Showing papers by "Marios Politis published in 2016"
TL;DR: Despite significant evidence for the utility of neuroim imaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice.
Abstract: The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP) and essential tremor. Imaging of the brain in patients with parkinsonism has the ability to increase the accuracy of differential diagnosis. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow brain imaging of structural, functional and molecular changes in vivo in patients with PD. Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane (DaTSCAN(TM)) SPECT is a valid tool in the differential diagnosis between PD and non-degenerative tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and 18F-fluorodeoxyglucose PET are valid in the differential diagnosis between PD and atypical parkinsonism (MSA-P, PSP). However, despite significant evidence for the utility of neuroimaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the financial benefits for the NHS in the longer term management of the patients.
91 citations
TL;DR: Findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders are reviewed, including cortical AChE being significantly reduced in Parkinson’s disease (PD), PD with dementia (PDD) and AD.
Abstract: 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.
78 citations
TL;DR: The findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs.
Abstract: Objective: To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD). Methods: Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[ 11 C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ( 11 C-DASB) and with SPECT and [ 123 I]N-w-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ( 123 I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters9 availability, respectively. We have employed a simplified reference tissue model for the quantification of 11 C-DASB, whereas a semiquantification approach was used for 123 I-ioflupane data. We calculated 11 C-DASB binding to 123 I-ioflupane uptake ratios for the caudate and the putamen. Results: Patients with PD showed striatal decreases in 11 C-DASB binding potential ( p 123 I-ioflupane mean uptake ( p 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls9 mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls9 mean) for the patients with dyskinesias. There was a statistically significant difference ( p 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher 11 C-DASB to 123 I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD ( r = 0.52; p Conclusions: Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs.
68 citations
TL;DR: Brain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD.
Abstract: Purpose
To review the developments of recent decades and the current status of PET molecular imaging in Huntington’s disease (HD).
63 citations
TL;DR: Measuring microstructure alterations with diffusion tensor imaging in PD is potentially a valuable tool to use as a biomarker for early diagnosis and to track disease progression.
Abstract: BACKGROUND: Measuring microstructure alterations with diffusion tensor imaging in PD is potentially a valuable tool to use as a biomarker for early diagnosis and to track disease progression. Previous studies have reported a specific decrease of nigral fractional anisotropy in PD. However, to date the effect of disease progression on nigral or striatal diffusion indices has not been fully explored.METHODS: We have conducted a cross-sectional and longitudinal diffusion tensor imaging study in 18 early stage, treated PD patients and 14 age-matched controls. PD patients were scanned on 2 occasions OFF medication, 19.3 months apart (standard deviation = 3.1 months). Longitudinal change of regional nigral and striatal measures of fractional anisotropy and mean diffusivity were calculated using a region-of-interest approach.RESULTS: Region-of-interest analysis demonstrated that at baseline, PD patients and controls did not differ in regard to diffusion indices in any region assessed. A significant difference of nigral fractional anisotropy and mean diffusivity between controls and PD patients at follow-up was detected and confirmed with longitudinal analysis within PD patients. Alterations in striatal regions were not detected in either group or over time.CONCLUSION: Our findings indicate that nigral diffusion measure may be a valuable measure of disease progression. In the future, larger longitudinal studies will confirm whether diffusion indices may serve as sensitive and clinically meaningful measures of disease progression in PD. © 2016 International Parkinson and Movement Disorder Society. (Less)
50 citations
TL;DR: Patents published in the last 5 years could be used in novel approaches to Parkinson's treatment by targeting specific pathophysiology proteins, such as Nurr1, PINK1 and NrF2, while patents to improve penetration of the blood brain barrier could allow improved efficacy of existing treatments.
Abstract: Background Parkinson's disease is a chronic neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. The pathophysiological mechanisms underlying Parkinson's are still unknown. Mitochondrial dysfunction, abnormal protein aggregation, increased neuroinflammation and impairment of brain glucose metabolism are shared processes among insulinresistance, diabetes and neurodegeneration and have been suggested as key mechanisms in development of Parkinson's and cognitive impairment. Objective To review experimental and clinical evidence of underlying Parkinson's pathophysiology in common with diabetes and cognitive impairment. Anti-diabetic agents and recent patents for insulin-resistance that might be repositioned in the treatment of Parkinson's also have been included in this review. Method A narrative review using MEDLINE database. Results Common antidiabetic treatments such as DPP4 inhibitors, GLP-1 agonists and metformin have shown promise in the treatment of Parkinson's disease and cognitive impairment in animals and humans. Study of the pathophysiology of neurodegeneration common between diabetes and Parkinson's disease has given rise to new treatment possibilities. Patents published in the last 5 years could be used in novel approaches to Parkinson's treatment by targeting specific pathophysiology proteins, such as Nurr1, PINK1 and NrF2, while patents to improve penetration of the blood brain barrier could allow improved efficacy of existing treatments. Conclusion Further studies using GLP-1 agonists and DPP-4 inhibitors to treat PD are warranted as they have shown promise.
