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Barthel H.,University of Leipzig | Seibyl J.,Institute for Neurodegenerative Disorders | Sabri O.,University of Leipzig
Expert Review of Neurotherapeutics | Year: 2015

PET is a non-invasive imaging technique which allows the visualization and quantification of molecular processes, offering sensitive and early disease detection. Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to memory loss and other functional impairments. By employing different tracers targeting neurodegeneration, amyloid and tau aggregates, cholinergic neurotransmission, neuroinflammation and other processes, PET imaging enhances our understanding of the potential triggers of AD, the chronology of molecular events in AD, the detection of early AD, differentiation of AD dementia from other dementia disorders and the development of better drugs to treat AD. As such, PET imaging at different disease stages (asymptomatic, prodromal and dementia stages) is on its way to becoming a valuable routine clinical biomarker and a drug testing and research tool in AD. © 2015 Informa UK, Ltd. Source

Cosgrove K.P.,Yale University | Esterlis I.,Yale University | McKee S.A.,Yale University | Bois F.,Yale University | And 6 more authors.
Archives of General Psychiatry | Year: 2012

Context: Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and response to nicotine therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β 2 subunit (β 2*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men. Objectives: To examine β 2*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among β 2*-nAChR availability, tobacco smoking characteristics, and female sex steroid hormone levels. Design: Male (n = 26) and female (n = 28) tobacco smokers participated in an iodide 123-labeled 5-iodo-A-85380 ([ 123I]5-IA) single-photon emission computed tomography (SPECT) imaging session at 7 to 9 days of abstinence. Age-matched male (n = 26) and female (n = 30) nonsmokers participated in a [ 123I]5-IA SPECT imaging session. All participants completed a magnetic resonance imaging study. Setting: Academic imaging center. Participants: Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56). Main Outcome Measure: The [ 123I]5-IA SPECT images were converted to equilibrium distribution volumes and were analyzed using regions of interest. Results: The β 2*-nAChR availability was significantly higher in male smokers compared with male nonsmokers in striatum, cortex, and cerebellum, but female smokers did not have higher β 2*-nAChR availability than female nonsmokers in any region. In women, β 2*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the SPECT imaging day. In female smokers on imaging day, the progesterone level was positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal. Conclusions: The regulatory effects of nicotine in the brain (ie, tobacco smoking-induced upregulation of β 2*-nAChRs) seem to be distinctly different between men and women, and female sex steroid hormones likely have a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. To treat female smokers more effectively, it is critical that nonnicotinic-mediated medications should be explored. ©2012 American Medical Association. All rights reserved. Source

Schapira A.H.V.,University College London | McDermott M.P.,University of Rochester | Barone P.,University of Salerno | Comella C.L.,Rush University Medical Center | And 7 more authors.
The Lancet Neurology | Year: 2013

Background: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). Methods: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854. Findings: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug. Interpretation: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects. © 2013 Elsevier Ltd. Source

Berg D.,German Center for Neurodegenerative Diseases | Marek K.,Institute for Neurodegenerative Disorders | Ross G.W.,VA Pacific Islands Health Care System | Ross G.W.,Kuakini Medical Center | Poewe W.,University of Innsbruck
Movement Disorders | Year: 2012

It is currently widely acknowledged that the natural history of PD includes a preclinical phase, and there are increasing efforts to identify markers that would allow the identification of individuals at risk for PD. Here, we discuss the issues related to defining at-risk populations for PD and review findings of current population-based cohorts that have reported potential biomarkers for PD, such as the Honolulu-Asia Aging Study (HAAS) and the PRIPS (Prospective Validation of Risk factors for the development of Parkinson Syndromes) study. We also discuss enriched risk cohorts designed to evaluate specificity and predictive value of markers exemplified by the PARS (Parkinson Associated Risk Study) and the TREND (Tübinger evaluation of Risk factors for the Early detection of NeuroDegeneration) study. Although there is still a long way to go, studies designed according to these concepts might eventually provide sufficient data to form the basis for future screening programs for PD risk to be applied at a population level. © 2012 Movement Disorder Society. Source

Di Iorio C.R.,Vanderbilt University | Watkins T.J.,Vanderbilt University | Dietrich M.S.,Vanderbilt University | Cao A.,Vanderbilt University | And 9 more authors.
Archives of General Psychiatry | Year: 2012

Context: MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial. Objective: To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin 2A receptor levels. Design: Cross-sectional case-control study comparing serotonin 2A receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin 2A receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin 2A receptor levels in the cerebral cortex were determined using serotonin 2A-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer. Setting: Academic medical center research laboratory. Participants: A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness. Main Outcome Measures: Cortical serotonin 2A receptor nondisplaceable binding potential (serotonin 2ABP ND). Results: MDMA users had increased serotonin 2ABP ND in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal- parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin 2ABP NDin frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin 2ABP ND. Conclusions: The recreational use of MDMA is associated with long-lasting increases in serotonin 2A receptor density. Serotonin 2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications. ©2012 American Medical Association. All rights reserved. Source

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