Win-Concurrent Sensory Cues Can Promote Riskier Choice.

Reward-related stimuli can potently influence behavior; for example, exposure to drug-paired cues can trigger drug use and relapse in people with addictions. Psychological mechanisms that generate such outcomes likely include cue-induced cravings and attentional biases. Recent animal data suggest another candidate mechanism: reward-paired cues can enhance risky decision making, yet whether this translates to humans is unknown. Here, we examined whether sensory reward-paired cues alter decision making under uncertainty and risk, as measured respectively by the Iowa Gambling Task and a two-choice lottery task. In the cued versions of both tasks, gain feedback was augmented with reward-concurrent audiovisual stimuli. Healthy human volunteers (53 males, 78 females) performed each task once, one with and the other without cues (cued Iowa Gambling Task/uncued Vancouver Gambling Task: n = 63; uncued Iowa Gambling Task/cued Vancouver Gambling Task: n = 68), with concurrent eye-tracking. Reward-paired cues did not affect choice on the Iowa Gambling Task. On the two-choice lottery task, the cued group displayed riskier choice and reduced sensitivity to probability information. The cued condition was associated with reduced eye fixations on probability information shown on the screen and greater pupil dilation related to decision and reward anticipation. This pupil effect was unrelated to the risk-promoting effects of cues: the degree of pupil dilation for risky versus risk-averse choices did not differ as a function of cues. Together, our data show that sensory reward cues can promote riskier decisions and have additional and distinct effects on arousal.SIGNIFICANCE STATEMENT Animal data suggest that reward-paired cues can promote maladaptive reward-seeking by biasing cost-benefit decision making. Whether this finding translates to humans is unknown. We examined the effects of salient reward-paired audiovisual cues on decision making under risk and uncertainty in human volunteers. Cues had risk-promoting effects on a risky choice task and independently increased task-related arousal as measured by pupil dilation. By demonstrating risk-promoting effects of cues in human participants, our data identify a mechanism whereby cue reactivity could translate into maladaptive behavioral outcomes in people with addictions.

Exercise increases caudate dopamine release and ventral striatal activation in Parkinson's disease.

BACKGROUND: The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD). METHODS: Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11 C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions. RESULTS: The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03). CONCLUSIONS: Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society.

Habitual exercisers versus sedentary subjects with Parkinson's Disease: Multimodal PET and fMRI study.

BACKGROUND: The benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum. OBJECTIVE: To examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD. METHODS: Eight habitual exercisers and 9 sedentary subjects completed [11 C]raclopride PET scans before and after stationary cycling to determine exercise-induced release of endogenous DA in the dorsal striatum. Additionally, functional MRI assessed ventral striatum activation during reward anticipation. All participants completed motor (UPDRS III; finger tapping; and timed-up-and-go) and nonmotor (Beck Depression Inventory; Starkstein Apathy Scale) assessments. RESULTS: [11 C]Raclopride analysis before and after stationary cycling demonstrated greater DA release in the caudate nuclei of habitual exercisers compared to sedentary subjects (P < 0.05). Habitual exercisers revealed greater activation of ventral striatum during the functional MRI reward task (P < 0.05) and lower apathy (P < 0.05) and bradykinesia (P < 0.05) scores versus sedentary subjects. CONCLUSIONS: Habitual exercise is associated with preservation of motor and nonmotor function, possibly mediated by increased DA release. This study formulates a foundation for prospective, randomized controlled studies. © 2018 International Parkinson and Movement Disorder Society.

A before-after study of hospital use in two frail populations receiving different home-based services over the same time in Vancouver, Canada.

BACKGROUND: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use. METHODS: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service. RESULTS: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively. CONCLUSIONS: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise.

In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers.

INTRODUCTION: We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. METHODS: All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). RESULTS: FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. CONCLUSIONS: Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene.

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.

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.

Effectiveness of educational interventions on asthma self-management in Punjabi and Chinese asthma patients: a randomized controlled trial.

BACKGROUND: Asthma tends to be less well controlled among ethnic minority groups, and its prevalence in new immigrants increases significantly the longer they are in Canada; mainly due to their lack of familiarity with English and difficulty understanding information regarding the disease, health literacy, cultural issues, housing conditions, and lack of access to appropriate care services. OBJECTIVE: To explore the effectiveness of different formats of culturally relevant information and its impact on asthma patients' self-management within the Punjabi, Mandarin, and Cantonese communities. METHODS: Using a participatory approach, we developed and tested knowledge and community educational videos (with similar information, but used a different approach, i.e., scientific vs. colloquial) and a pictorial pamphlet. A total of 92 physician-diagnosed adult asthma patients (47 Chinese and 45 Punjabi) were assigned at random to three experimental groups (watched one or both videos) and one comparison group (read pictorial pamphlet) and participated in three in-person interviews and one telephone interview within a 9-month period. Patients received education on asthma self-management via videos and pamphlet and outcomes, including their knowledge of asthma triggers (environmental-related and behavioral-related triggers) and symptoms; inhaler use skills and patient-reported medication adherence were measured. RESULTS: Knowledge of asthma symptoms, inhaler use, and understanding of physician's instructions improved significantly from pretest to 3 months post-intervention follow-up among all participants. CONCLUSIONS: Participants performed significantly better at follow-up than they did at baseline assessment, with the most notable improvements observed in the group that watched both community and knowledge videos. The results suggest that short, simple, culturally, and linguistically appropriate interventions can promote knowledge gain about asthma and improve inhaler use that can be sustained over the short term. Such interventions that provide authentic learning materials that draw on patients' life experiences and sociocultural context can overcome certain limitations of conventional patient education approaches.

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.

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.

Dopamine turnover increases in asymptomatic LRRK2 mutations carriers.

