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The intricacy of brain biology is such that the variation of imaging end-points in health and disease exhibits an unpredictable range of spatial distributions from the extremely localized to the very diffuse. This represents a challenge for the two standard approaches to analysis, the mass univariate and the multivariate that exhibit either strong specificity but not as good sensitivity (the former) or poor specificity and comparatively better sensitivity (the latter). In this work, we develop an analytical methodology for positron emission tomography that operates an extraction ('shaving') of coherent patterns of signal variation while maintaining control of the type I error. The methodology operates two rotations on the image data, one local using the wavelet transform and one global using the singular value decomposition. The control of specificity is obtained by using the gap statistic that selects, within each eigenvector, a subset of significantly coherent elements. Face-validity of the algorithm is demonstrated using a paradigmatic data-set with two radiotracers, [(11)C]-raclopride and [(11)C]-(R)-PK11195, measured on the same Huntington's disease patients, a disorder with a genetic based diagnosis. The algorithm is able to detect the two well-known separate but connected processes of dopamine neuronal loss (localized in the basal ganglia) and neuroinflammation (diffusive around the whole brain). These processes are at the two extremes of the distributional envelope, one being very sparse and the latter being perfectly Gaussian and they are not adequately detected by the univariate and the multivariate approaches.

Background: Neuroinflammation plays an important role in HIV-associated neurological disorders; however, its role prior to the onset of symptomatic disease is unclear. We imaged microglial activation, the hallmark of neuroinflammation, in asymptomatic HIV-infected patients on effective combination ART., Methods: Seven neurologically and cognitively asymptomatic adults with chronic HIV-infection and nine healthy volunteers were investigated with [11C]-PK11195 PET, a marker of translocator protein (TSPO) expressed by activated microglia. In the HIV-infected patients, cognitive speed, accuracy and executive function were also assessed. Between-group differences in [11C]-PK11195 binding potential were localized throughout the brain with statistical parametric mapping (SPM) and associations between levels of [11C]-PK11195 binding and cognitive performance were interrogated using linear regression modelling., Results: In HIV-infected patients, Statistical parametric mapping detected clusters of significantly increased [11C]-PK11195 binding in corpus callosum (P = 0.001), anterior cingulate (P = 0.001), posterior cingulate (P = 0.008) and temporal (P = 0.026) and frontal (P = 0.038) areas. Cognitive functions were intact in the HIV group, however, a significant association between greater [11C]-PK11195 binding and poorer executive function performance was observed in the anterior cingulate (P = 0.031), corpus callosum and posterior cingulate (P = 0.001)., Conclusion: Despite effective control of HIV infection, neuroinflammation, as evidenced by the presence of focal cortical areas of activated microglia, occurs in asymptomatic HIV-infected patients and levels correlate with poorer executive performance. Further studies are needed to establish whether detection of activated microglia in HIV-infected patients represents a marker of future neurocognitive decline.

The quadripolar electrodes used for deep brain stimulation are designed to give flexibility in contact configuration, optimize therapeutic effect, and minimize side-effects. A patient with essential tremor did not tolerate a bipolar setting due to the emergence of a pulling sensation in her face. However, when the polarity of the contacts was reversed, a 70% higher voltage was tolerated. Using an electric field model, we predicted that this effect was due to the proximity of the topmost contact to the internal capsule. Post-operative imaging supported this prediction. These results demonstrate how a multi-disciplinary approach allows us to optimize parameter settings.

We previously reported clinical improvement, increase in putamen [(18)F]-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.

