Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

Background: Obesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D-2/D-3 receptor [D2/3R] availability is lower in morbidly obese subjects. Methods: To confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [I-123]IBZM SPECT, in 15 obese women and 15 non-obese controls. Results: Striatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women. Conclusion: This study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesit

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ-  cognitively normal (CN) individuals and Aβ+  (CN and CI) individuals separately. RESULTS: In Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ-  individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies

Background and Objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. // Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). // Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91–0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = −0.52, CI −0.74 to −0.30, p < 0.001) and participants with AD (β = −0.30, CI −0.58 to −0.02, p = 0.04). // Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. // Classification of Evidence: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline. // Glossary: Aβ=β-amyloid; AD=Alzheimer disease; CU=cognitively unimpaired; DLB=dementia with Lewy bodies; US FDA=US Food and Drug Administration; GMM=Gaussian mixture model; LMM=linear mixed model; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; OR=odds ratio; ROI=region of interest; SCD=subjective cognitive decline; SUVr=standardized uptake value ratio

Head-To-Head Comparison of PET and Perfusion Weighted MRI Techniques to Distinguish Treatment Related Abnormalities from Tumor Progression in Glioma

The post-treatment imaging surveillance of gliomas is challenged by distinguishing tumor progression (TP) from treatment-related abnormalities (TRA). Sophisticated imaging techniques, such as perfusion-weighted magnetic resonance imaging (MRI PWI) and positron-emission tomography (PET) with a variety of radiotracers, have been suggested as being more reliable than standard imaging for distinguishing TP from TRA. However, it remains unclear if any technique holds diagnostic superiority. This meta-analysis provides a head-to-head comparison of the diagnostic accuracy of the aforementioned imaging techniques. Systematic literature searches on the use of PWI and PET imaging techniques were carried out in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov and the reference lists of relevant papers. After the extraction of data on imaging technique specifications and diagnostic accuracy, a meta-analysis was carried out. The quality of the included papers was assessed using the QUADAS-2 checklist. Nineteen articles, totaling 697 treated patients with glioma (431 males; mean age ± standard deviation 50.5 ± 5.1 years) were included. The investigated PWI techniques included dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labeling (ASL). The PET-tracers studied concerned [S-methyl- 11C]methionine, 2-deoxy-2-[ 18F]fluoro-D-glucose ([ 18F]FDG), O-(2-[ 18F]fluoroethyl)-L-tyrosine ([ 18F]FET) and 6-[ 18F]-fluoro-3,4-dihydroxy-L-phenylalanine ([ 18F]FDOPA). The meta-analysis of all data showed no diagnostic superior imaging technique. The included literature showed a low risk of bias. As no technique was found to be diagnostically superior, the local level of expertise is hypothesized to be the most important factor for diagnostically accurate results in post-treatment glioma patients regarding the distinction of TRA from TP

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case-control study (VeCosCO)

INTRODUCTION: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [ 18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. METHODS AND ANALYSIS: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [ 18F]DPA-714 PET, and brain functioning and structure using (f)MRI. ETHICS AND DISSEMINATION: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population

α-Synuclein Radiotracer Development and In Vivo Imaging: Recent Advancements and New Perspectives

α-Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of α-synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of α-synucleinopathies. Although dopaminergic deficits detected with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish α-synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated α-synuclein (αSyn) could be a suitable imaging biomarker in α-synucleinopathies, because αSyn aggregation and therefore, Lewy pathology is evidently an early driver of α-synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated αSyn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated αSyn and Lewy pathology inclusion bodies cannot be assessed ante-mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated αSyn as an imaging biomarker in α-synucleinopathies, the current limitations with and lessons learned from αSyn radiotracer development, and finally to propose antibody-based ligands for imaging αSyn aggregates as a complementary tool rather than an alternative to small molecule ligands. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society

Dopaminergic alterations in populations at increased risk for psychosis:A systematic review of imaging findings

Alterations of the dopaminergic system may be important neurobiological correlates of vulnerability and transition to psychosis. We systematically reviewed the evidence for dopaminergic alterations demonstrated by in-vivo imaging studies in humans at increased risk of developing psychosis, covering clinical, genetic, and environmental high-risk groups. All 63 included studies utilized Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), or neuromelanin-sensitive Magnetic Resonance Imaging (NM-MRI) methods to collect data concerning the dopaminergic system during rest and/or following pharmacological, behavioural, or cognitive challenges. The current evidence highlights that 1) striatal dopamine D2/3 receptor availability is unaltered in all three high-risk groups compared with healthy individuals; 2) striatal dopamine synthesis capacity (sDSC) is increased in some clinical and genetic high-risk individuals relative to controls (e.g. people that meet clinical criteria for being at ultra-high risk of developing psychosis and individuals with 22q11.2 deletion syndrome), while sDSC is decreased in cannabis-using environmental high-risk individuals. It seems likely that all three high-risk groups can be stratified into multiple subgroups, with varying risks to develop psychosis, transition rates, and underlying neurobiology. The present results support the hypothesis that dopaminergic abnormalities occur before high-risk individuals develop psychosis.</p

Imaging Dopaminergic Neurotransmission in Neurodegenerative Disorders

Imaging of dopaminergic transmission in neurodegenerative disorders such as Parkinson disease (PD) or dementia with Lewy bodies plays a major role in clinical practice and in clinical research. We here review the role of imaging of the nigrostriatal pathway, as well as of striatal receptors and dopamine release, in common neurodegenerative disorders in clinical practice and research. Imaging of the nigrostriatal pathway has a high diagnostic accuracy to detect nigrostriatal degeneration in disorders characterized by nigrostriatal degeneration, such as PD and dementia with Lewy bodies, and disorders of more clinical importance, namely in patients with clinically uncertain parkinsonism. Imaging of striatal dopamine D2/3 receptors is not recommended for the differential diagnosis of parkinsonian disorders in clinical practice anymore. Regarding research, recently the European Medicines Agency has qualified dopamine transporter imaging as an enrichment biomarker for clinical trials in early PD, which underlines the high diagnostic accuracy of this imaging tool and will be implemented in future trials. Also, imaging of the presynaptic dopaminergic system plays a major role in, for example, examining the extent of nigrostriatal degeneration in preclinical and premotor phases of neurodegenerative disorders and to examine subtypes of PD. Also, imaging of postsynaptic dopamine D2/3 receptors plays a role in studying, for example, the neuronal substrate of impulse control disorders in PD, as well as in measuring endogenous dopamine release to examine, for example, motor complications in the treatment of PD. Finally, novel MRI sequences as neuromelanin-sensitive MRI are promising new tools to study nigrostriatal degeneration in vivo