Beta amyloid deposition and cognitive decline in Parkinson's disease: a study of the PPMI cohort.

The accumulation of beta amyloid in the brain has a complex and poorly understood impact on the progression of Parkinson's disease pathology and much controversy remains regarding its role, specifically in cognitive decline symptoms. Some studies have found increased beta amyloid burden is associated with worsening cognitive impairment in Parkinson's disease, especially in cases where dementia occurs, while other studies failed to replicate this finding. To better understand this relationship, we examined a cohort of 25 idiopathic Parkinson's disease patients and 30 healthy controls from the Parkinson's Progression Marker Initiative database. These participants underwent [18F]Florbetaben positron emission tomography scans to quantify beta amyloid deposition in 20 cortical regions. We then analyzed this beta amyloid data alongside the longitudinal Montreal Cognitive Assessment scores across 3 years to see how participant's baseline beta amyloid levels affected their cognitive scores prospectively. The first analysis we performed with these data was a hierarchical cluster analysis to help identify brain regions that shared similarity. We found that beta amyloid clusters differently in Parkinson's disease patients compared to healthy controls. In the Parkinson's disease group, increased beta amyloid burden in cluster 2 was associated with worse cognitive ability, compared to deposition in clusters 1 or 3. We also performed a stepwise linear regression where we found an adjusted R2 of 0.495 (49.5%) in a model explaining the Parkinson's disease group's Montreal Cognitive Assessment score 1-year post-scan, encompassing the left gyrus rectus, the left anterior cingulate cortex, and the right parietal cortex. Taken together, these results suggest regional beta amyloid deposition alone has a moderate effect on predicting future cognitive decline in Parkinson's disease patients. The patchwork effect of beta amyloid deposition on cognitive ability may be part of what separates cognitive impairment from cognitive sparing in Parkinson's disease. Thus, we suggest it would be more useful to measure beta amyloid burden in specific brain regions rather than using a whole-brain global beta amyloid composite score and use this information as a tool for determining which Parkinson's disease patients are most at risk for future cognitive decline.

Neuroimaging of rapid eye movement sleep behavior disorder and its relation to Parkinson's disease.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by polysomnography-confirmed REM sleep without atonia and dream-enacting behaviors. This disorder is considered a prodromal syndrome of alpha-synucleinopathies like Parkinson's disease (PD), where it affects more than 50% of PD patients. The underlying pathology of RBD has been generally understood to involve the pontine nuclei within the brainstem. However, the complete pathophysiology beyond the brainstem remains unclear as does its relationship with PD pathology. Therefore, this review aims to survey the neuroimaging literature involving PET, SPECT, and MR imaging techniques to provide an updated understanding of the neuro-chemical, structural, and functional changes in both RBD and PD patients comorbid with RBD. This review found neuroimaging evidence that indicate alterations to the dopaminergic and cholinergic system, blood perfusion, and glucose metabolism in both RBD patients and PD patients with RBD. Beyond the brainstem, structural and functional changes were found to involve the nigrostriatal system, limbic system, and the cortex-suggesting that RBD is a multi-systemic neurodegenerative process. Future investigations are encouraged to follow RBD patients longitudinally using multimodal imaging techniques to enhance our understanding of this parasomnia disorder. Uncovering which individuals are most likely to develop an alpha-synuclein disorder in the prodromal phase will improve patient outcomes and potentially aid in the development of novel treatments for patients affected by RBD.

Contributions of sex, depression, and cognition on brain connectivity dynamics in Parkinson's disease.

Alterations in time-varying functional connectivity (FC) have been found in Parkinson's disease (PD) patients. To date, very little is known about the influence of sex on brain FC in PD patients and how this could be related to disease severity. The first objective was to evaluate the influence of sex on dynamic FC characteristics in PD patients and healthy controls (HC), while the second aim was to investigate the temporal patterns of dynamic connectivity related to PD motor and non-motor symptoms. Ninety-nine PD patients and sixty-two HC underwent a neuropsychological and clinical assessment. Rs-fMRI and T1-weighted MRI were also acquired. Dynamic FC analyses were performed in the GIFT toolbox. Dynamic FC analyses identified two States: State I, characterized by within-network positive coupling; and State II that showed between-network connectivity, mostly involving somatomotor and visual networks. Sex differences were found in dynamic indexes in HC but these differences were not observed in PD. Hierarchical clustering analysis identified three phenotypically distinct PD subgroups: (1) Subgroup A was characterized by mild motor symptoms; (2) Subgroup B was characterized by depressive and motor symptoms; (3) Subgroup C was characterized by cognitive and motor symptoms. Results revealed that changes in the temporal properties of connectivity were related to the motor/non-motor outcomes of PD severity. Findings suggest that while in HC sex differences may play a certain role in dynamic connectivity patterns, in PD patients, these effects may be overcome by the neurodegenerative process. Changes in the temporal properties of connectivity in PD were mainly related to the clinical markers of PD severity.

