Showing papers by "Marios Politis published in 2018"

Diabetes mellitus and Parkinson disease.

Abstract: Objective To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. Methods We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. Results The presence of diabetes mellitus was associated with higher motor scores ( p p p p p p p p Conclusions Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype.

Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson's disease.

Abstract: Currently, no reliable predictors of cognitive impairment in Parkinson's disease exist. We hypothesized that microstructural changes at grey matter T1-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson's disease. We performed a cross-sectional comparison between patients with Parkinson's disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson's disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson's disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson's disease without cognitive impairment. These results were confirmed both with region of interest and voxel-based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson's disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson's disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.

REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease

Abstract: Objective To investigate whether REM sleep behavior disorder (RBD) is associated with worse motor and cognitive decline in Parkinson disease (PD) Methods Four-hundred twenty-one drug-naive patients with early-stage PD and 196 controls without PD were included in this study. All participants underwent a [ 123 I]FP-CIT SPECT scan, CSF assessment, 3-tesla MRI, and thorough clinical assessments. Results At cross-sectional analyses, patients with PD and probable RBD (PD-RBD) had lower CSF β-amyloid 1–42 (Aβ 42 ) levels and higher total tau to Aβ 42 CSF ratio, higher nonmotor symptoms burden, and worse scores on neuropsychological tests of processing speed, visuospatial functioning, and delayed recognition memory compared to patients with PD without RBD. At longitudinal analyses, the presence of RBD was associated with faster motor progression (hazard ratio [HR] = 1.368, 95% confidence Interval [CI] = 1.036–1.806; p = 0.027) and cognitive decline (HR = 1.794, 95% CI = 1.163–2.768; p = 0.008) over 60-month follow-up. The presence of RBD was a predictor for motor progression only in patients with PD who had both low α-synuclein levels and low [ 123 I]FP-CIT uptake in the striatum (HR = 2.091, 95% CI = 1.116–3.918; p = 0.021) and a predictor for cognitive decline only in patients with PD who had both low Aβ 42 and low α-synuclein levels (HR = 2.810, 95% CI = 1.462–5.400; p = 0.002). In the population of controls without PD, the presence of RBD was not associated with cognitive decline or any baseline pathologic changes. Conclusion The presence of RBD in PD is associated with faster motor progression in patients with greater synuclein and dopaminergic pathology, and with higher risk of cognitive decline in patients with greater synuclein and amyloid pathology. Our findings provide an important direction toward understanding phenotypes and their prognosis in PD.

Advances in MRI Methodology.

Abstract: Magnetic resonance imaging (MRI) is a non-invasive technique which can provide comprehensive, multi-parametric information on brain anatomy, function and metabolism. This chapter will give a brief introduction to the basic principles of MR and cover the evolution of image acquisition. Given the versatility of MR, a vast range of MR applications will be discussed, including structural, diffusion tensor, functional, perfusion and neuromelanin-sensitive imaging, as well as quantitative susceptibility mapping. This chapter will also cover methodological developments in MRI, including image analysis approaches that can be tailored according to experimental design or aims. The ultimate goal of this chapter is to equip readers with a fundamental understanding of the proficiencies and limitations of MR techniques and their corresponding analysis approaches.

11C-PE2I and 18F-Dopa PET for assessing progression rate in Parkinson's: A longitudinal study

Abstract: Background 18F-dopa PET measuring aromatic l-amino acid decarboxylase activity is regarded as the gold standard for evaluating dopaminergic function in Parkinson's disease. Radioligands for dopamine transporters are also used in clinical trials and for confirming PD diagnosis. Currently, it is not clear which imaging marker is more reliable for assessing clinical severity and rate of progression. The objective of this study was to directly compare 18F-dopa with the highly selective dopamine transporter radioligand 11C-PE2I for the assessment of motor severity and rate of progression in PD. Methods Thirty-three mild-moderate PD patients underwent 18F-dopa and 11C-PE2I PET at baseline. Twenty-three were followed up for 18.8 ± 3.4 months. Results Standard multiple regression at baseline indicated that 11C-PE2I BPND predicted UPDRS-III and bradykinesia-rigidity scores (P < 0.05), whereas 18F-dopa Ki did not make significant unique explanatory contributions. Voxel-wise analysis showed negative correlations between 11C-PE2I BPND and motor severity across the whole striatum bilaterally. 18F-Dopa Ki clusters were restricted to the most affected putamen and caudate. Longitudinally, negative correlations were found between striatal Δ11C-PE2I BPND, ΔUPDRS-III, and Δbradykinesia-rigidity, whereas no significant associations were found for Δ18F-dopa Ki. One cluster in the most affected putamen was identified in the longitudinal voxel-wise analysis showing a negative relationship between Δ11C-PE2I BPND and Δbradykinesia-rigidity. Conclusions Striatal 11C-PE2I appears to show greater sensitivity for detecting differences in motor severity than 18F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. 11C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD. © 2017 International Parkinson and Movement Disorder Society

PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology

Abstract: Background Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A). Objective We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations. Methods We studied 6 subjects with PDE10A and ADCY5 mutations using [11 C]IMA107 PET, [123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively. Results We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices. Conclusions Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society.

