PET imaging of synaptic density in Parkinsonian disorders.

Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha-synuclein accumulation, two hallmarks of Parkinson's disease (PD) pathology, contribute to synaptic dysfunction and reduced synaptic density in PD. Atypical Parkinsonian disorders are likely to have unique spatiotemporal patterns of synaptic density, differentiating them from PD. Therefore, quantification of synaptic density has the potential to support diagnoses, monitor disease progression, and treatment efficacy. Novel radiotracers for positron emission tomography which target the presynaptic vesicle protein SV2A have been developed to quantify presynaptic density. The radiotracers have successfully investigated synaptic density in preclinical models of PD and people with Parkinsonian disorders. Therefore, this review will summarize the preclinical and clinical utilization of SV2A radiotracers in people with Parkinsonian disorders. We will evaluate how SV2A abundance is associated with other imaging modalities and the considerations for interpreting SV2A in Parkinsonian pathology.

Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results.

INTRODUCTION: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. HIGHLIGHTS: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Cognition affects gait adaptation after split-belt treadmill training in Parkinson's disease.

BACKGROUND: Split-belt treadmill (SBTM) training has been proposed to improve gait symmetry and overall gait performance of patients with Parkinson's disease (PD). OBJECTIVES: To determine whether patient's baseline features affect gait adaptation to SBTM in PD with freezing of gait (FOG). METHODS: Twenty participants with idiopathic PD and treatment-resistant FOG underwent several clinical assessments including the Toronto Cognitive Assessment (TorCA) prior to treadmill training. Velocity of the treadmill was adjusted to over-ground walking speed. During SBTM training, the belt velocity on the least-affected side was reduced by 25%. RESULTS: Participants who adapted to SBTM training demonstrated cognitively intact TorCA scores (p < 0.001), particularly intact working memory (p < 0.001). After-effects correlated with normal total TorCA (p = 0.02), working memory and visuospatial (p < 0.001) function. CONCLUSIONS: Cognitive impairment, particularly impaired working memory, reduces gait adaptation and after-effects in PD with FOG. This is informative for trials studying prolonged effects of SBTM training in FOG.

Preliminary Assessment of Reference Region Quantification and Reduced Scanning Times for [18F]SynVesT-1 PET in Parkinson's Disease.

Synaptic density in the central nervous system can be measured in vivo using PET with [18F]SynVesT-1. While [18F]SynVesT-1 has been proven to be a powerful radiopharmaceutical for PET imaging of neurodegenerative disorders such as Parkinson's disease (PD), its currently validated acquisition and quantification protocols are invasive and technically challenging in these populations due to the arterial sampling and relatively long scanning times. The objectives of this work were to evaluate a noninvasive (reference tissue) quantification method for [18F]SynVesT-1 in PD patients and to determine the minimum scan time necessary for accurate quantification. [18F]SynVesT-1 PET scans were acquired in 5 patients with PD and 3 healthy control subjects for 120 min with arterial blood sampling. Quantification was performed using the one-tissue compartment model (1TCM) with arterial input function, as well as with the simplified reference tissue model (SRTM) to estimate binding potential (BPND) using centrum semiovale (CS) as a reference region. The SRTM2 method was used with k2' fixed to either a sample average value (0.037 min-1) or a value estimated first through coupled fitting across regions for each participant. Direct SRTM estimation and the Logan reference region graphical method were also evaluated. There were no significant group differences in CS volume, radiotracer uptake, or efflux (ps > 0.47). Each fitting method produced BPND estimates in close agreement with those derived from the 1TCM (subject R2s > 0.98, bias < 10%), with no difference in bias between the control and PD groups. With SRTM2, BPND estimates from truncated scan data as short as 80 min produced values in excellent agreement with the data from the full 120 min scans (bias < 6%). While these are preliminary results from a small sample of patients with PD (n = 5), this work suggests that accurate synaptic density quantification may be performed without blood sampling and with scan time under 90 minutes. If further validated, these simplified procedures for [18F]SynVesT-1 PET quantification can facilitate its application as a clinical research imaging technology and allow for larger study samples and include a broader scope of patients including those with neurodegenerative diseases.

First-in-Human PET Imaging of [18F]SDM-4MP3: A Cautionary Tale.