VMAT2 availability in Parkinson's disease with probable REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson's disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD-). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD-, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD- was significantly lower than HC in all these regions. PD-RBD- showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

Extra-striatal dopamine in Parkinson's disease with rapid eye movement sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) is a common condition found in more than 50% of the patients with Parkinson's disease (PD). Molecular imaging shows that PD with RBD (PD-RBD+) have lower striatal dopamine transporter activity within the caudate and putamen relative to PD without RBD (PD-RBD-). However, the characterization of the extra-striatal dopamine within the mesocortical and mesolimbic pathways remains unknown. We aim to elucidate this with PET imaging in 15 PD-RBD+ and 15 PD-RBD- patients, while having 15 age-matched healthy controls (HC). Each participant underwent a single PET scan with [11 C]FLB-457 to detect the D2 receptor availability within the extra-striatal regions of interest (ROI), including the prefrontal, temporal, and limbic areas. [11 C]FLB-457 retention was expressed as the nondisplaceable binding potential. Our results reveal that relative to HC, PD-RBD+ and PD-RBD- patients have lower levels of D2 receptor availability within the uncus parahippocampus, superior, lateral, and inferior temporal cortex. PD-RBD+ showed steep decline in D2 receptors within the left uncus parahippocampus with increasing disease severity, but this was not observed for PD-RBD- patients. Findings imply that extra-striatal dopaminergic system may play a role in contributing to symptomatic progress in PD patients with RBD. However, validation with more advanced PD patients are needed.

Graph theory analysis of the dopamine D2 receptor network in Parkinson's disease patients with cognitive decline.

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disorder that has a large impact on patient well-being. Its physiological etiology, however, remains elusive. Our study used graph theory analysis to investigate the large-scale topological patterns of the extrastriatal dopamine D2 receptor network. We used positron emission tomography with [11 C]FLB-457 to measure the binding potential of cortical dopamine D2 receptors in two networks: the meso-cortical dopamine network and the meso-limbic dopamine network. We also investigated the application of partial volume effect correction (PVEC) in conjunction with graph theory analysis. Three groups were investigated in this study divided according to their cognitive status as measured by the Montreal Cognitive Assessment score, with a score ≤25 considered cognitively impaired: (a) healthy controls (n = 13, 11 female), (b) cognitively unimpaired PD patients (PD-CU, n = 13, 5 female), and (c) PD patients with mild cognitive impairment (PD-MCI, n = 17, 4 female). In the meso-cortical network, we observed increased small-worldness, normalized clustering, and local efficiency in the PD-CU group compared to the PD-MCI group, as well as a hub shift in the PD-MCI group. Compensatory reorganization of the meso-cortical dopamine D2 receptor network may be responsible for some of the cognitive preservation observed in PD-CU. These results were found without PVEC applied and PVEC proved detrimental to the graph theory analysis. Overall, our findings demonstrate how graph theory analysis can be used to detect subtle changes in the brain that would otherwise be missed by regional comparisons of receptor density.

Network Patterns of Beta-Amyloid Deposition in Parkinson's Disease.

Beta-amyloid (Aß) in the brain is a key pathological feature of certain neurodegenerative diseases. Recent studies using graph theory have shown that Aß brain networks are of pathological significance in Alzheimer's disease (AD). However, the characteristics of Aß brain networks in Parkinson's disease (PD) are unknown. In the present study using positron emission tomography (PET) with [11C]-Pittsburgh compound B (PiB), we applied a graph theory-based analysis to assess the topological properties of Aß brain network in PD patients with and without Aß burden (PiB-positive and PiB-negative, respectively) and healthy controls with Aß burden. We found that the PD PiB-positive group demonstrated significantly lower value in global efficiency and modularity compared with PD PiB-negative group. The less robust modular structure indicates the tendency of having increased inter-modular connections than intra-modular connectivity (i.e., reduced segregation). Results of hub organization showed that relative to PD PiB-negative group, different hubs were identified in the PiB-positive group, which were located mainly within the default mode network. Overall, our findings suggest disturbances in Aß topological organization characterized by abnormal network integration and segregation in PD patients with Aß burden. The stronger inter-modular connectivity observed in the PD PiB-positive group may suggest the spreading pattern of Aß between modules in those PD patients with elevated PiB burden, thus providing insight into the beta-amyloidopathy of PD.

DRD2 Genotype-Based Variants Modulates D2 Receptor Distribution in Ventral Striatum.

Dopaminergic signaling within the striatum is crucial for motor planning and mental function. Neurons within the striatum contain two dopamine D2 receptor isoforms-D2 long and D2 short. The amount of expression for these receptor isoforms is affected by the genotype within two single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C > A), found in the DRD2 gene. However, it is unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system. We aim to elucidate this with PET imaging in healthy young adults using [11C]-(+)-PHNO. Participants were genotyped for the DRD2 rs2283265 SNP and a total of 20 enrolled: 9 with CC, 6 with CA, and 5 with AA genotype. The main effect of genotype on [11C]-(+)-PHNO binding was tested and we found significant group effect within the ventral striatum. Specifically, CC and CA carriers had higher binding in this region compared to AA carriers. There were no observed differences between genotypes in other regions within the basal ganglia. Our preliminary results implicate that the polymorphism genotype affects the dopaminergic signaling by controlling either the quantity of D2 receptors, D2 affinity, or a combination thereof within the ventral striatum.

Imaging behavioural complications of Parkinson's disease.

In addition to motor symptoms, behavioural complications are commonly found in patients with Parkinson's disease (PD). Behavioural complications, including depression, anxiety, apathy, impulse control disorder and psychosis, together have a large impact on PD patient's quality of life. Many neuroimaging studies using PET, SPECT and MRI techniques have been conducted to study the underlying neural mechanisms of PD pathogenesis and pathophysiology in relation to its behavioural complications. This review will survey these PET, SPECT and MRI studies to describe the current understanding of the neuro-chemical, functional and structural changes associated with behavioural complications in PD patients.

Brain degeneration in Parkinson's disease patients with cognitive decline: a coordinate-based meta-analysis.

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disease, with its severity increasing as the neurodegenerative process advances. The present meta-analysis used anisotropic effect size seed-based d mapping software to perform analyses using both functional and structural brain imaging data. The analyses were between PD patients with mild cognitive impairment (PD-MCI) and PD patients with dementia (PDD) compared to PD cognitively unimpaired patients (PD-CU) and PD patients without dementia (PD-ND) respectively. Thirty-four studies were found and split into three analyses: 405 PD-MCI patients compared to 559 PD-CU patients from 1) 15 studies with structural imaging modalities and 2) eight studies with functional imaging modalities, as well as 178 PDD patients compared to 278 PD-ND patients (which includes both PD-CU and PD-MCI) in 3) 11 studies with structural imaging modalities. Statistical threshold was set to uncorrected p < 0.001. We found several brain regions that differed between PD-MCI and PD-CU patients: the left insula, bilateral dorsolateral prefrontal cortex, left angular gyrus, midcingulate cortex, and right supramarginal gyrus. The brain regions identified in the PD-MCI analyses are associated with the somatosensory network and executive processing. In PDD patients, the bilateral insula and right hippocampus were found as regions of structural atrophy. The insula was found in both structural analyses of PD-MCI and PDD, with unilateral insula involvement in PD-MCI extending to bilateral insula involvement in PDD. The results found both a spectrum of increasing brain atrophy in PD cognitive impairment and supports the existence of sub-typing in PD-MCI.

Molecular Imaging of Addictive Behavior in Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is commonly associated with motor symptoms, however cognitive and neurobehavioral complications are increasingly recognized and contribute to long-term disability. Dopamine replacement therapy is effective for motor symptoms, but can also lead to motor side-effects and addictive behavior such as impulse control disorders. Molecular imaging is advancing our knowledge of the mechanisms involved in the development of behavioral addictions. This chapter will discuss potential risk factors and associations with the development of addictive behavior in PD including the role of dopaminergic medication and genetic predisposition. We further will describe the common neurobiology and similarities of addictive behavior in PD to addiction, particularly the neuroanatomy of reward processing and its alteration in substance and behavioral addictions. Finally, we will discuss molecular imaging approaches which are helping to delineate the structure as well as the dynamic interactions between different components involving neurotransmitters, transporters, and receptors.