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1.  Genetic impact on cognition and brain function in newly diagnosed Parkinson’s disease: ICICLE-PD study 
Brain  2014;137(10):2743-2758.
See Dujardin (doi:10.1093/brain/awu218) for a scientific commentary on this article. Nombela et al. present data from the ICICLE-PD study of cognition in newly diagnosed Parkinson’s disease. Consistent with the ‘Dual Syndrome’ hypothesis, impairments in executive function reflect a frontal dopaminergic syndrome modulated by COMT genotype, while visuospatial and memory deficits reflect disruption of temporo-parietal systems modulated by MAPT and APOE.
Parkinson’s disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the ‘Dual Syndrome’ hypothesis for cognitive impairment in Parkinson’s disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson’s disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson’s disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson’s disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson’s disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson’s disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson’s disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson’s disease.
doi:10.1093/brain/awu201
PMCID: PMC4163033  PMID: 25080285
Parkinson’s disease; cognition; functional MRI; genetics
2.  Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images 
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.
doi:10.1038/jcbfm.2011.177
PMCID: PMC3318150  PMID: 22214903
GABA; imaging; kinetic modelling; pharmacokinetics; positron emission tomography
3.  The spectrum of nonmotor symptoms in early Parkinson disease 
Neurology  2013;80(3):276-281.
Objective:
Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS in a cohort of patients with newly diagnosed PD.
Methods:
A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the Nonmotor Symptom Questionnaire. Other assessments included measures of motor disability (Movement Disorders Society–revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), disease severity (Hoehn & Yahr staging), depression (Geriatric Depression Scale), and global cognitive function (Mini-Mental State Examination and Montreal Cognitive Assessment).
Results:
The PD group reported a significantly greater number of NMS compared with controls (8.4 [4.3] vs 2.8 [2.6]). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS.
Conclusion:
NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
doi:10.1212/WNL.0b013e31827deb74
PMCID: PMC3589180  PMID: 23319473
4.  Characterizing mild cognitive impairment in incident Parkinson disease 
Neurology  2014;82(4):308-316.
Objective:
To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers.
Methods:
Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria.
Results:
The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold.
Conclusions:
In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.
doi:10.1212/WNL.0000000000000066
PMCID: PMC3929202  PMID: 24363137
5.  Investigating expectation and reward in human opioid addiction with [11C]raclopride PET 
Addiction Biology  2013;19(6):1032-1040.
The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [11C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.
doi:10.1111/adb.12073
PMCID: PMC4282066  PMID: 23829344
Addiction; dopamine; expectation; heroin; opioid; PET
6.  Reference region automatic extraction in dynamic [11C]PIB 
The positron emission tomography (PET) radiotracer [11C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [11C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [11C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [11C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [11C]PIB studies.
doi:10.1038/jcbfm.2013.133
PMCID: PMC3824180  PMID: 23921900
[11C]PIB; PET; reference region; supervised clustering
7.  Test–retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [11C]MePPEP 
Neuroimage  2014;97:151-162.
Background
Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand [11C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo.
Methods
Fifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [11C]MePPEP of 364 MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~ 30–60 min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity.
Results
Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (> 0.75) or excellent (> 0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions ± standard deviation 0.83 ± 0.03), rank shaping regularised spectral analysis (0.82 ± 0.05), and the 2kbv model (0.82 ± 0.09), but mSUVs were also reliable for most regions (0.79 ± 0.13). Mean test–retest changes among the five well-performing methods ranged from 12 ± 10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32 ± 13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6).
Conclusion
Quantification of CB1 receptor availability using [11C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [11C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
Graphical abstract
Cannabinoid receptor concentrations assessed with [11C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric VT map.
Highlights
•[11C]MePPEP is a PET tracer for cannabinoid receptors (CB1R).•Extensive evaluation of [11C]MePPEP data quantification strategies in large sample•We highlight successful methods to quantify CB1R in regions of interest.•Highly reliable parametric maps (ICC 0.83 ± 0.03) allow whole-brain surveys.•Modified standard uptake values also reliable, without arterial input functions
doi:10.1016/j.neuroimage.2014.04.020
PMCID: PMC4283194  PMID: 24736184
CB1; Positron Emission Tomography; Reliability; Intra-class correlation coefficient
8.  Amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease patients treated with bapineuzumab: A retrospective analysis 
Lancet neurology  2012;11(3):241-249.