[18F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [18F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols. Further investigation, including imaging in rats as well as proton and carbon 2D-NMR spectroscopic studies, led to the discovery that a derivative of the precursor had been received from the manufacturer. Hence, we report our investigation and the first-in-human study of [18F]SDM-4MP3, a structural variant of [18F]SynVesT-1, which does not have the requisite characteristics as a PET radiopharmaceutical for imaging SV2A in the central nervous system.

Structural and Molecular Imaging for Clinically Uncertain Parkinsonism.

Neuroimaging is an important adjunct to the clinical assessment of Parkinson disease (PD). Parkinsonism can be challenging to differentiate, especially in early disease stages, when it mimics other movement disorders or when there is a poor response to dopaminergic therapies. There is also a discrepancy between the phenotypic presentation of degenerative parkinsonism and the pathological outcome. The emergence of more sophisticated and accessible neuroimaging can identify molecular mechanisms of PD, the variation between clinical phenotypes, and the compensatory mechanisms that occur with disease progression. Ultra-high-field imaging techniques have improved spatial resolution and contrast that can detect microstructural changes, disruptions in neural pathways, and metabolic and blood flow alterations. We highlight the imaging modalities that can be accessed in clinical practice and recommend an approach to the diagnosis of clinically uncertain parkinsonism.

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.

Single-Trajectory Multiple-Target Deep Brain Stimulation for Parkinsonian Mobility and Cognition.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.

Development and Validation of Automated Magnetic Resonance Parkinsonism Index 2.0 to Distinguish Progressive Supranuclear Palsy-Parkinsonism From Parkinson's Disease.

BACKGROUND: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. OBJECTIVE: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. METHODS: We enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. RESULTS: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. CONCLUSIONS: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The neuroimaging evidence of brain abnormalities in functional movement disorders.

Neuroimaging has been pivotal in identifying and reframing our understanding of functional movement disorders. If accessible, it compensates for the limitations of the clinical exam and is especially useful where there is overlap of functional symptoms with classical presentations of disease. Imaging in functional movement disorders has increasingly identified structural and functional abnormalities that implicate hypoactivation of the cortical and subcortical motor pathways and increased modulation by the limbic system. Neurobiological theories suggest an impaired sense of agency, faulty top-down regulation of motor movement and abnormal emotional processing in these individuals. This framework challenges our traditional understanding of functional movement disorders as distinct from the deceptive term of 'organic' diseases and proposes that these conditions are not considered as mutually exclusive. This update summarizes the literature to date and explores the role of imaging in the diagnosis of functional movement disorders and in detecting its underlying molecular network.

Reversible neurological and brain MRI changes following COVID-19 vaccination: A case report.

BACKGROUND: Various neurological sequalae have been described following COVID-19 vaccination. Here we describe the first case of untreated post COVID-19 vaccine encephalitis with spontaneous resolution of contrast enhancing hyperintensities on MRI concomitant with clinical improvement. CASE PRESENTATION: A 59-year-old woman presented with a two-day history of unsteady gait, incoordination, visual symptoms, and lethargy. She had received AZD1222 (AstraZeneca) and mRNA-1273 (Moderna) COVID-19 vaccines at 3 months and 12 days, respectively, before presentation. Brain MRI showed no abnormality on the non-enhanced sequences, but numerous enhancing lesions in the cerebral cortex, deep grey matter, brainstem, and cerebellum. Treatment was expectant, the patient improved clinically over 10 days, and repeat MRI showed near complete resolution of the imaging abnormality. CONCLUSIONS: We describe neurological deterioration 12 days after a second dose of COVID-19 vaccine. There was no evidence of edema or demyelinating lesions in the brain on MRI, but there was extensive contrast-enhancement indicating loss of blood-brain barrier (BBB) integrity. This provides a potential in vivo, clinical-imaging correlate of the post-mortem evidence that SARS-CoV-2 spike protein may induce loss of BBB permeability. While this adds to the list of rare adverse neurological reactions to COVID-19 vaccination, the benefits of receiving the vaccine far outweigh these risks.

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.

Dopamine Receptors in Parkinson's Disease: A Meta-Analysis of Imaging Studies.

Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta-analysis of the available PET and single-photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single-photon emission computed tomography imaging; dopamine receptor tracers (D1-like or D2-like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2-like studies had 1925 patients. Data were insufficient for an analysis of D1-like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA-P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist-induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A New MRI Measure to Early Differentiate Progressive Supranuclear Palsy From De Novo Parkinson's Disease in Clinical Practice: An International Study.

BACKGROUND: Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). METHODS: We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. RESULTS: In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. CONCLUSION: Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.

Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals.

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = -0.38, q = 0.04; dACC: r = -0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Automated MRI Classification in Progressive Supranuclear Palsy: A Large International Cohort Study.

BACKGROUND: The Magnetic Resonance Parkinsonism Index is listed as one of the most reliable imaging morphometric markers for diagnosis of progressive supranuclear palsy (PSP). However, the use of this index in diagnostic workup has been limited until now by the low generalizability of published results because of small monocentric patient cohorts, the lack of data validation in independent patient series, and manual measurements used for index calculation. The objectives of this study were to investigate the generalizability of Magnetic Resonance Parkinsonism Index performance validating previously established cutoff values in a large international cohort of PSP patients subclassified into PSP-Richardson's syndrome and PSP-parkinsonism and to standardize the use of the automated Magnetic Resonance Parkinsonism Index by providing a web-based platform to obtain homogenous measures around the world. METHODS: In a retrospective international multicenter study, a total of 173 PSP patients and 483 non-PSP participants were enrolled. A web-based platform (https://mrpi.unicz.it) was used to calculate automated Magnetic Resonance Parkinsonism Index values. RESULTS: Magnetic Resonance Parkinsonism Index values showed optimal performance in differentiating PSP-Richardson's syndrome and PSP-parkinsonism patients from non-PSP participants (93.6% and 86.5% of accuracy, respectively). The Magnetic Resonance Parkinsonism Index was also able to differentiate PSP-Richardson's syndrome and PSP-parkinsonism patients in an early stage of the disease from non-PSP participants (90.1% and 85.9%, respectively). The web-based platform provided the automated Magnetic Resonance Parkinsonism Index calculation in 94% of cases. CONCLUSIONS: Our study provides the first evidence on the generalizability of automated Magnetic Resonance Parkinsonism Index measures in a large international cohort of PSP-Richardson's syndrome and PSP-parkinsonism patients. The web-based platform enables widespread applicability of the automated Magnetic Resonance Parkinsonism Index to different clinical and research settings. © 2020 International Parkinson and Movement Disorder Society.

Dynamic functional connectivity changes associated with dementia in Parkinson's disease.

Dynamic functional connectivity captures temporal variations of functional connectivity during MRI acquisition and it may be a suitable method to detect cognitive changes in Parkinson's disease. In this study, we evaluated 118 patients with Parkinson's disease matched for age, sex and education with 35 healthy control subjects. Patients with Parkinson's disease were classified with normal cognition (n = 52), mild cognitive impairment (n = 46), and dementia (n = 20) based on an extensive neuropsychological evaluation. Resting state functional MRI and a sliding-window approach were used to study the dynamic functional connectivity. Dynamic analysis suggested two distinct connectivity 'States' across the entire group: a more frequent, segregated brain state characterized by the predominance of within-network connections, State I, and a less frequent, integrated state with strongly connected functional internetwork components, State II. In Parkinson's disease, State I occurred 13.89% more often than in healthy control subjects, paralleled by a proportional reduction of State II. Parkinson's disease subgroups analyses showed the segregated state occurred more frequently in Parkinson's disease dementia than in mild cognitive impairment and normal cognition groups. Further, patients with Parkinson's disease dementia dwelled significantly longer in the segregated State I, and showed a significant lower number of transitions to the strongly interconnected State II compared to the other subgroups. Our study indicates that dementia in Parkinson's disease is characterized by altered temporal properties in dynamic connectivity. In addition, our results show that increased dwell time in the segregated state and reduced number of transitions between states are associated with presence of dementia in Parkinson's disease. Further studies on dynamic functional connectivity changes could help to better understand the progressive dysfunction of networks between Parkinson's disease cognitive states.

Decreased pallidal vesicular monoamine transporter type 2 availability in Parkinson's disease: The contribution of the nigropallidal pathway.

To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.

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.