Showing papers by "Marios Politis published in 2017"

Cognitive decline in Parkinson disease

Abstract: Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*e4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

The psychosis spectrum in Parkinson disease

Abstract: In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.

Molecular imaging to track Parkinson's disease and atypical parkinsonisms: New imaging frontiers

Abstract: Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting new tracer developments hold the potential for in vivo markers of underlying pathology. Herein, we provide an overview of molecular imaging advances and how these approaches help us to understand PD and atypical parkinsonisms. © 2016 International Parkinson and Movement Disorder Society.

Serotonin transporter in Parkinson's disease: A meta-analysis of positron emission tomography studies.

Abstract: Positron emission tomography (PET) is a powerful analytical tool for in vivo molecular imaging of the human brain. Over the past years, a number of PET studies imaging the serotonin transporter (SERT) have been used and provided evidence for the key role of serotonergic pathology in patients with Parkinson's disease (PD). Here, we review the role of SERT in the development of motor and nonmotor complications in patients with PD, and we performed a meta-analysis to identify the patterns of SERT pathology and the relevance to symptoms. Consistent SERT pathology in raphe nuclei, striatum, thalamus, and hypothalamus and associations with aging, PD progression, development of dyskinesias, and cognitive decline were observed. Ann Neurol 2017;81:171-180.

PET image reconstruction using multi-parametric anato-functional priors.

Abstract: In this study, we investigate the application of multi-parametric anato-functional (MR-PET) priors for the maximum a posteriori (MAP) reconstruction of brain PET data in order to address the limitations of the conventional anatomical priors in the presence of PET-MR mismatches In addition to partial volume correction benefits, the suitability of these priors for reconstruction of low-count PET data is also introduced and demonstrated, comparing to standard maximum-likelihood (ML) reconstruction of high-count data The conventional local Tikhonov and total variation (TV) priors and current state-of-the-art anatomical priors including the Kaipio, non-local Tikhonov prior with Bowsher and Gaussian similarity kernels are investigated and presented in a unified framework The Gaussian kernels are calculated using both voxel- and patch-based feature vectors To cope with PET and MR mismatches, the Bowsher and Gaussian priors are extended to multi-parametric priors In addition, we propose a modified joint Burg entropy prior that by definition exploits all parametric information in the MAP reconstruction of PET data The performance of the priors was extensively evaluated using 3D simulations and two clinical brain datasets of [18F]florbetaben and [18F]FDG radiotracers For simulations, several anato-functional mismatches were intentionally introduced between the PET and MR images, and furthermore, for the FDG clinical dataset, two PET-unique active tumours were embedded in the PET data Our simulation results showed that the joint Burg entropy prior far outperformed the conventional anatomical priors in terms of preserving PET unique lesions, while still reconstructing functional boundaries with corresponding MR boundaries In addition, the multi-parametric extension of the Gaussian and Bowsher priors led to enhanced preservation of edge and PET unique features and also an improved bias-variance performance In agreement with the simulation results, the clinical results also showed that the Gaussian prior with voxel-based feature vectors, the Bowsher and the joint Burg entropy priors were the best performing priors However, for the FDG dataset with simulated tumours, the TV and proposed priors were capable of preserving the PET-unique tumours Finally, an important outcome was the demonstration that the MAP reconstruction of a low-count FDG PET dataset using the proposed joint entropy prior can lead to comparable image quality to a conventional ML reconstruction with up to 5 times more counts In conclusion, multi-parametric anato-functional priors provide a solution to address the pitfalls of the conventional priors and are therefore likely to increase the diagnostic confidence in MR-guided PET image reconstructions

Motor associations of iron accumulation in deep grey matter nuclei in Parkinson's disease: a cross-sectional study of iron-related magnetic resonance imaging susceptibility.

Abstract: Background and purpose: To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD). Methods: Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS-III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS-III scores using analysis of covariance, adjusting for age and regional area. Results: Parkinson's disease patients had significantly (P < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians (P < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS-III and bradykinesia-rigidity subscores, but not with tremor subscores. ancova followed by post hoc Bonferroni-adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS-III scores compared to both lowest UPDRS-III PD and HV groups (P < 0.001). Conclusions: Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi-quantitative in vivo iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies. (Less)

Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer's disease

Abstract: Background and purpose A growing body of evidence suggests that cardiovascular disease risk factors including hypertension may be linked to sporadic Alzheimer's disease (AD). It is well known that hypertension is associated with cerebrovascular disease and vascular dementia on the basis of vascular remodeling. However, the mechanisms linking hypertension and AD remain unclear. Methods We studied 197 patients with AD (86 male; mean age ± SD: 75.8 ± 7.4 years) from the Alzheimer's Disease Neuroimaging Initiative database with (n = 97) and without (n = 100) hypertension. We explored associations between hypertension and clinical, plasma, cerebrospinal fluid and imaging markers of AD pathology in order to elucidate the underlying mechanisms that may link AD and hypertension. Results We found that patients with AD with hypertension had worse cognitive function (Alzheimer's disease Assessment Scale-cognitive subscale, P = 0.038) and higher neuropsychiatric symptom burden (Neuropsychiatric Inventory Questionnaire, P = 0.016) compared with those without hypertension. Patients with AD with hypertension showed reduced glucose hypometabolism in the right (P < 0.001) and left (P = 0.007) hippocampus. No differences were found in magnetic resonance imaging volumetric measurements, [18F]florbetapir uptakes, plasma and cerebrospinal fluid between patients with AD with and without hypertension. Conclusions Although hypertension is associated with worse cognitive function, behavioural symptoms and hippocampal glucose hypometabolism, it is not associated with evidence of increased amyloid or tau pathology. Effective management of hypertension may potentially have a therapeutic role in the alleviation of symptoms in AD.

Molecular Imaging Markers to Track Huntington's Disease Pathology.

Abstract: Huntington’s disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in pre-symptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD disease progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-section and longitudinal human studies, as biomarkers for HD and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation and recently phosphodiesterase 10A (PDE10A) as markers to track HD disease progression. Alterations in PDE10A expression is the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD disease progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology.

Imaging in Parkinson's Disease

Abstract: Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by the loss of nigrostriatal dopaminergic neurons and aggregation of misfolded α-synuclein in Lewy bodies. The underlying mechanisms of neurodegeneration in PD are still unknown, and there are no disease-modifying treatments to slow the neurodegenerative processes. 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), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) have provided important advances in our understanding of PD. MRI provides information about structural and functional organization of the brain, while SPECT and PET can detect molecular changes in the brain. Here, we review the current neuroimaging literature in sporadic and genetic PD, which have contributed to our understanding of the physiopathological mechanisms of the disease.

Loss of phosphodiesterase 4 in Parkinson disease: Relevance to cognitive deficits

Abstract: Objective: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [11C]rolipram PET. Methods: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [11C]rolipram volume of distribution (VT) values were determined with the Logan plot. Results: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [11C]rolipram VT compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [11C]rolipram VT values in patients with PD were decreased by 12%–32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [11C]rolipram VT values in patients with PD were decreased by 11%–20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [11C]rolipram VT values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. Conclusions: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD.

Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson’s disease: evidence for dopaminergic basis?

Abstract: Parkinson’s disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale.

Sustained striatal dopamine levels following intestinal levodopa infusions in Parkinson's disease patients

Abstract: Background The objective of this study was to investigate in vivo the ability of levodopa/carbidopa intestinal gel infusions to produce sustained striatal dopamine levels and to improve clinical outcomes in Parkinson's disease patients. Methods Six advanced Parkinson's disease patients had serial [11C]raclopride PET to assess levodopa/carbidopa intestinal gel infusion-induced rises in striatal dopamine as reflected by a fall in dopamine-D2/3 receptor availability. Parkinson's disease patients had baseline scan OFF-dopaminergic stimulation and 2 scans following initiation of levodopa/carbidopa intestinal gel infusions. Striatal D2/3 binding was measured in striatal subregions corresponding to sensorimotor, limbic, and cognitive/associative function. Results Mean striatal [11C]raclopride nondisplaceable binding potential decreased by 14.0% to 16.7% in sensorimotor, 12.0%-14.4% in limbic, and 8.7%-11.6% in cognitive/associative function subregions at 1- to 10-hour points (P < 0.01). Sensorimotor subregion [11C]raclopride nondisplaceable binding potential reductions correlated with reductions in Unified Parkinson's Disease Rating Scale Part III scores over the course of the infusion (r = 0.81; P < 0.05). Conclusions Levodopa/carbidopa intestinal gel infusions generate a stable rise in striatal dopamine levels and are associated with improvements in motor manifestations. © 2016 International Parkinson and Movement Disorder Society.