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinson's disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: ¹8F-fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate K(occ), a marker of DA synthesis and storage; ¹¹C-methylphenidate (MP, a DAT marker) and ¹¹C-dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BP(ND_MP) and BP(ND_DTBZ). On average, EDV showed the largest reduction from age-matched control values (42%) followed by BP(ND_MP) (23%) and BP(ND_DTBZ) (17%), whereas K(occ) remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT.

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.

The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review.

STUDY OBJECTIVE: To synthesize the evidence on the effect of a bolus dose of etomidate on adrenal function, mortality, and health services utilization compared with other induction agents used for rapid sequence intubation. METHODS: We developed a systematic search strategy and applied it to 10 electronic bibliographic databases. We hand searched journals; reviewed conference proceedings, gray literature, and bibliographies of relevant literature; and contacted content experts for studies comparing a bolus dose of etomidate with other induction agents. Retrieved articles were reviewed and data were abstracted with standardized forms. Data were pooled with the random-effects model if at least 4 clinically homogenous studies of the same design reported the same outcome measure. All other data were reported qualitatively. RESULTS: From 3,083 titles reviewed, 20 met our inclusion criteria. Pooled mean cortisol levels were lower in elective surgical patients induced with etomidate compared with those induced with other agents between 1 and 4 hours postinduction. The differences varied from 6.1 microg/dL (95% confidence interval [CI] 2.4 to 9.9 microg/dL; P=.001) to 16.4 microg/dL (95% CI 9.7 to 23.1 microg/dL; P<.001). Two studies in critically ill patients reported significantly different cortisol levels up to 7 hours postinduction. None of the studies reviewed, nor our pooled estimate (odds ratio 1.14; 95% CI 0.81 to 1.60), showed a statistically significant effect on mortality. Only one study reported longer ventilator, ICU, and hospital lengths of stay in patients intubated with etomidate. CONCLUSION: The available evidence suggests that etomidate suppresses adrenal function transiently without demonstrating a significant effect on mortality. However, no studies to date have been powered to detect a difference in hospital, ventilator, or ICU length of stay or in mortality.

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.

Influence of the mother's preceding pregnancies on fetal development and postnatal survival of the neonate, in normal pregnancy. An immunological phenomenon?

OBJECTIVES: The objective of this study is to test for an association between the sex of conceptuses of the mother's preceding pregnancies and fetal development and early neonatal survival in normal pregnancy. METHODS: A population of 27,243 neonates, including a subsample of 7,773 "newborn/mother/placenta units" were divided into cohorts according to the sex of the neonate and the sex and number of conceptuses of the mother's preceding pregnancies. The average birth weight, placenta weight and early neonatal mortality rate were measured for each cohort and compared. The "dose effect" of preceding pregnancy was tested by linear and quadratic regression analysis, and by chi-square trend test for linearity of proportions. RESULTS: The results have shown an association between these three variables and the preceding pregnancies of the mother. Fetal development and early survival of the neonate are positively associated with the mother's preceding pregnancies of same sex as the neonate, and negatively associated with the preceding pregnancies of opposite sex to the neonate. The strength of the phenomenon increases with parity, at least for the first three parities. The association is statistically significant. CONCLUSIONS: The association between fetal development and neonatal survival and preceding pregnancies of the mother would be compatible with the action of male and female specific antigens capable of affecting selective implantation of blastocysts, which commands subsequent fetal development as well as early neonatal survival.

Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study.

Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-raclopride (D2-type receptor marker). For denervation <75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation <90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with (11)C-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to approximately 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.

Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease.

OBJECTIVE: To determine the sensitivity of positron emission tomography with 11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. METHODS: Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. RESULTS: Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. INTERPRETATION: Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible "floor" effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident.

Visualizing vesicular dopamine dynamics in Parkinson's disease.

It has been suggested that dopamine derived from exogenous levodopa may not follow vesicular dynamics in Parkinson's disease (PD). Using a novel PET method based on the sensitivity of [(11)C]-dihydrotetrabenazine (DTBZ) binding to changes in vesicular dopamine levels, we show here that striatal [(11)C]-DTBZ binding decreases after levodopa administration in advanced PD, likely reflecting an increase in vesicular dopamine levels. Endogenous dopamine and exogenously derived dopamine seem to follow the same vesicular dynamics.

Effect of school-based physical activity interventions on body mass index in children: a meta-analysis.

BACKGROUND: The prevalence of childhood obesity is increasing at an alarming rate. Many local governments have enacted policies to increase physical activity in schools as a way to combat childhood obesity. We conducted a systematic review and meta-analysis to determine the effect of school-based physical activity interventions on body mass index (BMI) in children. METHODS: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials up to September 2008. We also hand-searched relevant journals and article reference lists. We included randomized controlled trials and controlled clinical trials that had objective data for BMI from before and after the intervention, that involved school-based physical activity interventions and that lasted for a minimum of 6 months. RESULTS: Of 398 potentially relevant articles that we identified, 18 studies involving 18 141 children met the inclusion criteria. The participants were primarily elementary school children. The study duration ranged from 6 months to 3 years. In 15 of these 18 studies, there was some type of co-intervention. Meta-analysis showed that BMI did not improve with physical activity interventions (weighted mean difference -0.05 kg/m(2), 95% confidence interval -0.19 to 0.10). We found no consistent changes in other measures of body composition. INTERPRETATION: School-based physical activity interventions did not improve BMI, although they had other beneficial health effects. Current population-based policies that mandate increased physical activity in schools are unlikely to have a significant effect on the increasing prevalence of childhood obesity.

Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system. OBJECTIVE: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design. METHODS: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra. RESULTS: Longitudinal [11C]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [11C]PBR28 binding from baseline averaging 0.128±0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed. CONCLUSION: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.