We review PET- and MR studies on hepatic encephalopathy (HE) metabolism in human subjects from the point of views of methods, methodological assumptions and use in studies of cirrhotic patients with clinically overt HE, cirrhotic patients with minimal HE, cirrhotic patients with no history of HE and healthy subjects. Key results are: (1) Cerebral oxygen uptake and blood flow are reduced to 2/3 in cirrhotic patients with clinically overt HE but not in cirrhotic patients with minimal HE or no HE compared to healthy subjects. (2) Cerebral ammonia metabolism is enhanced due to increased blood ammonia in cirrhotic patients but the kinetics of cerebral ammonia uptake and metabolism is not affected by hyperammonemia. (3) Recent advantages in MR demonstrate low-grade cerebral oedema not only in astrocytes but also in the white matter in cirrhotic patients with HE., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Deep brain stimulation (DBS) is a successful surgical therapy used to treat the disabling symptoms of movement disorders such as Parkinson's disease. It involves the chronic stimulation of disorder-specific nuclei. However, the mechanisms that lead to clinical improvements remain unclear. Consequently, this slows the optimization of present-day DBS therapy and hinders its future development and application. We used a computational model to calculate the distribution of electric potential induced by DBS and study the effect of stimulation on the spiking activity of a subthalamic nucleus (STN) projection neuron. We previously showed that such a model can reveal detailed spatial effects of stimulation in the vicinity of the electrode. However, this multi-compartmental STN neuron model can fire in either a burst or tonic mode and, in this study, we hypothesized that the firing mode of the cell will have a major impact on the DBS-induced effects. Our simulations showed that the bursting model exhibits behaviour observed in studies of high-frequency stimulation of STN neurons, such as the presence of a silent period at stimulation offset and frequency-dependent stimulation effects. We validated the model by simulating the clinical parameter settings used for a Parkinsonian patient and showed, in a patient-specific anatomical model, that the region of affected tissue is consistent with clinical observations of the optimal DBS site. Our results demonstrated a method of quantitatively assessing neuronal changes induced by DBS, to maximize therapeutic benefit and minimize unwanted side effects., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Post-mortem studies of multiple system atrophy (MSA) patients have shown widespread subcortical neurodegeneration. In this study, we have used 18F-dopa PET, a marker of monoaminergic nerve terminal function, to explore in vivo changes in striatal and extrastriatal dopamine, noradrenaline, and serotonin transmission for a cohort of patients with MSA with predominant parkinsonism. Fourteen patients with MSA, ten patients with idiopathic Parkinson's disease (PD) matched for disease duration, and ten healthy controls were studied with 18F-dopa PET. Regions of interest (ROIs) were placed to sample 18F-dopa uptake in thirteen structures and mean activity was compared between groups. The MSA patients showed significantly decreased 18F-dopa uptake in putamen, caudate nucleus, ventral striatum, globus pallidus externa and red nucleus compared to controls, whereas PD patients only had decreased 18F-dopa uptake in putamen, caudate nucleus, and ventral striatum. MSA cases with orthostatic hypotension had lower 18F-dopa uptake in the locus coeruleus than patients without this symptom. In conclusion, 18F-dopa PET showed more widespread basal ganglia dysfunction in MSA than in PD with similar disease duration, and extrastriatal loss of monoaminergic innervation could be detected in the red nucleus and locus coeruleus. In contrast to PD, there was no evidence of early compensatory increases in regional 18F-dopa uptake., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) has led to significant advances in the knowledge of the neurobiology and pathophysiology of Parkinson's disease (PD) and has also greatly contributed to the understanding of potential mechanisms involved in the development of treatment-induced complications. Initially, PET was mostly used to assess in vivo the severity of the nigrostriatal dopaminergic dysfunction and the resulting motor symptomatology in PD. It has been demonstrated that PET measurements of putaminal dopaminergic function, as measured by [(18)F]-Fluorodopa uptake, correlate well with stages of disease and symptom severity in PD patients, particularly with bradykinesia and rigidity. Analysis of metabolic changes across the brain has identified specific brain networks associated with the main motor features of the disease, including bradykinesia and tremor. In more recent years, the growing availability of new imaging radiotracers for monoaminergic and cholinergic neurons has enabled the evaluation of the non-dopaminergic brain pathways that are likely to be involved in the pathophysiology of non motor symptoms of PD, including depression, fatigue, sleep disorders, and cognitive impairment. Finally, β-amyloid imaging agents have been used to assess the influence of coexistent cortical Alzheimer pathology in PD. This review summarizes the findings from PET studies that have investigated pathophysiology and treatment of motor dysfunction and cognitive impairment in PD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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 ((1)H-MRS) and positron emission tomography (PET) using a (11)C-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 (1)H-MRS, 8 underwent PET. Of 57 HIVmono controls completing NCT, 12 underwent (1)H-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 (1)H-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 (11)C-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 (11)C-PK11195 BP was not observed in subjects with aHCV, but was observed in subjects not on cART.

Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons associated with intracellular Lewy inclusion bodies. The result is poverty of movement, increased muscle rigidity, and tremor at rest and on posture. Midbrain/nigral structural abnormalities can be demonstrated in vivo with both transcranial sonography (TCS) and diffusion tensor magnetic resonance imaging (DTI) while positron emission tomography (PET) and single photon emission computed tomography (SPECT) ligands exist to demonstrate dopamine terminal dysfunction. These radiotracers are markers of dopamine storage capacity, vesicular monoamine and dopamine transporter availability. While loss of putamen dopaminergic function leads to motor disability, Lewy bodies not only target dopamine neurons but have also been observed in serotoninergic, noradrenergic, and cholinergic neurons. As a consequence, non-dopaminergic neurotransmission is also impaired resulting in non-motor symptoms including sleep disturbance, fatigue, depression, dementia, and autonomic dysfunction. PET and SPECT ligands exist to interrogate the function of monoaminergic and cholinergic neurons. Cortical and limbic Lewy body disease is seen in more advanced PD and this can be detected with FDG PET as abnormal covariance between levels of resting brain metabolism in these regions. Additionally, widespread microglial activation can be detected in PD with PET. This review discusses the role of structural and functional imaging for understanding parkinsonian syndromes and aiding in their diagnosis and management., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Post-mortem and neuroimaging studies in Parkinson's disease (PD) have shown involvement of the brain serotoninergic, noradrenergic and cholinergic pathways alongside the characteristic degeneration of nigrostriatal dopamine neurons. The rate of progression of the degenerative process in these extrastriatal areas is still unclear. We used (18)F-dopa PET, a marker of aromatic aminoacid decarboxylase activity in monoaminergic neurons, to assess longitudinal changes in tracer uptake in brain noradrenergic, serotoninergic and extrastriatal dopaminergic structures over a 3-year period in a group of early PD patients. Ten PD patients had (18)F-dopa PET twice: at baseline and again after 37.1±21.5 months follow up. A standard object map was used to extract tracer influx constants (Ki) in 11 striatal and extrastriatal regions. Progressive decreases in (18)F-dopa Ki occurred over the follow-up period in the majority of the investigated areas, the fastest annual declines occurring in putamen (8.1%), locus coeruleus (7.8%), and globus pallidus interna (7.7%). Caudate and hypothalamus showed 6.3% and 6.1% annual Ki declines, respectively. At baseline, some structures showed increased levels of (18)F-dopa uptake in PD compared to controls (internal pallidum, locus coeruleus), indicating possible compensatory upregulation of monoamine turnover. These increased levels had normalised (globus pallidus interna) or become subnormal (locus coeruleus) at follow-up suggesting exhaustion of these mechanisms within the first years of disease. Loss of monoaminergic function in extrastriatal regions, as reflected by(18)F-dopa PET, is delayed and occurs independently from nigrostriatal degeneration. When assessing the efficacy of novel neuroprotective agents on nigrostriatal dysfunction in PD, (18)F-dopa PET could provide supplementary information concerning function of extrastriatal monoaminergic structures., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: In Positron Emission Tomography (PET) quantification of physiological parameters at the voxel level may result in unreliable estimates due to the high noise of voxel time activity curves. Global-Two-Stage (GTS), an estimation technique belonging to the group of "population approaches", can be used to tackle this problem. GTS was previously tested on simulated PET data and yielded substantial improvements when compared to standard estimation approaches such as Weighted NonLinear Least Squares (WNLLS) and Basis Function Method (BFM). In this work GTS performance is assessed in a clinical context using the neuroinflammation marker [(11)C]-(R)-PK11195 applied to a cohort of Huntington's disease (HD) patients with and without symptoms., Materials and Methods: Parametric maps of binding potential (BP(ND)) of 12 normal controls (NC), 9 symptomatic and 9 presymptomatic HD patients were generated by applying a modified reference tissue model that accounts for tracer vascular activity in both reference and target tissues (SRTMV). GTS was then applied to SRTMV maps and its performance compared with that of SRTMV. Three smoothed versions of SRTMV, obtained by filtering the original SRTMV maps with Gaussian filters of 3 mm, 5 mm and 7 mm Full Width Half Maximum (FWHM), were also included in the comparison. Since striatal degeneration is the hallmark of HD, sensitivity was assessed for all methods by computing the mean of z-scores in caudate, putamen and globus pallidus in the voxel-by-voxel statistical comparison of BP(ND) between HD and NC., Results: Application of GTS to parametric maps brought a substantial qualitative improvement to SRTMV maps to the extent that anatomical structures often became visible. In addition, most parameter estimates that were outside the physiological range with SRTMV were corrected by GTS. GTS yielded a 2.3-fold increase in sensitivity with respect to SRTMV for the symptomatic cohort (mean of striatal z-scores of 0.76 for SRTMV and 1.79 for GTS) and an even more substantial increase for the presymptomatic cohort (mean of striatal z-scores of 0.34 for SRTMV and 0.96 for GTS). The sensitivity of GTS was similar to the one obtained with a filter of 7 mm FWHM applied to the initial SRTMV maps but GTS images were not characterized by the notable loss of resolution typical of smoothed maps. GTS, additionally, does not require to change/define settings according to the tracer and level of noise, whereas the choice of the FWHM value of the Gaussian filter normally employed in the smoothing procedure is typically arbitrary., Conclusions: GTS is a powerful and robust tool for improving the quality of parametric maps in PET. The method is particularly appealing in that it can be applied to any tracer and estimation method, provided that initial estimates of the parameter vector and of its covariance are available. Although the benefits of GTS are far from being exhaustively assessed, the significant improvements obtained both on real and simulated data suggest that it could become an important tool for dynamic PET in the future., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Levodopa-induced dyskinesias are a common complication of long-term therapy in Parkinson's disease. Although both pre- and post-synaptic mechanisms seem to be implicated in their development, the precise physiopathology of these disabling involuntary movements remains to be fully elucidated. Abnormalities in glutamate transmission (over expression and phosphorylation of N-methyl-D-aspartate receptors) have been associated with the development of levodopa-induced dyskinesias in animal models of Parkinsonism. The role of glutamate function in dyskinetic patients with Parkinson's disease, however, is unclear. We used (11)C-CNS 5161 [N-methyl-3(thyomethylphenyl)cyanamide] positron emission tomography, a marker of activated N-methyl-D-aspartate receptor ion channels, to compare in vivo glutamate function in parkinsonian patients with and without levodopa-induced dyskinesias. Each patient was assessed with positron emission tomography twice, after taking and withdrawal from levodopa. Striatal and cortical tracer uptake was calculated using a region of interest approach. In the 'OFF' state withdrawn from levodopa, dyskinetic and non-dyskinetic patients had similar levels of tracer uptake in basal ganglia and motor cortex. However, when positron emission tomography was performed in the 'ON' condition, dyskinetic patients had higher (11)C-CNS 5161 uptake in caudate, putamen and precentral gyrus compared to the patients without dyskinesias, suggesting that dyskinetic patients may have abnormal glutamatergic transmission in motor areas following levodopa administration. These findings are consistent with the results of animal model studies indicating that increased glutamatergic activity is implicated in the development and maintenance of levodopa-induced dyskinesias. They support the hypothesis that blockade of glutamate transmission may have a place in the management of disabling dyskinesias in Parkinson's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5-year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, (11)C-PK11195 and (11)C-raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat-matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease-burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD., (Copyright © 2010 Wiley-Liss, Inc.)