Background
Amyloid-related imaging abnormalities (ARIA) have been reported in Alzheimer’s disease (AD) patients treated with bapineuzumab, a humanized monoclonal antibody to amyloid-β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). A better understanding of the incidence and risk factors for ARIA may further the development of amyloid-modifying treatments for AD.
Methods
Two neuroradiologists independently reviewed (kappa=0.76) and then reached consensus reads on over 2500 FLAIR-MRIs from 262 participants in three phase 2 studies of bapineuzumab. Subjects (n=210) were included in risk analyses if they had no evidence of ARIA-E on pre-treatment MRI, received bapineuzumab, and had at least one post-treatment MRI.
Findings
36/210 (17%) subjects developed ARIA-E during treatment; 28 of these 36 (78%) did not report associated symptoms. Adverse events reported in 8 symptomatic patients included headache, confusion, neuropsychiatric and gastrointestinal symptoms. 15/36 of the ARIA-E cases (42%) were detected only on central review. 13/15 received additional infusions while ARIA-E was present, without any associated symptoms reported. ARIA-E incidence increased with bapineuzumab dose (Hazard Ratio [HR] 2.24 per mg/kg increase in dose; p<0·001) and with APOE ε4 allele number (HR 2.55 per allele; p<0·001).
Interpretation
ARIA appears to represent a spectrum of imaging findings with variable clinical correlates, with some cases remaining asymptomatic even when treated through ARIA-E. The increased risk of ARIA with APOE ε4 and bapineuzumab dose, and the time course in relation to dosing, is consistent with alterations in vascular amyloid burden.
doi:10.1016/S1474-4422(12)70015-7
PMCID: PMC4063417  PMID: 22305802
9.  Microglia, Amyloid, and Glucose Metabolism in Parkinson's Disease with and without Dementia 
Neuropsychopharmacology  2013;38(6):938-949.
[11C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [11C]PIB-PET is a marker of amyloid, while [18F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [11C](R)PK11195, [18F]FDG, and [11C]PIB PET scans. Parametric maps of [11C](R)PK11195 binding potential, rCMRGlc, and [11C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [11C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression.
doi:10.1038/npp.2012.255
PMCID: PMC3629382  PMID: 23303049
Amyloid; Cognition; glucose metabolism; Imaging; Clinical or Preclinical; Microglia; Movement Disorders; Neurology; Parkinson's disease; Parkinson's disease dementia; PK11195; amyloid; microglia; Parkinson's disease; Parkinson's disease dementia; glucose metabolism
10.  Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation 
Neurology  2013;81(13):1176-1178.
We previously reported clinical improvement, increase in putamen [18F]-dopa uptake on PET imaging, and neuropathologic evidence of sprouting of dopaminergic fibers following chronic intraputaminal delivery of glial cell line–derived neurotrophic factor (GDNF) in idiopathic Parkinson disease (PD).1–3 We now provide clinical and PET evidence of persistent efficacy lasting for at least 3 years following cessation of GDNF infusion in a patient with PD. This is a single-case observational study, providing Class IV evidence.
doi:10.1212/WNL.0b013e3182a55ea5
PMCID: PMC3795600  PMID: 23946313
11.  Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients 
The Journal of Clinical Investigation  2014;124(3):1340-1349.
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.
doi:10.1172/JCI71640
PMCID: PMC3934188  PMID: 24531549
12.  Ventral striatal dopamine synthesis capacity is associated with individual differences in behavioral disinhibition 
Pathological gambling, alongside addictive and antisocial disorders, forms part of a broad psychopathological spectrum of externalizing disorders, which share an underlying genetic vulnerability. The shared externalizing propensity is a highly heritable, continuously varying trait. Disinhibitory personality traits such as impulsivity and novelty seeking (NS) function as indicators of this broad shared externalizing tendency, which may reflect, at the neurobiological level, variation in the reactivity of dopaminergic (DAergic) brain reward systems centered on the ventral striatum (VS). Here, we examined whether individual differences in ventral striatal dopamine (DA) synthesis capacity were associated with individual variation in disinhibitory personality traits. Twelve healthy male volunteers underwent 6-[18F]Fluoro-L-DOPA (FDOPA) positron emission tomography (PET) scanning to measure striatal DA synthesis capacity, and completed a measure of disinhibited personality (NS). We found that levels of ventral, but not dorsal, striatal DA synthesis capacity were significantly correlated with inter-individual variation in disinhibitory personality traits, particularly a propensity for financial extravagance and irresponsibility. Our results are consistent with preclinical models of behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of personality based vulnerability to pathological gambling and other externalizing disorders.
doi:10.3389/fnbeh.2014.00086
PMCID: PMC3954060  PMID: 24672449
addiction; dopamine; externalizing; impulsivity; positron emission tomography; pathological gambling; reward; ventral striatum
13.  Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD 
Neurology  2013;80(20):1850-1855.
