A PET-CT study on neuroinflammation in Huntington's disease patients participating in a randomized trial with laquinimod.

Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington's disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller-Gartner algorithm) were applied. Differences were sought in Unified Huntington's Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.

Dissociable effects of age and Parkinson's disease on instruction-based learning.

The cognitive deficits associated with Parkinson's disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson's disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson's disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson's might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson's Disease. Seventeen participants with Parkinson's disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson's group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson's show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.

Longitudinal changes in movement-related functional MRI activity in Parkinson's disease patients.

INTRODUCTION: Functional brain imaging has shown alterations in the basal ganglia, cortex and cerebellum in Parkinson's disease patients. However, few functional imaging studies have tested how these changes evolve over time. Our study aimed to test the longitudinal progression of movement-related functional activity in Parkinson's disease patients. METHODS: At baseline, 48 Parkinson's disease patients and 16 healthy controls underwent structural and functional magnetic resonance imaging during a joystick motor task. Patients had repeated imaging after 18-months (n = 42) and 36-months (n = 32). T-tests compared functional responses between Parkinson's disease patients and controls, and linear mixed effects models examined longitudinal differences within Parkinson's disease. Correlations of motor-activity with bradykinesia, rigidity and tremor were undertaken. All contrasts used whole-brain analyses, thresholded at Z > 3.1 with a cluster-wise P < 0.05. RESULTS: Baseline activation was significantly greater in patients than controls across contralateral parietal and occipital regions, ipsilateral precentral gyrus and thalamus. Longitudinally, patients showed significant increases in cerebellar activity at successive visits following baseline. Task-related activity also increased in the contralateral motor, parietal and temporal areas at 36 months compared to baseline, however this was reduced when controlling for motor task performance. CONCLUSION: We have shown that there are changes over time in the blood-activation level dependent response of patients with Parkinson's disease undertaking a simple motor task. These changes are observed primarily in the ipsilateral cerebellum and may be compensatory in nature.

Parkinson's disease laterality: a 11C-PE2I PET imaging study.

Asymmetry of striatal dopaminergic deficits and motor symptoms is a typical characteristic of idiopathic Parkinson's disease (PD). This study aims to characterise the trend of asymmetry in moderate-stage PD. We performed a 19-month longitudinal study in 27 patients with PET-CT imaging and appropriate clinical assessments. 11C-PE2I non-displaceable binding potential (BPND) was calculated bilaterally for the striatum at baseline and follow-up to estimate the in vivo density of striatal dopamine transporters (DAT). Changes in striatal 11C-PE2I BPND over time were more prominent in the ipsilateral as compared to contralateral side. Changes in MDS-UPDRS-III (motor component of the Movement Disorders Society Unified PD Rating Scale) were not different between the clinically most and least affected body sides. Our data support that the asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage PD. In contrast, during the above period, the asymmetry of motor symptoms was maintained between the clinically most and least affected body sides.

Astrocytes in Parkinson's disease: from preclinical assays to in vivo imaging and therapeutic probes.

Parkinson's disease (PD) is increasingly thought to be associated with glial pathology. Recently, research in neurodegenerative disorders has applied a greater focus to better understanding the role of astrocytes in the disease pathophysiology. In this article, we review results from the latest preclinical and clinical work, including functional imaging studies on astrocytes in PD and highlight key molecules that may prove valuable as biomarkers. We discuss how astrocytes may contribute to the initiation and progression of PD. We additionally present trials of investigational medicinal products and the current background for the design of future clinical trials.

Multimodal dopamine transporter (DAT) imaging and magnetic resonance imaging (MRI) to characterise early Parkinson's disease.

Idiopathic Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterised by the progressive loss of dopaminergic nigrostriatal terminals. Currently, in early idiopathic PD, dopamine transporter (DAT)-specific imaging assesses the extent of striatal dopaminergic deficits, and conventional magnetic resonance imaging (MRI) of the brain excludes the presence of significant ischaemic load in the basal ganglia as well as signs indicative of other forms of Parkinsonism. In this article, we discuss the use of multimodal DAT-specific and MRI protocols for insight into the early pathological features of idiopathic PD, including: structural MRI, diffusion tensor imaging, nigrosomal iron imaging and neuromelanin-sensitive MRI sequences. These measures may be acquired serially or simultaneously in a hybrid scanner. From current evidence, it appears that both nigrosomal iron imaging and neuromelanin-sensitive MRI combined with DAT-specific imaging are useful to assist clinicians in diagnosing PD, while conventional structural MRI and diffusion tensor imaging protocols are better suited to a research context focused on characterising early PD pathology. We believe that in the future multimodal imaging will be able to characterise prodromal PD and stratify the clinical stages of PD progression.

Dopamine Transporter Density in de novo Parkinson's Disease Does Not Relate to the Development of Levodopa-Induced Dyskinesias.