Disabling fatigue is a symptom in a number of neurological diseases, including multiple sclerosis, stroke and Parkinson's disease. We used ¹⁸F-dopa and ¹¹C-DASB [N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine] positron emission tomography, markers of dopamine storage capacity and serotonin transporter availability, to investigate whether fatigue in Parkinson's disease is associated with dopaminergic and serotonergic dysfunction in basal ganglia and limbic circuits. Ten patients with Parkinson's disease and fatigue and 10 patients without fatigue had a ¹⁸F-dopa scan. Seven patients with and eight patients without fatigue also had a ¹¹C-DASB scan. The two groups were matched for age, disease duration and severity and daily intake of levodopa equivalent units. None had a history of depression or sleep disturbance. Using a region of interest analytical approach, we found that patients with fatigue had significantly lower serotonin transporter binding than patients without fatigue in the caudate, putamen, ventral striatum and thalamus. Striatal ¹⁸F-dopa uptake was similar in the fatigued and non-fatigued groups. Voxel-based analysis localized further relative serotonin transporter binding reductions in the cingulate and amygdala of the fatigue group, and ¹⁸F-dopa uptake reductions in the caudate and insula. We conclude that fatigue in Parkinson's disease is associated with reduced serotonergic function in the basal ganglia and limbic structures. Insular dopaminergic dysfunction could also play a role. These findings imply that strategies to increase brain level of serotonin would be a rational approach for relieving fatigue symptoms in Parkinson's disease and may also be relevant to alleviating fatigue in other clinical conditions.

PET studies in parkin-linked parkinsonism have generally been performed to assess striatal dopaminergic dysfunction and very little is known about the involvement of other monoaminergic structures in these patients. Measurements of (18)F-dopa uptake into serotonergic and noradrenergic structures provide an indication of the functional integrity of these nerve terminals. We used (18)F-dopa PET to assess changes in brain monoaminergic function associated with parkin mutations. Twelve patients with parkin-linked parkinsonism and 12 asymptomatic parkin heterozygotes were included in the study. Eleven healthy controls, 12 patients with idiopathic Parkinson's disease (IPD), and four patients with PINK1 mutations were also investigated for comparison. parkin patients and IPD patients were matched for striatal dopaminergic dysfunction, as measured by (18)F-dopa uptake. Compared to controls, parkin patients showed significant (18)F-dopa reductions in the caudate, putamen, ventral striatum, locus coeruleus, midbrain raphe, and pallidum. The same structures showed reduced uptake in IPD patients, who additionally had significant reductions in hypothalamus, ventral anterior thalamus, and pineal gland. Direct comparison of parkin with IPD patients showed that hypothalamus was targeted in IPD and midbrain raphe in parkin disease. Patients with PINK1 mutation and several parkin heterozygotes also showed monoaminergic dysfunction. These findings suggest that parkin patients and IPD patients with similar striatal dysfunction have different patterns of monoaminergic involvement, with more widespread dysfunction in IPD., (Copyright 2009 Elsevier Inc. All rights reserved.)

