Flavia Niccolini

Serotonin in Parkinson's disease

Parkinsons disease is a chronic neurodegenerative disorder characterized by the motor symptoms of bradykinesia, tremor, rigidity and postural instability. However, non-motor symptoms such as chronic fatigue, depression, dementia and sleep disturbances are also frequent and play a significant role with negative consequences in the quality of life of patients with Parkinsons disease. Although the progressive dopaminergic denervation is the cardinal pathology in the brains of patients with Parkinsons disease, others systems such as the serotonergic are affected as well. Over the last decade, several lines of evidence suggest that a progressive and non-linear loss of serotonergic terminals takes place in Parkinsons disease, though this is at a slower pace compared to the dopaminergic loss. Several studies have indicated that serotonergic dysfunction in Parkinsons disease is associated with the development of motor and non-motor symptoms and complications. Here, we aim to review the current evidence with regards to the serotonergic pathology in Parkinsons disease and its relevance to the development of clinical symptoms. We are primarily revising in vivo human studies from research with positron emission tomography molecular imaging.

Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson’s disease

The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinsons disease are still only partially understood. Phosphodiesterase 10A (PDE10A) is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinsons disease using positron emission tomography molecular imaging with (11)C-IMA107, a highly selective PDE10A radioligand. We studied 24 patients with levodopa-treated, moderate to advanced Parkinsons disease. Their positron emission tomography imaging data were compared to those from a group of 12 healthy controls. Parametric images of (11)C-IMA107 binding potential relative to non-displaceable binding (BPND) were generated from the dynamic (11)C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean (11)C-IMA107 BPND in the caudate (P < 0.001), putamen (P < 0.001) and globus pallidus (P = 0.025) in patients with Parkinsons disease compared to healthy controls, which was confirmed with voxel-based analysis. Longer Parkinsons duration correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.65; P = 0.005), putamen (r = -0.51; P = 0.025), and globus pallidus (r = -0.47; P = 0.030). Higher Unified Parkinsons Disease Rating Scale part-III motor scores correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.54; P = 0.011), putamen (r = -0.48; P = 0.022), and globus pallidus (r = -0.70; P < 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinsons disease with levodopa-induced dyskinesias (n = 12), correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.73; P = 0.031) and putamen (r = -0.74; P = 0.031). Our findings demonstrate striatal and pallidal loss of PDE10A expression, which is associated with Parkinsons duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinsons disease.

Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntingtons disease. Huntingtons disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntingtons disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntingtons disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntingtons disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntingtons disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntingtons disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntingtons disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntingtons disease gene carriers.

Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers

Previous studies have shown activation of the immune system and altered immune response in Huntingtons disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carriers. We sought to investigate our hypothesis using [(11)C]PK11195 PET as a translocator protein (TSPO) marker of central microglial activation, together with assessment of peripheral plasma cytokine levels in a cohort of premanifest HD gene carriers who were more than a decade from predicted symptomatic conversion. Data were also compared to those from a group of healthy controls matched for age and gender. We found significantly increased peripheral plasma IL-1β levels in premanifest HD gene carriers compared to the group of normal controls (P=0.018). Premanifest HD gene carriers had increased TSPO levels in cortical, basal ganglia and thalamic brain regions (P<0.001). Increased microglial activation in somatosensory cortex correlated with higher plasma levels of IL-1β (rs=0.87, P=0.013), IL-6 (rs=0.85, P=0.013), IL-8 (rs=0.68, P=0.045) and TNF-α (rs=0.79; P=0.013). Our findings provide first in vivo evidence for an association between peripheral and central immune responses in premanifest HD gene carriers, and provide further supporting evidence for the role of immune dysfunction in the pathogenesis of HD.

Current status of PET imaging in Huntington’s disease

PurposeTo review the developments of recent decades and the current status of PET molecular imaging in Huntington’s disease (HD).MethodsA systematic review of PET studies in HD was performed. The MEDLINE, Web of Science, Cochrane and Scopus databases were searched for articles in all languages published up to 19 August 2015 using the major medical subject heading “Huntington Disease” combined with text and key words “Huntington Disease”, “Neuroimaging” and “PET”. Only peer-reviewed, primary research studies in HD patients and premanifest HD carriers, and studies in which clinical features were described in association with PET neuroimaging results, were included in this review. Reviews, case reports and nonhuman studies were excluded.ResultsA total of 54 PET studies were identified and analysed in this review. Brain metabolism ([18F]FDG and [15O]H2O), presynaptic ([18F]fluorodopa, [11C]β-CIT and [11C]DTBZ) and postsynaptic ([11C]SCH22390, [11C]FLB457 and [11C]raclopride) dopaminergic function, phosphodiesterases ([18F]JNJ42259152, [18F]MNI-659 and [11C]IMA107), and adenosine ([18F]CPFPX), cannabinoid ([18F]MK-9470), opioid ([11C]diprenorphine) and GABA ([11C]flumazenil) receptors were evaluated as potential biomarkers for monitoring disease progression and for assessing the development and efficacy of novel disease-modifying drugs in premanifest HD carriers and HD patients. PET studies evaluating brain restoration and neuroprotection were also identified and described in detail.ConclusionBrain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression. However, no single technique may be currently considered an optimal biomarker and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD.