BACKGROUND: In Parkinson's disease (PD), the onset of levodopa-induced dyskinesias (LIDs) is difficult to predict. This study examines whether dopamine transporter (DAT)-specific SPECT imaging in de novo PD relates to later development of LIDs. METHODS: 42 de novo unilateral PD participants received DAT-specific SPECT imaging with 123I-FP-CIT at time of diagnosis. At five years post-diagnosis, all PD patients were clinically evaluated and divided into two groups based on whether they had or had not developed LIDs. Fourteen gender- and age-matched healthy volunteers undertook 123I-FP-CIT SPECT imaging and were included as controls. A semi-quantification approach was used for the 123I-FP-CIT data using the occipital cortex as the reference region. We calculated specific binding ratios (SBR) for the caudate and putamen (posterior and anterior putaminal subregions). In parallel, we analysed our 123I-FP-CIT dataset with a voxel-based analysis approach. RESULTS: PD patients had significantly lower striatal 123I-FP-CIT SBR values in comparison to controls (p<0.001). After five years, dyskinetic patients (N=10) were taking higher daily doses of dopaminergic medication (p<0.001) and had more severe disease (difference in Hoehn & Yahr staging scores p<0.05) as compared to the non-dyskinetic group (N=32). At the time of diagnosis, 123I-FP-CIT SBR values were not statistically different between the two groups for all striatal regions (p>0.05). SPM voxel-based analysis did not show a statistically significant difference between the two groups (p>0.05). CONCLUSION: 123I-FP-CIT SPECT imaging, performed at diagnosis in de novo early-stage PD could not differentiate patients who will develop LIDs within five years from those who will not.

Brain Imaging and Impulse Control Disorders in Parkinson's Disease.

PURPOSE OF REVIEW: Parkinson's disease (PD) has a wide spectrum of symptoms including the presence of psychiatric disease. At present, most treatment plans, comprised of dopaminergic drugs, are chronic and complex. Though dopaminergic agents are quite efficient in managing the motor aspects of the disease, chronic pharmacotherapy specifically with dopamine receptor agonists has been highly linked to the occurrence of Impulse Compulsive disorder (ICD), which can be problematic for individual patients. RECENT FINDINGS: Much of what is known today about PD-related ICD stems from brain imaging studies, however, evidence is not quite conclusive. Research in the field has been focused on identifying the underlying mechanisms of PD-related ICD and understanding the functions of the structures involved in the reward network. This article presents an update of recent findings from key neuroimaging studies in PD-related ICD, discusses results from controversial studies, and identifies areas for future research in the field.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Pallidal dopaminergic denervation and rest tremor in early Parkinson's disease: PPMI cohort analysis.

BACKGROUND: s: Over recent years there have been some conflicting reports upon the role of pallidal dopaminergic denervation in rest tremor in Parkinson's disease. OBJECTIVES: To clarify this issue we analyzed the clinical and 123I-FP-CIT SPECT data of a large cohort of early Parkinson's disease patients enrolled in the PPMI study. METHODS: Pallidal and striatal dopamine transporter uptake ratios were calculated in 382 patients (120 no-tremor, 60 tremor-dominant, and 202 indeterminate) and 150 controls. A region of interest (ROI) approach was used to estimate DAT uptake ratios from 123I-FP-CIT SPECT scans in the caudate nucleus, putamen, and globus pallidus after normalization to a DAT template. DAT uptake ratios for each region were compared between subgroups using ANCOVA and linear regression analyses were performed to evaluate the relationship between severity of rest tremor and regional DAT uptake ratios. RESULTS: PD patients had significantly lower DAT uptake ratios in the pallidum, putamen and caudate as compared to healthy controls (p < 0.001). ANCOVA showed inter-PD subgroup differences in DAT uptake ratios in the putamen and pallidum (p < 0.05) after adjustment for age and disease duration, with post-hoc comparisons revealing significantly higher DAT uptake ratios for the tremor-dominant subgroup as compared to non-tremor and indeterminate subgroups (p < 0.016). There was no significant relationship between rest tremor severity and pallidal DAT either in the tremor-dominant subgroup or in the total PD population. CONCLUSIONS: Pallidal dopaminergic denervation appears unrelated to rest tremor severity in early Parkinson's disease.

Restorative Strategies in Movement Disorders: the Contribution of Imaging.

PURPOSE OF REVIEW: The purpose of this review was to review the imaging, particularly positron emission tomography (PET), findings in neurorestoration studies in movement disorders, with specific focus on neural transplantation in Parkinson's disease (PD) and Huntington's disease (HD). RECENT FINDINGS: PET findings in PD transplantation studies have shown that graft survival as reflected by increases in dopaminergic PET markers does not necessarily correlate with clinical improvement. PD patients with more denervated ventral striatum and more imbalanced serotonin-to-dopamine ratio in the grafted neurons tended to have worse outcome. In HD transplantation studies, variable graft survival and clinical responses may be related to host inflammatory/immune responses to the grafts. Information gleaned from imaging findings in previous neural transplantation studies has been used to refine study protocol and patient selection in future trials. This includes identifying suitable candidates for transplantation using imaging markers, employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.