We used (11)C-raclopride PET, a marker of D(2) dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D(2) receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D(2) binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D(2) binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D(2) binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.

In this chapter the imaging changes associated with non-motor aspects of Parkinson's disease (PD) are reviewed. The relationship between reduced monoaminergic and cholinergic function and cognitive difficulties, depression, fatigue, sleep disorders, and dysautonomia is discussed and the relevance of Alzheimer pathology to PD dementia debated. Finally the discordance between the development of functional changes in PD and Braak staging is highlighted., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The most challenging issue when testing putative neuroprotective agents for Parkinson's disease (PD) in clinical trials is the assessment of the effect of the treatment on the neurodegenerative process. By measuring changes in symptoms severity, clinical rating scales represent an important tool to rate the progression of the disease. However, the rating of clinical symptoms is dependent on the examiner and the neuroprotective effect can be masked by the symptomatic effect of the therapy. 18F-dopa PET and 123I-beta-CIT SPECT have been shown to be able to monitor the progressive loss of presynaptic nigrostriatal projections in PD and have been used as surrogate biomarkers of disease in several recent clinical trials. In this article the value of imaging as a biomarker for testing neuroprotective agents in PD is reviewed., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Little is known about the rate of progression of striatal dysfunction in subjects with parkin-linked parkinsonism. Being a heterozygous parkin gene carrier may confer susceptibility to Parkinson's disease (PD). In a previous (18)F-dopa PET study, we reported that 69% of carriers of a single parkin mutation showed subclinical loss of putamen dopaminergic function. Using serial (18)F-dopa PET, the present longitudinal study addresses rates of progression of nigrostriatal dysfunction in both compound heterozygous (parkin-linked parkinsonism) and single heterozygous parkin gene carriers. Three symptomatic patients who were compound heterozygotes for parkin gene mutations and six asymptomatic heterozygous carriers were clinically assessed and had (18)F-dopa PET at baseline and again after 5 years. The patients with symptomatic parkin showed a mean 0.5% annual reduction in putamen (18)F-dopa uptake over 5 years while caudate (18)F-dopa uptake declined by a mean annual rate of 2 %. The asymptomatic heterozygote gene carriers showed a mean 0.56% annual reduction in putamen and 0.62 % annual reduction in caudate (18)F-dopa uptake. Neurological examination at both baseline and follow-up showed no evidence of parkinsonism. Loss of nigrostriatal dysfunction in parkin-linked parkinsonism occurs at a very slow rate compared to the 9-12% annual loss of putamen (18)F-dopa uptake reported for idiopathic PD. Although subclinical reductions of striatal (18)F-dopa uptake are common in carriers of a single parkin mutation their slow rate of progression suggests that few if any of these will develop clinical parkinsonism.

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.

Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson's disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD.

[11C](R)PK11195-PET is a marker of activated microglia while [11C]PIB-PET detects raised amyloid load. Here we studied in vivo the distributions of amyloid load and microglial activation in Alzheimer's disease (AD) and their relationship with cognitive status. Thirteen AD subjects had [11C](R)PK11195-PET and [11C]PIB-PET scans. Ten healthy controls had [11C](R)PK11195-PET and 14 controls had [11C]PIB-PET scans. Region-of-interest analysis of [11C](R)PK11195-PET detected significant 20-35% increases in microglial activation in frontal, temporal, parietal, occipital and cingulate cortices (p<0.05) of the AD subjects. [11C]PIB-PET revealed significant two-fold increases in amyloid load in these same cortical areas (p<0.0001) and SPM (statistical parametric mapping) analysis confirmed the localisation of these increases to association areas. MMSE scores in AD subjects correlated with levels of cortical microglial activation but not with amyloid load. The inverse correlation between MMSE and microglial activation is compatible with a role of microglia in neuronal damage.

Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntington's disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptor's loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntington's disease patients and premanifest Huntington's disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntington's disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntington's disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntington's disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntington's disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntington's disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntington's disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntington's disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.