48 citations
TL;DR: There may be a threshold of SERT-over-DAT availability in the putamen, above which PD patients are likely to become dyskinetic, as reflected by the increase of the SERT–to–DAT ratio over time.
Abstract: Background/Aim Serotonergic terminals play an important role in levodopa-induced dyskinesias (LIDs) in patients with Parkinson9s disease (PD). In particular the SERT/DAT ratio changes may be critical for the appearance of LIDs. We investigated serotonergic terminal changes and dopaminergic loss in the putamen over time and their relationship to LIDs. Methods Twelve PD patients underwent PET with 11C-DASB and 11C-PE2I; which are specific in vivo markers of SERT and DAT respectively. All patients repeated 11C-DASB and 11C-PE2I PET after 17 months (±11 weeks). The simplified reference tissue model was employed using the cerebellum as a reference. 11C-DASB binding potential (BP), 11C-PE2I BP and 11C-DASB-to-11C-PE2I BP ratios were calculated. Results At baseline, all PD patients were non-dyskinetic. The mean 11C-DASB BP was 1.28 (±0.14), the mean 11C-PE2I BP was 1.63 (±0.41), and the median of the SERT-to-DAT ratio was 0.779 (±0.19). At follow-up, mean 11C-PE2I BP was reduced by 14.52% from baseline (p 0.10).). The SERT-to-DAT ratios significantly increased by 12.76% (p Conclusion The imbalance in the rate of decline of SERT and DAT is reflected by the increase of the SERT–to–DAT ratio over time. There may be a threshold of SERT-over-DAT availability in the putamen, above which PD patients are likely to become dyskinetic.
38 citations
TL;DR: PET molecular imaging has provided valuable insight for understanding the mechanisms underlying atypical parkinsonism and changes at a molecular level occur early in the course of neurodegenerative diseases and PET imaging provides the means to aid differential diagnosis, monitor disease progression, identify of novel targets for pharmacotherapy, and monitor response to new treatments.
Abstract: Purpose
To systematically review the previous studies and current status of positron emission tomography (PET) molecular imaging research in atypical parkinsonism.
35 citations
TL;DR: The findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.
34 citations
TL;DR: Patients with schizophrenia have normal availability of PDE10A in brain regions thought to be involved in the pathophysiology of this disorder, and the findings do not support the proposal of an altered PDE 10A availability in schizophrenia.
Abstract: Objective:Phosphodiesterase 10A (PDE10A) is an enzyme present in striatal medium spiny neurons that degrades the intracellular second messengers triggered by dopamine signaling. The pharmaceutical industry has considerable interest in PDE10A inhibitors because they have been shown to have an antipsychotic-like effect in animal models. However, the status of PDE10A in schizophrenia is unknown. Using a newly developed and validated radioligand, [11C]IMA107, the authors report the first in vivo assessment of PDE10A brain expression in patients with schizophrenia.Method:The authors compared PDE10A availability in the brains of 12 patients with chronic schizophrenia and 12 matched healthy comparison subjects using [11C]IMA107 positron emission tomography (PET). Regional estimates of the binding potential (BPND) of [11C]IMA107 were generated from dynamic PET scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding.Results:There was no significant diff...
34 citations
TL;DR: The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease is referred to by Maillet et al. (doi:10.1093/brain/aww162) .
Abstract: This scientific commentary refers to ‘The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease’, by Maillet et al. (doi:10.1093/brain/aww162) .
Disentangling the contributions of various neurotransmitter systems to specific clinical manifestations of Parkinson’s disease is important for understanding their pathogenesis and for developing effective treatments. The clinical phenomenology of Parkinson’s disease encompasses a range of motor and non-motor disorders, of which neuropsychiatric presentations such as depression, anxiety, dementia, impulse control disorders and apathy are among the most deleterious for patients’ and carers’ quality of life. Apathy, characterized by diminished goal-oriented behaviour, cognition, interests, and emotional expression (Starkstein, 2012), is common in Parkinson’s disease, affecting ∼40% of patients in cross-sectional studies. It is under-recognized (Gallagher et al. , 2010) and often confused with dementia or depression, of which it can also be an integral part (Pagonabarraga et al. , 2015). Understanding its distinct nature can help improve families’ approaches to dealing with apathy and ensure its appropriate management. The underlying pathology of apathy is poorly understood, although clinical and imaging findings support the role of dopaminergic dysfunction in apathy in patients with (Magnard et al. , 2016; Wen et al. , 2016;) and without Parkinson’s disease (Starkstein, 2012; Pagonabarraga et al. , 2015). In this issue of Brain , Maillet and co-workers use PET molecular imaging to …