The serotonergic system in Parkinson’s patients with dyskinesia: evidence from imaging studies

Abstract: The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson's patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson's disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson's patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT1A and 5-HT1B receptors agonists partially reduced these motor complications. In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs.

Molecular Imaging of the Serotonergic System in Parkinson's Disease.

Abstract: In the last decades, the main focus of molecular imaging of Parkinson's disease has been on non-dopaminergic systems involved in the disease alongside the pathognomonic dopaminergic changes. Molecular imaging can detect, in vivo, both presynaptic and postsynaptic serotonergic changes in the brain and has played a key role in elucidating the pathophysiology of the serotonergic system in Parkinson's disease. Alterations in the serotonergic system may happen very early in the course of the disease and have shown a leading role in the development of tremor and dyskinesias, and in several non-motor symptoms, including sleep, cognitive and neuropsychiatric disturbances. These studies increasingly recognize that the regional topography of serotonergic brain areas associates with specific dysfunctions. In parallel with this trend, more recent molecular serotonergic imaging approaches are investigating serotonergic modulatory treatment and their contributions to the improvement of cognitive functions. In this review, we discussed post-mortem, preclinical and imaging evidence of serotonergic system changes in Parkinson's disease, and described how disease-specific serotonergic changes are relevant for motor and non-motor symptoms and complications. Future directions of serotonergic imaging have been also described alongside with the novel findings on the role of serotonergic system in asymptomatic LRRK2 carriers.

Disease-related patterns of in vivo pathology in Corticobasal syndrome

Abstract: To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer’s disease. We assessed tau aggregates with [18F]AV1451 PET, amyloid-β depositions with [18F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [18F]AV1451 binding. CBS patients showed increases in [18F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in the affected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in the affected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patient who underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased [18F]AV1451 signal. Cortical and subcortical [18F]AV45 uptake was within normal levels in CBS patients. In parietal and frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity (P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients. Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motor symptoms. Our findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence of amyloid-β, which distinguish CBS from non-affected individuals and MCI patients.

Constipation is not associated with dopamine transporter pathology in early drug-naïve patients with Parkinson's disease.

Abstract: BACKGROUND AND PURPOSE Constipation is a common non-motor symptom of Parkinson's disease (PD). Deposition of α-synuclein inclusions that spread from the gut to the substantia nigra through the vagus nerve has recently been speculated to be a pre-motor and early stage of PD. The aim of the study was to investigate whether constipation is associated with dopaminergic pathology on dopamine transporter (DAT) single-photon emission computed tomography in early drug-naive patients with PD. Our hypothesis was that constipation is associated with other signs of pre-motor PD and is independent of DAT pathology. We then investigated for associations with motor and non-motor symptoms, and with cerebrospinal fluid biomarkers of PD pathology. METHODS Using the Parkinson's Progression Markers Initiative database, we investigated the prevalence of constipation and the association between constipation and clinical features, striatal [123 I]Ioflupane uptake and non-imaging (cerebrospinal fluid and serum) biomarkers. Constipation was evaluated using Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I item 1.11. RESULTS One third (132/398) of de-novo patients with PD had constipation. Higher severity of constipation correlated with older age (r = 0.728, P < 0.001), higher MDS-UPDRS total score (r = 0.285, P < 0.001), worse postural instability (r = 0.190, P = 0.012), rapid eye movement sleep behaviour disorder (r = 0.228, P < 0.0001) and depression (r = 0.187, P = 0.024). No correlation was found with cerebrospinal fluid, serum and imaging markers of PD pathology. CONCLUSIONS Constipation was not associated with DAT pathology but with rapid eye movement sleep behaviour disorder and depression, which are speculated to be pre-motor symptoms of PD. This confirms the hypothesis that constipation may be a pre-motor sign of PD due to an impairment of non-dopaminergic pathways.

Molecular Imaging of the Dopaminergic System in Idiopathic Parkinson's Disease.

Abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic nigrostriatal connections which is recognized as the major pathophysiological event underlying the onset of motor symptoms. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging allow the study of these connections in vivo at a molecular level. Several radiotracers have been developed targeting the synthesis and metabolism of dopamine and dopaminergic receptors to investigate the nigrostriatal pathway in vivo. Molecular imaging has greatly increased our knowledge on the progression and natural history of PD, as well as the development of motor and non-motor symptoms. PET molecular imaging could be a reliable biomarker to aid earlier diagnosis and for monitoring disease progression. Furthermore, PET imaging could be used as outcome measure in the design of clinical trials testing novel pharmacological compounds aiming to slow, and ultimately halt, disease progression.