A mild to moderate reduction in dopamine, noradrenaline and serotonin levels alongside a progressive loss of hypocretin cells and melanin hormone concentrating cells has been reported in the hypothalamus of PD at postmortem. Hypothalamic uptake of (18)F-dopa PET, an in vivo marker of dysfunction of monoaminergic neurons, is also significantly reduced in these patients. These data indicate a general impairment of hypothalamic function in PD. Dopamine receptors play an important role in the regulation of hypothalamic pathways. To date, possible changes in hypothalamic D(2) receptor availability have not been investigated in PD. The objective in this study was to assess dopamine D(2) receptor availability in hypothalamus of patients with idiopathic Parkinson's disease (PD) using positron emission tomography (PET) with (11)C-raclopride (RAC). We evaluated D(2) binding in RAC PET images of 14 PD patients using both region of interest (ROI) analysis and a voxel based approach. ROIs for the hypothalamus were traced on the subject's MRI co-registered to the PET image. (11)C-raclopride binding potentials (BP) for hypothalamus were obtained by applying ROIs onto parametric images. Findings were compared with those of 9 normal controls. We found a significant reduction in the mean hypothalamic RAC BP of the PD patients compared with the normal controls (0.2714+/-0.06 vs. 0.3861+/-0.04; mean+/-SD; p=0.0005). ROI results were confirmed with statistical parametric mapping (SPM). Individual hypothalamic BP values of PD patients did not correlate with age, disease duration, disease severity and levodopa equivalent dose. It remains to be ascertained whether the reductions in hypothalamic D(2) receptor availability seen in PD are disease related, the results of chronic exposure to levodopa or both. Our results provide further evidence of dopaminergic dysfunction in the hypothalamus in PD, and this may contribute to the development of sleep, endocrine and autonomic disorders.

Idiopathic Parkinson's disease (PD) is often accompanied by a pattern of executive deficits similar to those found in patients with frontal lobe lesions. We investigated whether such cognitive deficits are attributable to frontal lobe dysfunction as a direct consequence of impaired mesocortical dopaminergic transmission or an indirect consequence of impaired nigrostriatal dopaminergic function. For this purpose, changes in synaptic dopamine levels during task performance were monitored using a marker of dopamine D2-receptor availability (11)C-raclopride (RAC) PET. During RAC PET, seven patients with early symptomatic PD and seven age-matched healthy controls performed two types of behavioural task, a spatial working memory task (SWT) and a visuomotor control task (VMT). The SWT involves an executive process which is known to be impaired by both frontal lobe lesions and PD while the VMT is a control test for the visuomotor component of the SWT. Parametric images of RAC binding potential during performance of each task were generated, and compared between the tasks using voxel-based statistical parametric mapping as well as region of interest analysis. In controls, RAC binding was reduced in the dorsal caudate during performance of the SWT compared with the VMT, compatible with increased levels of endogenous dopamine release due to the executive process. In PD patients, this RAC binding reduction was not observed. In contrast, RAC binding in the anterior cingulate cortex within the medial prefrontal cortex was reduced by a comparable level during the SWT both in controls and PD patients. Statistical comparisons between controls and PD patients confirmed significantly attenuated dopamine release in the dorsal caudate in PD, but preserved levels of medial prefrontal dopamine release. Our data suggest that executive deficits in early patients with PD are associated with impaired nigrostriatal dopaminergic function resulting in abnormal processing in the cortico-basal ganglia circuit. In contrast, mesocortical dopaminergic transmission appears well preserved in early PD patients.

Unlabelled: PET allows the imaging of functional properties of the living tissue, whereas other modalities (CT, MRI) provide structural information at significantly higher resolution and better image quality. Constraints for injected radioactivity, technologic limitations of current instrumentation, and inherent spatial uncertainties on the decaying process affect the quality of PET images. In this article we illustrate how structural information of matched anatomic images can be used in a multiresolution model to enhance the signal-to-noise ratio of PET images. The model states a flexible relation between function and structure in the brain and replaces high-resolution information of PET images with appropriately scaled MRI or CT local detail. The method can be naturally extended to other functional imaging modalities (SPECT, functional MRI)., Methods: The methodology is based on the multiresolution property of the wavelet transform (WT). First, the coregistered structural image (MRI/CT) is downgraded to the resolution of the PET volume through appropriate filtering. Second, a redundant version of the WT is applied to both volumes. Third, a linear model is applied to the set of local coefficients of both image volumes and resulting parameters are recorded. The overall set of linear coefficients is then modeled as a mixture of multivariate gaussian distributions and fitted through a k-means algorithm. Finally, the local wavelet coefficients of the PET image are substituted by the corresponding values of the MRI/CT set calibrated according to the resulting clustering. The methodology was validated on digital simulated images and clinical data to evaluate its quantitative potential for individual as well as group analysis., Results: Application to real and simulated datasets shows very effective noise reduction (15% SD) while resolution is preserved., Conclusion: The methodology is robust to errors in the coregistration parameters, practical to implement, and computationally fast.