Cholinergic imaging in dementia spectrum disorders

The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer’s disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [11C]MP4A and [11C]PMP PET for acetylcholinesterase (AChE), [123I]5IA SPECT for the α4β2 nicotinic acetylcholine receptor and [123I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson’s disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders.

Neuroimaging in Huntington’s disease

Huntingtons disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded trinucleotide CAG sequence in huntingtin gene (HTT) on chromosome 4. HD manifests with chorea, cognitive and psychiatric symptoms. Although advances in genetics allow identification of individuals carrying the HD gene, much is still unknown about the mechanisms underlying the development of overt clinical symptoms and the transitional period between premanifestation and manifestation of the disease. HD has no cure and patients rely only in symptomatic treatment. There is an urgent need to identify biomarkers that are able to monitor disease progression and assess the development and efficacy of novel disease modifying drugs. Over the past years, neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have provided important advances in our understanding of HD. MRI provides information about structural and functional organization of the brain, while PET can detect molecular changes in the brain. MRI and PET are able to detect changes in the brains of HD gene carriers years ahead of the manifestation of the disease and have also proved to be powerful in assessing disease progression. However, no single technique has been validated as an optimal biomarker. An integrative multimodal imaging approach, which combines different MRI and PET techniques, could be recommended for monitoring potential neuroprotective and preventive therapies in HD. In this article we review the current neuroimaging literature in HD.

Dopamine receptor mapping with PET imaging in Parkinson’s disease

Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterised pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta. These neurons project to the striatum, and their loss leads to alterations in the activity of the neural circuits that regulate movement. The striatal output of the circuit related to the control of movement is mediated by two pathways: the direct striatal pathway, which is mediated through facilitation of D1 receptors, and the indirect striatal pathway, mediated through D2 receptors. Positron emission tomography (PET) molecular imaging is a powerful in vivo technique in which using selective dopaminergic radioligands has been employed to investigate the dopaminergic system in humans. In this article we aim to review the role of PET imaging in understanding the postsynaptic dopaminergic mechanisms in PD. PET studies have allowed us to gain important insights into the functions of the dopaminergic system, the mechanisms of drug-induced motor and non-motor complications, and the placebo effect in PD.

Recent imaging advances in neurology

Over the recent years, the application of neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) has considerably advanced the understanding of complex neurological disorders. PET is a powerful molecular imaging tool, which investigates the distribution and binding of radiochemicals attached to biologically relevant molecules; as such, this technique is able to give information on biochemistry and metabolism of the brain in health and disease. MRI uses high intensity magnetic fields and radiofrequency pulses to provide structural and functional information on tissues and organs in intact or diseased individuals, including the evaluation of white matter integrity, grey matter thickness and brain perfusion. The aim of this article is to review the most recent advances in neuroimaging research in common neurological disorders such as movement disorders, dementia, epilepsy, traumatic brain injury and multiple sclerosis, and to evaluate their contribution in the diagnosis and management of patients.

Morphometric changes in the reward system of Parkinson's disease patients with impulse control disorders

Impulse control disorders (ICDs) occur in a subset of patients with Parkinson’s disease (PD) who are receiving dopamine replacement therapy. In this study, we aimed to investigate structural abnormalities within the mesocortical and limbic cortices and subcortical structures in PD patients with ICDs. We studied 18 PD patients with ICDs, 18 PD patients without ICDs and a group of 24 age and sex-matched healthy controls. Cortical thickness (CTh) and subcortical nuclei volume analyses were carried out using the automated surface-based analysis package FreeSurfer (version 5.3.0). We found significant differences in MRI measures between the three groups. There was volume loss in the nucleus accumbens of both PD patients with ICDs and without ICDs compared to the control group. In addition, PD patients with ICDs showed significant atrophy in caudate, hippocampus and amygdala compared to the group of healthy controls. PD patients with ICDs had significant increased cortical thickness in rostral anterior cingulate cortex and frontal pole compared to PD patients without ICDs. Cortical thickness in rostral anterior cingulate and frontal pole was increased in PD patients with ICDs compared to the control group, but the differences failed to reach corrected levels of statistical significance. PD patients with ICDs showed increased cortical thickness in medial prefrontal regions. We speculate that these findings reflect either a pre-existing neural trait vulnerability to impulsivity or the expression of a maladaptive synaptic plasticity under non-physiological dopaminergic stimulation.