This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.

Purpose

Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer’s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.

Methods

In this study 238 [11C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [11C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 ± 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 ± 8 years) and 51 healthy controls (mean age 67.4 ± 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 ± 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.

Results

[11C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [11C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [11C]PIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted.

Conclusion

This study demonstrated the robustness of [11C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.

Electronic supplementary material

The online version of this article (doi:10.1007/s00259-012-2237-2) contains supplementary material, which is available to authorized users.

Background

Non-motor symptoms are present in Parkinson's disease (PD) and a key determinant of quality of life. The Non-motor Symptoms Scale (NMSS) is a validated scale that allows quantifying frequency and severity (burden) of NMS. We report a proposal for using NMSS scores to determine levels of NMS burden (NMSB) and to complete PD patient classification.

Methods

This was an observational, cross-sectional international study of 935 consecutive patients. Using a distribution of NMSS scores by quartiles, a classification based on levels from 0 (no NMSB at all) to 4 (very severe NMSB) was obtained and its relation with Hoehn and Yahr (HY) staging, motor and health-related quality of life scales was analyzed. Concordance between NMSB levels and grouping based on clinician's global impression of severity, using categorical regression, was determined. Disability and HRQoL predictors were identified by multiple regression models.

Results

The distribution of motor and QoL scales scores by HY and NMSB levels was significantly discriminative. The difference in the classification of cases for both methods, HY and NMSB, was significant (gamma = 0.45; ASE = 0.032). Concordance between NMSB and global severity-based levels from categorical regression was 91.8%, (kappaw = 0.97). NMS score was predictor of disability and QoL.

Conclusions

Current clinical practice does not address a need for inclusion of non-motor scores in routine assessment of PD in spite of the overwhelming influence of NMS on disability and quality of life. Our data overcome the problems of “pure motor assessment” and we propose a combined approach with addition of NMSB levels to standard motor assessments.

[11C]Pittsburgh Compound B positron emission tomography has now been extensively used to evaluate the amyloid load in different types of dementia and has become a powerful research tool in the field of neurodegenerative diseases. In the present short review we discuss the properties of amyloid imaging agent [11C]Pittsburgh Compound B, the different modalities of molecular imaging, image processing and data analysis, and newer amyloid imaging agents.

Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used 18F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one 18F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen 18F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal 18F-dopa uptake. Increased putaminal 18F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.

Ecstasy (MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used 18F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean 3·22 years. We studied 14 ex-ecstasy users, 14 polydrug-using controls (matched to the ex-users for other recreational drug use) and 12 drug-naïve controls. Each participant underwent one 18F-dopa PET, cognitive assessments, and hair and urinary analysis to corroborate drug use history. The putamen 18F-dopa uptake of ex-ecstasy users was 9% higher than drug-naïve controls (p=0·021). The putamen uptake of polydrug-using controls fell between the other two groups, suggesting the hyperdopaminergic state in ex-ecstasy users may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy use and striatal 18F-dopa uptake. Increased putaminal 18F-dopa uptake in ex-ecstasy users after an abstinence of over three years (mean) suggests that the effects are long-lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are needed to elucidate the significance of these findings as they may have important public health implications.

After 40 years of clinical experience, levodopa remains the gold standard treatment for Parkinson’s disease (PD) despite the recent emergence of a host of new therapies. Some physicians are cautious when prescribing levodopa because of its association with motor complications. Evidence now suggests that levodopa-associated complications are a result of deep troughs in delivery of levodopa to the brain caused by the short plasma half-life of conventional levodopa formulations (levodopa and a dopa decarboxylase inhibitor [DDCI]). Dosing strategies, such as dose increases and dose fractionation, may be effective in the short term. For the longer-term, levodopa/carbidopa/entacapone provides pharmacokinetically optimized levodopa therapy that significantly increases the plasma half-life and bioavailability of levodopa, providing more consistent plasma levodopa levels without deep troughs. Evidence from clinical trials in PD patients experiencing re-emergence of symptoms due to wearing-off has consistently shown that levodopa/DDCI and entacapone significantly increases ON-time and affords greater functionality, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) with conventional levodopa. These trials have also shown that levodopa/DDCI and entacapone is generally well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re-emergence of symptoms due to wearing-off may benefit from optimized levodopa therapy with levodopa/carbidopa/entacapone.

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson's Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson's Disease Rating Scale III score in the off‐medication state. Seven patients had 18F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal 18F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal 18F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.

In this review we report novel sensitive imaging biomarkers for Parkinson’s disease (PD) and its atypical variants. Diffusion tensor imaging and transcranial brain sonography are potentially promising techniques that can differentiate typical PD from atypical variants (multiple system atrophy and progressive supranuclear palsy) and from benign tremor disorders. Non-motor symptoms, such as dementia, depression, and sleep disruption, are often more distressing to PD patients than their slowness and stiffness. Dopamine replacement treatment can also lead to complications such as dyskinesias, impulse control disorders, and psychosis. Recent positron emission tomography studies have helped to clarify the physiopathological mechanisms underlying dementia and compulsive gambling in PD and provide a rationale for therapeutic strategies.

Background

Microglial cell activation and cerebral function impairment are described in both chronic hepatitis C viral (HCV) and Human-Immune-Deficiency viral (HIV) infections. The aim of this study was to investigate the effect of acute HCV infection upon cerebral function and microglial cell activation in HIV-infected individuals.

Methods

A case-control study was conducted. Subjects with acute HCV and chronic HIV coinfection (aHCV) were compared to matched controls with chronic HIV monoinfection (HIVmono). aHCV was defined as a new positive plasma HCV RNA within 12 months of a negative RNA test. Subjects underwent neuro-cognitive testing (NCT), cerebral proton magnetic resonance spectroscopy (1H-MRS) and positron emission tomography (PET) using a 11C-radiolabeled ligand (PK11195), which is highly specific for translocator protein 18 kDA receptors on activated microglial cells. Differences between cases and controls were assessed using linear regression modelling.

Results

Twenty-four aHCV cases completed NCT and 1H-MRS, 8 underwent PET. Of 57 HIVmono controls completing NCT, 12 underwent 1H-MRS and 8 PET. Subjects with aHCV demonstrated on NCT, significantly poorer executive function (mean (SD) error rate 26.50(17.87) versus 19.09(8.12), p = 0.001) and on 1H-MRS increased myo-inositol/creatine ratios (mI/Cr, a marker of cerebral inflammation) in the basal ganglia (ratio of 0.71(0.22) versus 0.55(0.23), p = 0.03), compared to subjects with HIVmono. On PET imaging, no difference in 11C-PK11195 binding potential (BP) was observed between study groups (p>0.10 all cerebral locations), however lower BPs were associated with combination antiretroviral therapy (cART) use in the parietal (p = 0.01) and frontal (p = 0.03) cerebral locations.

Discussion

Poorer cognitive performance and disturbance of cerebral metabolites are observed in subjects with aHC,V compared to subjects with HIVmono. Higher 11C-PK11195 BP was not observed in subjects with aHCV, but was observed in subjects not on cART.