Objective:
The underlying pathophysiology of tremor in Parkinson disease (PD) is unclear; however, it is known that tremor does not appear to be as responsive to dopaminergic medication as bradykinesia or rigidity. It is suggested that serotonergic dysfunction could have a role in tremor development.
Methods:
Using 11C-DASB PET, a marker of serotonin transporter binding, and clinical observations, we have investigated function of serotonergic terminals in 12 patients with tremor-predominant and 12 with akinetic-rigid PD. Findings were compared with those of 12 healthy controls.
Results:
Reductions of 11C-DASB in caudate, putamen, and raphe nuclei significantly correlated with tremor severity on posture and action, but not with resting tremor. The tremor-predominant group also showed reductions of 11C-DASB in other regions involved in motor circuitry, including the thalamus and Brodmann areas 4 and 10.
Conclusions:
Our findings support a role for serotonergic dysfunction in motor circuitries in the generation of postural tremor in PD.
doi:10.1212/WNL.0b013e318292a31d
PMCID: PMC3908354  PMID: 23596065
14.  Ventral Striatal Dopamine Synthesis Capacity Predicts Financial Extravagance in Parkinson’s Disease 
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.
doi:10.3389/fpsyg.2013.00090
PMCID: PMC3583186  PMID: 23450713
dopa decarboxylase; dopamine; disordered gambling; externalizing; impulse control disorders; impulsivity; reward; ventral striatum
15.  A Proposal for a Comprehensive Grading of Parkinson's Disease Severity Combining Motor and Non-Motor Assessments: Meeting an Unmet Need 
PLoS ONE  2013;8(2):e57221.
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.
doi:10.1371/journal.pone.0057221
PMCID: PMC3584126  PMID: 23468940
16.  Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study 
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.
doi:10.1136/jnnp.2006.106021
PMCID: PMC2117739  PMID: 17220289
17.  A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease 
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.
doi:10.1007/s00259-012-2237-2
PMCID: PMC3510420  PMID: 22961445
Amyloid; Multicentre PET; PIB; MCI; Alzheimer’s disease; Mild cognitive impairment; Cognition
18.  Acute HCV/HIV Coinfection Is Associated with Cognitive Dysfunction and Cerebral Metabolite Disturbance, but Not Increased Microglial Cell Activation 
PLoS ONE  2012;7(7):e38980.
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.
doi:10.1371/journal.pone.0038980
PMCID: PMC3395624  PMID: 22808022
19.  Technical aspects of amyloid imaging for Alzheimer's disease 
[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.
doi:10.1186/alzrt87
PMCID: PMC3226280  PMID: 21888692
20.  Persistent Nigrostriatal Dopaminergic Abnormalities in Ex-Users of MDMA (‘Ecstasy'): An 18F-Dopa PET Study 
Neuropsychopharmacology  2010;36(4):735-743.
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.
doi:10.1038/npp.2010.201
PMCID: PMC3037848  PMID: 21160467
MDMA; ecstasy; addiction; dopamine; F-dopa; PET; addiction & substance abuse; dopamine; imaging, clinical or preclinical; psychopharmacology; ecstasy
21.  Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective 
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.
PMCID: PMC2515910  PMID: 18728816
levodopa; wearing-off; dyskinesia; entacapone; Stalevo
23.  Persistent nigrostriatal dopaminergic abnormalities in ex-users of MDMA (‘Ecstasy’): an 18F-dopa PET study 
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.
doi:10.1038/npp.2010.201
PMCID: PMC3037848  PMID: 21160467
MDMA; ecstasy; addiction; dopamine; F-dopa; PET
24.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
doi:10.1212/WNL.0b013e31829d86e8
PMCID: PMC3776529  PMID: 23897875
25.  Recent imaging advances in the diagnosis and management of Parkinson’s disease 
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.
doi:10.3410/M1-82
PMCID: PMC2948338  PMID: 20948696

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