Parkinson's Disease: Clinical Signs and Symptoms, Neural Mechanisms, Positron Emission Tomography, and Therapeutic Interventions

Parkinson's disease is one of the most frequent neurodegenerative brain diseases. Its time course is slow and is characterized by progressive loss of dopaminergic and other brainstem neurons resulting in malfunctioning of the cerebral neuronal systems responsible for motor functions. The clinical signs are slowness of movement, muscle rigidity and rest-tremor amongst other features. The cause of the disease is unknown, but recently involvement of genetic factors is being researched. Positron emission tomography (PET) allows in vivo determination of striatai dopaminergic activity. This has increased our insight in the pathophysiology of the disease and permits direct study of disease progression at a biochemical level and equally to monitor whether potential neuroprotective interventions are indeed effective. Thus far no drug has emerged but promising substances are currently being studied

Reward Processing in the Brain: A Prerequisite for Movement Preparation?

In the last decade, expanding animal studies on the cerebral organization of reward processing toward human in vivo situations has become possible. In this review, we define some of the concepts associated with reward, summarize the crucial importance of the dopaminergic system, and discuss the currently available neuroimaging studies in man. We will show that abstract concepts of human behavior like emotions, drive, arousal, and reinforcement are now open for further exploration in man at the level of neuronal circuit organization. The cerebral dopaminergic neurotransmitter circuitry does play an important role in the organization of both the motor and motivational system

Circuit imaging biomarkers in preclinical and prodromal Parkinson's disease

Abstract Parkinson’s disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD

Treatment of Parkinson’s Disease:Early, Late, and Combined

Medical therapy in de novo Parkinson’s disease typically starts with a dopamine agonist or levodopa in combination with a decarboxylase inhibitor or if symptoms are still very mild with a MAO-B inhibitor. When patients do not (or no longer) respond satisfactorily to these initial therapies, different drugs can be initiated or combined (i.e., “add-on” treatments). These add-on therapies not only comprise oral agents but also intra-jejunal and intra-cutaneous treatments and functional neurosurgical procedures. This chapter starts with the treatment of de novo Parkinson’s disease whereafter indications and expected effects of the different “add-on” therapies will be described. The “add-on” therapies will be described in a hierarchical way and treatment algorithms will be provided based on prevailing symptoms including non-motor symptoms. The symptoms that will be discussed are: (1) bradykinesia and “wearing-OFF, " (2) tremor at rest, (3) dyskinesia, (4) gait and postural symptoms including freezing of gait, and (5) important non-motor symptoms. Finally, a comprehensive add-on treatment algorithm will be provided that takes into account non-motor symptoms that may limit the efficacy and tolerability of the different add-on therapies.</p

Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold &gt;3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression

Exploring the impact of social network change:Experiences of older adults ageing in place

Social networks are sources of support and contribute to the well-being of older adults who are ageing in place. As social networks change, especially when accompanied by health decline, older adults' sources of support change and their well-being is challenged. Previous studies predominantly used quantitative measures to examine how older adults' social networks change. Alternatively, this study explores the impact of changing social networks on older adults' lives by examining their personal experiences. We held four focus groups, two with a total of 14 older adults who are ageing in place and receiving home care and two with a total of 20 home-care nurses from different regions and organisations in the Netherlands. Subsequently, an expert team of home-care professionals and managers discussed and verified the results. Procedures for grounded theory building were used for analysis. We revealed four themes of high-impact experiences: (a) struggling with illness/death of the spouse; (b) working out a changing relationship with (grand)children; (c) regretting the loss of people they have known for so long and (d) feeling dependent and stressed when helpers enter the network. Also, network dynamics were found to follow three consecutive stages: (a) awareness of social network change; (b) surprise when social network change actually occurs and (c) acceptance and adjusting to new circumstances. Together, the four themes of experiences and three stages of network change form an integrative model of the role of social network dynamics for older adults' lives when ageing in place

Occipital hypometabolism is a risk factor for conversion to Parkinson’s disease in isolated REM sleep behaviour disorder

Purpose: Isolated REM sleep behaviour disorder (iRBD) patients are at high risk of developing clinical syndromes of the α-synuclein spectrum. Progression markers are needed to determine the neurodegenerative changes and to predict their conversion. Brain imaging with 18F-FDG PET in iRBD is promising, but longitudinal studies are scarce. We investigated the regional brain changes in iRBD over time, related to phenoconversion.Methods: Twenty iRBD patients underwent two consecutive 18F-FDG PET brain scans and clinical assessments (3.7 ± 0.6 years apart). Seventeen patients also underwent 123I-MIBG and 123I-FP-CIT SPECT scans at baseline. Four subjects phenoconverted to Parkinson’s disease (PD) during follow-up. 18F-FDG PET scans were compared to controls with a voxel-wise single-subject procedure. The relationship between regional brain changes in metabolism and PD-related pattern scores (PDRP) was investigated.Results: Individual hypometabolism t-maps revealed three scenarios: (1) normal 18F-FDG PET scans at baseline and follow-up (N = 10); (2) normal scans at baseline but occipital or occipito-parietal hypometabolism at follow-up (N = 4); (3) occipital hypometabolism at baseline and follow-up (N = 6). All patients in the last group had pathological 123I-MIBG and 123I-FP-CIT SPECT. iRBD converters (N = 4) showed occipital hypometabolism at baseline (third scenario). At the group level, hypometabolism in the frontal and occipito-parietal regions and hypermetabolism in the cerebellum and limbic regions were progressive over time. PDRP z-scores increased over time (0.54 ± 0.36 per year). PDRP expression was driven by occipital hypometabolism and cerebellar hypermetabolism.Conclusions: Our results suggest that occipital hypometabolism at baseline in iRBD implies a short-term conversion to PD. This might help in stratification strategies for disease-modifying trials.</p

Four-YearFollow-upof [F-18]Fluorodeoxyglucose Positron Emission Tomography-Based Parkinson's Disease-Related Pattern Expression in 20 Patients With Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression

Background: Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18F]fluorodeoxyglucose-positron emission tomography (PET)–based PD-related brain pattern can be used to monitor disease progression. Objective: We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. Methods: Subjects underwent two [18F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. Results: At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic–determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD. Conclusions: Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder