a semi-structured panel interview or an unstructured one-on-one interview.

Reliability has been shown to be higher in structured medical admissions interviews as compared to unstructured interviews. This study reports the comparison of a proposed semi-structured panel interview with a current individual unstructured medical admissions interview. Inter-rater reliability coefficients were calculated, and correlations were estimated between panel, individual and academic scores. Admission status in 2003 was related to these scores by means of logistic regression. Both individual and panel interviews were significantly correlated with admissions status. The inter rater reliability coefficient (from individual interviews) was 0.12 whereas the interpanel reliability coefficient was 0.52. Panel interview: good across panel and within panel consistency of scoring. No effect of who asked the questions, question order, or interview duration on scoring. No correlation between panel interview scores and academic variables (MCAT, GPA). We found good inter-panel reliability, a high consistency within and between interview panels, and uniformly positive questionnaire responses. The panel interview measures something different from academic variables. These data, in conjunction with a strong sense from the medical and psychological literature supporting the reliability and validity of a semi-structured panel interview, support our decision to replace our individual interview with the panel interview.

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Interferon-gamma1b therapy in idiopathic pulmonary fibrosis: a metaanalysis.

CONTEXT: Despite the investigation of multiple therapeutic options, idiopathic pulmonary fibrosis (IPF) remains a devastating, progressively fatal disease. Much interest has focused on the use of interferon (IFN)-gamma1b therapy, but the efficacy of this treatment has not been proven. OBJECTIVE: To determine whether IFN treatment reduces mortality in patients with IPF. DESIGN: A meta-analysis of randomized controlled trials evaluating the use of IFN-gamma1b as treatment for IPF. MAIN OUTCOME MEASURE: Mortality in patients treated with IFN-gamma1b was compared to mortality in patients treated with control therapies. RESULTS: A total of three studies involving 390 patients was included in the analysis. IFN-gamma1b therapy was associated with reduced mortality (hazard ratio [HR], 0.418; 95% confidence interval [CI], 0.253 to 0.690; p = 0.0003). A comparison of mortality at different time points revealed that IFN-gamma1b therapy was associated with significantly reduced mortality at 1 year (0.0861; 95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p < 0.0001), 650 days (0.1939; 95% CI, 0.1386 to 0.2492; p < 0.0001), and 2 years (0.2652; 95% CI, 0.1652 to 0.3652; p < 0.0001). CONCLUSION: When the results of multiple studies are combined in a meta-analysis, IFN-gamma1b therapy is associated with reduced mortality.

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis.

BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.

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.