At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

Microglial activation may play a role in the pathogenesis of Huntington's disease (HD). Using 11C-(R)-PK11195 (PK) positron emission tomography (PET), we investigated microglial activation in HD presymptomatic gene carriers (PGCs), its relationship with striatal neuronal dysfunction measured with 11C-raclopride (RAC) PET, and the role of PK PET as a possible marker of subclinical disease progression in PGCs. Eleven HD PGCs underwent PK and RAC PET. Their results were compared with those of healthy controls. PK and RAC binding was measured using region-of-interest analysis. Regional increases in PK binding were also localized with voxel-based statistical parametric mapping. HD PGCs had lower striatal RAC binding than the controls but significantly higher striatal and cortical PK binding. Individual levels of higher striatal PK binding in PGCs correlated with lower striatal RAC binding and, after excluding one outlier, with a higher probability of developing HD in 5 years. The inverse association between striatal PK and RAC binding in PGCs continues into early to moderate stages of HD. This study demonstrated for the first time in vivo widespread microglial activation in preclinical HD which correlated with striatal neuronal dysfunction. These findings indicate that microglial activation is an early event in the pathogenic processes of HD and is associated with subclinical progression of disease. PK PET may be a useful marker of active subclinical disease and a means of investigating the efficacy of neuroprotection strategies in PGCs.

[(11)C]-(R)-PK11195 is presently the most widely used radiotracer for the monitoring of microglia activity in the central nervous system (CNS). Microglia, the resident immune cells of the brain, play a critical role in acute and chronic diseases of the central nervous system and in host defence against neoplasia. The purpose of this investigation was to evaluate the reliability and sensitivity of five kinetic modelling methods for the formation of parametric maps from dynamic [(11)C]-(R)-PK11195 studies. The methods we tested were the simplified reference tissue model (SRTM), basis pursuit, a simple target-to-reference ratio, the Logan plot and a wavelet based Logan plot. For the reliability assessment, the test-retest data consisted of four Alzheimer's patients that were scanned twice at approximately a six-week interval. For the sensitivity assessment, comparison of [(11)C]-(R)-PK11195 binding in Huntington's disease (HD) patients and normal subjects was performed using a group contrast to localize significant increases in mean pixel volume of distribution (VD) in HD. In all instances, a reference region kinetic extracted by a supervised clustering technique was used as input function. Reliability was assessed by use of the intra-class correlation coefficient (ICC) across a wide set of anatomical regions and it was found that the wavelet-based Logan plot, basis pursuit and SRTM gave the highest ICC values on average. The same methods produced the highest z-scores resulting from increases in mean striatal VD in HD patients compared with controls. The reference-to-target ratio and the Logan graphical approach were significantly less reliable and less sensitive.

Activated microglia have been proposed to play a major role in the pathogenesis of Huntington's Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using (11)C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with (11)C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.

Unlabelled: PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level., Methods: The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease., Results: The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596)., Conclusion: Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.

Objective: A small group of Parkinson's disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa-induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients., Methods: We used a two-scan positron emission tomography protocol to calculate the percentage change in (11)C-raclopride binding potential from a baseline withdrawal (off drug) state to the binding potential after an oral dose of levodopa. We related the subjective effects of levodopa to the effects on endogenous dopamine release of a pharmacological challenge with levodopa in eight control PD patients and eight patients with DDS., Results: PD patients with DDS exhibited enhanced levodopa-induced ventral striatal dopamine release compared with levodopa-treated patients with PD not compulsively taking dopaminergic drugs. The sensitized ventral striatal dopamine neurotransmission produced by levodopa in these individuals correlated with self-reported compulsive drug "wanting" but not "liking" and was related to heightened psychomotor activation (punding)., Interpretation: This provides evidence that links sensitization of ventral striatal circuitry in humans to compulsive drug use.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.

Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18F-dopa and 11C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased 18F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of 18F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of 18F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between 18F-dopa uptake and methamphetamine-induced change of 11C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between 11C-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of 18F-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.