Neuroimaging of Sleep Disturbances in Movement Disorders.

Abstract: Sleep dysfunction is recognized as a distinct clinical manifestation in movement disorders, often reported early on in the disease course. Excessive daytime sleepiness, rapid eye movement sleep behavior disorder and restless leg syndrome, amidst several others, are common sleep disturbances that often result in significant morbidity. In this article, we review the spectrum of sleep abnormalities across atypical Parkinsonian disorders including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), as well as Parkinson's disease (PD) and Huntington's disease (HD). We also explore the current concepts on the neurobiological underpinnings of sleep disorders, including the role of dopaminergic and non-dopaminergic pathways, by evaluating the molecular, structural and functional neuroimaging evidence based on several novel techniques including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Based on the current state of research, we suggest that neuroimaging is an invaluable tool for assessing structural and functional correlates of sleep disturbances, harboring the ability to shed light on the sleep problems attached to the limited treatment options available today. As our understanding of the pathophysiology of sleep and wake disruption heightens, novel therapeutic approaches are certain to transpire.

Imaging Markers of Progression in Parkinson's Disease.

Abstract: Background Parkinson's disease (PD) is the second-most common neurodegenerative disorder after Alzheimer's disease; however, to date, there is no approved treatment that stops or slows down disease progression. Over the past decades, neuroimaging studies, including molecular imaging and MRI are trying to provide insights into the mechanisms underlying PD. Methods This work utilized a literature review. Results It is now becoming clear that these imaging modalities can provide biomarkers that can objectively detect brain changes related to PD and monitor these changes as the disease progresses, and these biomarkers are required to establish a breakthrough in neuroprotective or disease-modifying therapeutics. Conclusions Here, we provide a review of recent observations deriving from PET, single-positron emission tomography, and MRI studies exploring PD and other parkinsonian disorders.

Dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease.

Abstract: This study was funded by Parkinson's UK (ref. F-1201) and an imaging grant from GE Healthcare.

Striatal molecular alterations in HD gene carriers: A systematic review and meta-analysis of PET studies

Abstract: Background Over the past years, positron emission tomography (PET) imaging studies have investigated striatal molecular changes in premanifest and manifest Huntington’s disease (HD) gene expansion carriers (HDGECs), but they have yielded inconsistent results. Objective To systematically examine the evidence of striatal molecular alterations in manifest and premanifest HDGECs as measured by PET imaging studies. Methods MEDLINE, ISI Web of Science, Cochrane Library and Scopus databases were searched for articles published until 7 June 2017 that included PET studies in manifest and premanifest HDGECs. Meta-analyses were conducted with random effect models, and heterogeneity was addressed with I 2 index, controlling for publication bias and quality of study. The primary outcome was the standardised mean difference (SMD) of PET uptakes in the whole striatum, caudate and putamen in manifest and premanifest HDGECs compared with healthy controls (HCs). Results Twenty-four out of 63 PET studies in premanifest (n=158) and manifest (n=191) HDGECs and HCs (n=333) were included in the meta-analysis. Premanifest and manifest HDGECs showed significant decreases in dopamine D 2 receptors in caudate (SMD=−1.233, 95% CI −1.753 to −0.713, p Conclusions PET imaging has the potential to detect striatal molecular changes even at the early premanifest stage of HD, which are relevant to the neuropathological mechanisms underlying the development of the disease.

Structural Magnetic Resonance Imaging in Huntington's Disease.

Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by expansion of the CAG repeat in the huntingtin gene. HD is characterized clinically by progressive motor, cognitive and neuropsychiatric symptoms. There are currently no disease modifying treatments available for HD, and there is a great need for biomarkers to monitor disease progression and identify new targets for therapeutic intervention. Neuroimaging techniques provide a powerful tool for assessing disease pathology and progression in premanifest stages, before the onset of overt motor symptoms. Structural magnetic resonance imaging (MRI) is non-invasive imaging techniques which have been employed to study structural and microstructural changes in premanifest and manifest HD gene carriers. This chapter described structural imaging techniques and analysis methods employed across HD MRI studies. Current evidence for structural MRI abnormalities in HD, and associations between atrophy, structural white matter changes, iron deposition and clinical performance are discussed; together with the use of structural MRI measures as a diagnostic tool, to assess longitudinal changes, and as potential biomarkers and endpoints for clinical trials.

Imaging Transplantation in Movement Disorders.

Abstract: Cell replacement therapy with graft transplantation has been tested as a disease-modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.

Molecular Imaging in Huntington's Disease

Abstract: Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non-invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD.