The Interaction Between Neuroinflammation and ß-Amyloid in Cognitive Decline in Parkinson's Disease.

Activated microglia have been reported to play an important role in Parkinson's disease (PD). A more rapid cognitive decline has been associated with deposits of ß-amyloid. In this study, the aim was to evaluate the role of brain ß-amyloid and its relationship with activated microglia in PD patients with normal and impaired cognition. We studied 17 PD patients with normal cognition (PDn), 12 PD patients with mild cognitive impairment (PD-MCI), and 12 healthy controls (HCs) with [11C] Pittsburgh compound B (PIB) to assess the impact of ß-amyloid deposition in the brain on microglial activation evaluated using the translocator protein 18-kDa (TSPO) radioligand [18F]-FEPPA. [11C] PIB distribution volume ratio was measured in cortical and subcortical regions. [18F]-FEPPA total distribution volume values were compared for each brain region between groups to evaluate the effect of PIB positivity while adjusting for the TSPO rs6971 polymorphism. Factorial analysis of variance revealed a significant main effect of PIB positivity in the frontal lobe (F(1, 34) = 7.1, p = 0.012). Besides the frontal (p = 0.006) and temporal lobe (p = 0.001), the striatum (p = 0.018), the precuneus (p = 0.019), and the dorsolateral prefrontal cortex (p = 0.010) showed significant group × PIB positivity interaction effects. In these regions, PD-MCIs had significantly higher FEPPA VT if PIB-positive. Our results indicate an interaction between amyloid-ß deposition and microglial activation in PD. Further investigations are necessary to evaluate if amyloid deposits cause neuroinflammation and further neurodegeneration or if increased microglia activation develops as a protective response.

PET Evaluation of Microglial Activation in Non-neurodegenerative Brain Diseases.

PURPOSE OF THE REVIEW: Microglial cell activation is an important component of neuroinflammation, and it is generally well accepted that chronic microglial activation is indicative of accumulating tissue damage in neurodegenerative conditions, particularly in the earlier stages of disease. Until recently, there has been less focus on the role of neuroinflammation in other forms of neurological and neuropsychiatric conditions. Through this review, we hope to demonstrate the important role TSPO PET imaging has played in illuminating the pivotal role of neuroinflammation and microglial activation underpinning these conditions. RECENT FINDINGS: TSPO is an 18 kDa protein found on the outer membrane of mitochondria and can act as a marker of microglial activation using nuclear imaging. Through the development of radiopharmaceuticals targeting TSPO, researchers have been able to better characterise the spatial-temporal evolution of chronic neurological conditions, ranging from the focal autoimmune reactions seen in multiple sclerosis to the Wallerian degeneration at remote parts of the brain months following acute cerebral infarction. Development of novel techniques to investigate neuroinflammation within the central nervous system, for the purposes of diagnosis and therapeutics, has flourished over the past few decades. TSPO has proven itself a robust and sensitive biomarker of microglial activation and neuroimaging affords a minimally invasive technique to characterise neuroinflammatory processes in vivo.

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.

New and Old TSPO PET Radioligands for Imaging Brain Microglial Activation in Neurodegenerative Disease.

PURPOSE OF REVIEW: We will discuss the developments in TSPO PET imaging and the contribution this technique has had to understanding neuroinflammation in vivo, as well as the limitations inherent to the currently available radioligands and the potential future direction. RECENT FINDINGS: Positron emission tomography (PET) imaging targeting the translocator protein 18 kDa (TSPO) has led to major advances in understanding the pathological role played by microglia activation and neuroinflammation in a diverse range of neurodegenerative conditions. The first-generation radioligand 11[C](R)-PK11195 has been the most widely studied and has led to considerable advancements in defining the role of neuroinflammation in neuronal degeneration and dysfunction. However, limitations including low signal-to-noise ratio and high nonspecific binding have led to the development of new TSPO-specific radioligands in an attempt to improve the quality of TSPO imaging. Unfortunately, these new radioligands have not been without their own problems, and the expected improvement in image quality has not been achieved.

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.

New Imaging Markers for Movement Disorders.

PURPOSE OF REVIEW: For decades, identifying in vivo imaging biomarkers to accurately differentiate between various movement disorders as well as to understand their underlying pathophysiological abnormalities has been the aim of scientific work. Recent advances in multimodal imaging enable the visualization of structural and functional brain changes in these pathological conditions, thus raising the value of imaging techniques as powerful tools to improve sensitivity and specificity of clinical diagnoses. This article reviews well-established and recent developments in imaging markers for movement disorders. RECENT FINDINGS: Whereas several imaging approaches seem to be promising, many modalities are still under development and may not provide decisive answers. Thus, the use of combined imaging modalities as well as the acquisition of methodological consensus in the scientific community may provide more conclusive findings in the future of biomarkers. Although a single biomarker has yet not been identified, multiple markers derived from different imaging modalities may represent the right approach.

[18F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP.

This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451.

Imaging Markers of Progression in Parkinson's Disease.

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.

Feasibility study of TSPO quantification with [18F]FEPPA using population-based input function.

PURPOSE: The input function (IF) is a core element in the quantification of Translocator protein 18 kDa with positron emission tomography (PET), as no suitable reference region with negligible binding has been identified. Arterial blood sampling is indeed needed to create the IF (ASIF). In the present manuscript we study individualization of a population based input function (PBIF) with a single arterial manual sample to estimate total distribution volume (VT) for [18F]FEPPA and to replicate previously published clinical studies in which the ASIF was used. METHODS: The data of 3 previous [18F]FEPPA studies (39 of healthy controls (HC), 16 patients with Parkinson's disease (PD) and 18 with Alzheimer's disease (AD)) was reanalyzed with the new approach. PBIF was used with the Logan graphical analysis (GA) neglecting the vascular contribution to estimate VT. Time of linearization of the GA was determined with the maximum error criteria. The optimal calibration of the PBIF was determined based on the area under the curve (AUC) of the IF and the agreement range of VT between methods. The shape of the IF between groups was studied while taking into account genotyping of the polymorphism (rs6971). RESULTS: PBIF scaled with a single value of activity due to unmetabolized radioligand in arterial plasma, calculated as the average of a sample taken at 60 min and a sample taken at 90 min post-injection, yielded a good interval of agreement between methods and optimized the area under the curve of IF. In HC, gray matter VTs estimated by PBIF highly correlated with those using the standard method (r2 = 0.82, p = 0.0001). Bland-Altman plots revealed PBIF slightly underestimates (~1 mL/cm3) VT calculated by ASIF (including a vascular contribution). It was verified that the AUC of the ASIF were independent of genotype and disease (HC, PD, and AD). Previous clinical results were replicated using PBIF but with lower statistical power. CONCLUSION: A single arterial blood sample taken 75 minute post-injection contains enough information to individualize the IF in the groups of subjects studied; however, the higher variability produced requires an increase in sample size to reach the same effect size.

Positron emission tomography imaging of tau pathology in progressive supranuclear palsy.

Progressive supranuclear palsy is a rare form of atypical Parkinsonism that differs neuropathologically from other parkinsonian disorders. While many parkinsonian disorders such as Parkinson's disease, Lewy body dementia, and multiple system atrophy are classified as synucleinopathies, progressive supranuclear palsy is coined a tauopathy due to the aggregation of pathological tau in the brain. [18F]AV-1451 (also known as [18F]-T807) is a positron emission tomography radiotracer that binds to paired helical filaments of tau in Alzheimer's disease. We investigated whether [18F]AV-1451 could be used as biomarker for the diagnosis and disease progression monitoring in progressive supranuclear palsy. Six progressive supranuclear palsy, six Parkinson's disease, and 10 age-matched healthy controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio from 60 to 90 min post-injection was calculated in each region of interest, using the cerebellar cortex as a reference region. No significant differences in standardized uptake value ratios were detected in our progressive supranuclear palsy group compared to the two control groups. [18F]AV-1451 may bind selectivity to the paired helical filaments in Alzheimer's disease, which differ from the straight conformation of tau filaments in progressive supranuclear palsy.

Microglial activation in Parkinson's disease using [18F]-FEPPA.

BACKGROUND: Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. METHODS: Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. RESULTS: Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). CONCLUSIONS: Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.

Disrupted Nodal and Hub Organization Account for Brain Network Abnormalities in Parkinson's Disease.

The recent application of graph theory to brain networks promises to shed light on complex diseases such as Parkinson's disease (PD). This study aimed to investigate functional changes in sensorimotor and cognitive networks in Parkinsonian patients, with a focus on inter- and intra-connectivity organization in the disease-associated nodal and hub regions using the graph theoretical analyses. Resting-state functional MRI data of a total of 65 participants, including 23 healthy controls (HCs) and 42 patients, were investigated in 120 nodes for local efficiency, betweenness centrality, and degree. Hub regions were identified in the HC and patient groups. We found nodal and hub changes in patients compared with HCs, including the right pre-supplementary motor area (SMA), left anterior insula, bilateral mid-insula, bilateral dorsolateral prefrontal cortex (DLPFC), and right caudate nucleus. In general, nodal regions within the sensorimotor network (i.e., right pre-SMA and right mid-insula) displayed weakened connectivity, with the former node associated with more severe bradykinesia, and impaired integration with default mode network regions. The left mid-insula also lost its hub properties in patients. Within the executive networks, the left anterior insular cortex lost its hub properties in patients, while a new hub region was identified in the right caudate nucleus, paralleled by an increased level of inter- and intra-connectivity in the bilateral DLPFC possibly representing compensatory mechanisms. These findings highlight the diffuse changes in nodal organization and regional hub disruption accounting for the distributed abnormalities across brain networks and the clinical manifestations of PD.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

BACKGROUND: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity. OBJECTIVES: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty. METHODS: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor. RESULTS: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%. CONCLUSION: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.

R2* mapping for brain iron: associations with cognition in normal aging.

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.