Unlabelled: We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6 different PET centers around the world and then analyzed at a single site. To our knowledge, this is the first time such a centralized approach has been employed with (18)F-DOPA PET and this descriptive basic science article outlines the methods used., Methods: One hundred eighty-six PD patients were randomized (1:1) to ropinirole or L-DOPA therapy, and (18)F-DOPA PET was performed at baseline and again at 2 y. The primary outcome measure was the percentage change in putamen (18)F-DOPA influx rate constant (K(i)) from Patlak graphical analysis. Dynamic images were acquired and reconstructed using each center's individual protocols before being transferred to the site performing the central analysis. Once there, individual parametric K(i) images were created using a single analysis program without file formats being transformed from the original. Parametric images were then normalized to standard space and K(i) values extracted with a region of interest analysis. Significant K(i) changes were also localized at a voxel level with statistical parametric mapping. These processes required numerous checks to ensure the integrity of each dataset., Results: Three hundred twenty-five (170 baseline, 155 follow-up) dynamic PET datasets were acquired, of which 12 were considered uninterpretable due to missing time frames, radiopharmaceutical problems, lack of measured attenuation correction, or excessive head movement. In those datasets suitable for central analysis, after quality control and spatial normalization of the images had been applied, putamen (18)F-DOPA signal decline was found to be significantly (one third) slower in the ropinirole group compared with that of the L-DOPA group., Conclusion: Paired (18)F-DOPA-PET images acquired from multiple sites can be successfully analyzed centrally to assess the efficacy of potential disease-modifying therapies in PD. However, numerous options must be considered and data checks put in place before adopting such an approach. Centralized analysis offers the potential for improved detection of outcomes due to the standardization of the analytic approach and allows the analysis of large numbers of PET studies.

To investigate striatal and cortical pre- and postsynaptic dopaminergic function in parkin-linked parkinsonism, 13 unrelated patients homozygous or compound heterozygous for parkin mutations were studied with [(18)F]dopa and [(11)C]raclopride (RAC) PET. Data were compared with a young-onset Parkinson's disease (YOPD) cohort, matched for age, disease severity and duration, but negative for parkin mutations. Significant changes in [(18)F]dopa uptake and RAC binding potential (BP) were localized in striatum using regions of interest (ROIs) and throughout the entire brain volume with statistical parametric mapping (SPM). As expected, both YOPD and parkin patients showed significant decreases in striatal [(18)F]dopa uptake; however, in parkin patients, additional reductions in caudate and midbrain were localized with SPM. The RAC-BP was significantly decreased in striatal, thalamic and cortical areas (temporal, orbito-frontal and parietal cortex) in parkin compared with YOPD patients. Our [(18)F]dopa PET findings suggest that, compared with YOPD, parkin disease is associated with more severe and widespread presynaptic dopaminergic deficits. The global decreases in D2 binding found in parkin compared with YOPD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term dopaminergic agent exposure. Cortical reductions in D2 binding may contribute to the behavioural problems reported in parkin patients.

Cardiovascular responses after intravenous methamphetamine were assessed in 11 Parkinson's disease (PD) patients. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and electrocardiogram (ECG) were monitored for 103 minutes. After methamphetamine administration, SBP and DBP increased significantly in both PD and normal controls whereas placebo had no effect. In PD patients, however, the duration of SBP and DBP responses to methamphetamine and the maximum increase from baseline was attenuated compared with the controls. A significant correlation was found between individual BP responsiveness and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These findings suggest that in PD there is impairment of catecholamine release from peripheral sympathetic presynaptic terminals, which correlates with motor impairment., (Copyright 2003 Movement Disorder Society)

Using (11)C-raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in (11)C-raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by (18)F-dopa uptake. Localization of significant changes in (11)C-raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Molecular and clinical characterization of parkin-associated parkinsonism is well described; however, there are no data available on progression of dopamine terminal dysfunction in parkin-associated disease. We have used [(18)F]dopa PET serially to study members of a family with young-onset parkinsonism who are compound heterozygous for mutations in the parkin gene, having an exonic deletion and a novel intronic splice site mutation. Four patients have been studied twice, 10 years apart, to assess disease progression. Additionally, we have studied five asymptomatic family members, four of whom carry a single parkin mutation and one individual who has a normal genotype. Two of the carriers and the individual with the normal genotype had repeat [(18)F]dopa PET. The group of parkin patients showed a significantly slower loss of putamen [(18)F]dopa uptake (P = 0.0008) compared with a group of idiopathic Parkinson's disease (IPD) patients who had baseline putamen [(18)F]dopa uptake and disease severity similar to the parkin group. These results indicate that disease progression in patients with parkin mutations is slower than that of IPD patients. The group of asymptomatic parkin carriers also showed significant striatal dopaminergic dysfunction, and three of them developed subtle extrapyramidal signs. However, the two carriers scanned twice showed no progression over a 7-year period. The slower rate of disease progression in parkin patients may explain the near normal longevity of these patients with young onset parkinsonism.

Severe dyskinesias during the 'off' phases (periods of increased Parkinson's disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by (18)F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.