PET Molecular Imaging Research of Levodopa-Induced Dyskinesias in Parkinson's Disease.

Abstract: To review the current status of positron emission tomography (PET) molecular imaging research of levodopa-induced dyskinesias (LIDs) in Parkinson’s disease (PD). Recent PET studies have provided robust evidence that LIDs in PD are associated with elevated and fluctuating striatal dopamine synaptic levels, which is a consequence of the imbalance between dopaminergic and serotonergic terminals, with the latter playing a key role in mishandling presynaptic dopamine release. Long-term exposure to levodopa is no longer believed to solely induce LIDs, as studies have highlighted that PD patients who go on to develop LIDs exhibit elevated putaminal dopamine release before the initiation of levodopa treatment, suggesting the involvement of other mechanisms, including altered neuronal firing and abnormal levels of phosphodiesterase 10A. Dopaminergic, serotonergic, glutamatergic, adenosinergic and opioid systems and phosphodiesterase 10A levels have been shown to be implicated in the development of LIDs in PD. However, no system may be considered sufficient on its own for the development of LIDs, and the mechanisms underlying LIDs in PD may have a multisystem origin. In line with this notion, future studies should use multimodal PET molecular imaging in the same individuals to shed further light on the different mechanisms underlying the development of LIDs in PD.

Imaging the Nonmotor Symptoms in Parkinson's Disease.

Abstract: Parkinson's disease is acknowledged to be a multisystem syndrome, manifesting as a result of multineuropeptide dysfunction, including dopaminergic, cholinergic, serotonergic, and noradrenergic deficits. This multisystem disorder ultimately leads to the presentation of a range of nonmotor symptoms, now appreciated to be an integral part of the disease-specific spectrum of symptoms, often preceding the diagnosis of motor Parkinson's disease. In this chapter, we review the dopaminergic and nondopaminergic basis of these symptoms by exploring the neuroimaging evidence based on several techniques including positron emission tomography, single-photon emission computed tomography molecular imaging, magnetic resonance imaging, functional magnetic resonance imaging, and diffusion tensor imaging. We discuss the role of these neuroimaging techniques in elucidating the underlying pathophysiology of NMS in Parkinson's disease.

Urinary dysfunction in early de novo patients with Parkinson's disease.

Abstract: Urinary dysfunction is one of the most common nonmotor symptoms of Parkinson’s disease (PD), is associated with a poorer quality of life, and is often unresponsive to dopaminergic treatment. The autonomic nervous system plays an important role in the control of bladder function, and a lesion or neurodegeneration of the brainstem can cause bladder overactivity and subsequently urinary urgency, increased frequency, and incontinence. In humans, dopamine transporter singlepositron emission tomography binding was lower in PD patients with urinary dysfunction than those without urinary dysfunction. Using the Parkinson’s Progression Markers Initiative database, we extracted and analyzed data from 398 early de novo PD patients and compared them with those from a group of ageand gender-matched healthy controls. We investigated associations between urinary dysfunction and motor and nonmotor symptoms, striatal [I]Ioflupane uptake, and CSF a-synuclein levels. Urinary dysfunction was evaluated using the MDS-UPDRS part-I item 1.10. (Complete methods are included in the Supplementary Data.) The prevalence of urinary dysfunction was 51.5% (205/ 398) in the early de novo PD patients and was higher when compared with the group of ageand gender-matched healthy controls (24.3%; 46/189; P < .001). In PD patients, urinary dysfunction was associated with older age (r 5 0.22, P < .001), and therefore we used age as a covariate. With regard to motor symptoms, worse urinary dysfunction correlated with greater postural instability (r 5 0.241, P 5 .012). The nonmotor symptoms that were associated with urinary dysfunction were autonomic dysfunction as measured by the Assessment of autonomic dysfunction in Parkinson’s disease (SCOPA-AUT) (r 5 0.56, P < .001) and Rapid eye movements sleep behavior disorder (r 5 0.22, P 5 .008; Supplementary Figure 1). Worse urinary dysfunction correlated with lower striatum (r 5 20.247, P < .001), caudate (r 5 20.224, P < .001), and putamen (r 5 20.247, P < .001) [I]Ioflupane uptake values and higher CSF a-synuclein levels (r 5 0.161, P 5 .035; Fig. 1). (Complete results are included in the Supplementary Data.) Postmortem studies have shown that the deposition of a-synuclein in the autonomic nervous system is concomitant to dopaminergic damage. Deposition of a-synuclein in the lateral collateral pathway, a region of the sacral spinal dorsal horn important for the relay of pelvic visceral afferents, may contribute to the development of urinary dysfunction. It is important to note that only half of our population had urinary dysfunction. The presence of this symptom may be suggestive of a specific premotor subphenotype of PD characterized by urinary dysfunction, Rapid eye movements sleep behavior disorder, depression, and autonomic dysfunction. This PD subtype was previously suggested by Van Rooden and colleagues. They demonstrated that the presence of urinary dysfunction, sleep problems, depression, autonomic dysfunctions, and worse axial symptoms describes a PD subtype that might also be reflected in our population. The remaining 50% of PD patients without urinary dysfunction might have developed PD starting from a different subsetting of premotor symptoms, without having a damage of autonomic system. The identification of a PD subtype exploring the heterogeneous preand nonmotor PD phenotype might assist in the discovery of the aetiologies of the disease and lead to neuroprotective treatments in the future specific for each PD patient. A limitation of this study is that some of these early de novo PD patients may then reclassified as multiple system atrophy at follow-up. Our findings show that early de novo PD patients with urinary dysfunction have poorer motor and nonmotor functions and greater dopaminergic deficits when compared with those without urinary dysfunction, and worse urinary dysfunction is associated with increased CSF a-synuclein levels. This confirms and expands on previous studies showing that urinary dysfunction is a marker of a more severe PD subtype. (A complete discussion is included in the Supplementary Data.)

A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism (Niccolini and Politis, 2016) : Reply to Jean-Claude Baron Letter to Editor.

Abstract: Dear Editor, RE: BA systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism | EJNM-D-16-00995 [25]^ Reply to Jean-Claude Baron Letter to Editor We are most grateful for the comments and criticism. D’Antona et al. [6] is indeed the first [F]FDG PET report demonstrating glucose hypometabolism in the frontal lobe of six patients with progressive supranuclear palsy (PSP) but has some methodological limitations. The authors used an autoradiographic paradigm to measure the cerebral metabolic rate of glucose (CMR Glu) and only four out of six PSP patients showed reliable images due to difficulties related to neck stiffness. When the authors tried to overcome this issue by using CMR Glu values generated by means of the kinetic method only three PSP patients and five control subjects could be analysed [6]. Additionally, no reliable volumetric brain measures have been reported, thus cortical atrophy could have affected the results. The other studies mentioned (i.e. [11, 20, 21]) were conducted before the establishment of PSP diagnostic criteria [National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP) criteria; [22]]. As such, one of the patients clinically diagnosed with PSP and included in the analysis, revealed to have multiple system atrophy (MSA) at postmortem examination [11]. In our study, we have limited our review to the findings from studies using more reliable methodology, larger sample size and more selective inclusion criteria for the diagnosis of PSP (please see [8, 14, 15, 19, 24, 33]). With regards to correlation between frontal lobe hypometabolism and severity of cognitive dysfunction in PSP patients, we have discussed in our review the findings from Takahashi et al. [31] that used well-established measures of cognitive impairment for both groups of PSP patients and healthy controls, together with voxel-based analysis of [F]FDG uptakes. We have not reported findings from previous studies investigating striatal dopamine D2 receptors availability using [Br]bromospiperone PET in PSP patients ([2, 3]). [Br]Bromospiperone PET has similar kinetics and affinity as [C]methylspiperone PET [34]. [C]Methylspiperone has shown to have lower affinity for dopamine D2 receptors compared to [C]raclopride and to be unsuitable for evaluating the degeneration of dopamine D2 receptors in the rat striatum following injection of excitotoxin quinolinic acid by PET and ex vivo and in vitro autoradiography [16, 17]. Moreover, in contrast to [C]raclopride, [C]methylspiperone PET failed to detect D2 receptor occupancy by quetiapine in schizophrenic patients [13]. As stated in the inclusion criteria in the Methods section, we only reported findings from PET studies using the [C]raclopride PET radioligand with regards to dopamine D2 receptor availability in atypical parkinsonism. Bhatt et al. [4] showed decreased [F]Fdopa uptake in large striatal regions of interest (12 cm) of six PSP patients. In our study, we reported the results fromBrooks et al. [5] who used more reliable methods of analysis [28] and quantified [F]Fdopa uptake in specific striatal regions such as the caudate and the putamen. This Editorial Commentary refers to the article http://dx.doi.org/10.1007 /s00259-016-3596-x.