Association of Early β-Amyloid Accumulation and Neuroinflammation Measured With [11C]PBR28 in Elderly Individuals Without Dementia

OBJECTIVE: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ40, Aβ42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype-, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope -0.004, p = 0.88) participants. Higher CSF soluble TREM2 (rs = 0.72, p = 0.01) and YKL-40 (rs = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease. CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.</p

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro Assessment

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach

Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects

<p>Abstract</p> <p>Background</p> <p>To get insight into molecular mechanisms underlying insulin resistance, we compared acute in vivo effects of insulin on adipose tissue transcriptional profiles between obese insulin-resistant and lean insulin-sensitive women.</p> <p>Methods</p> <p>Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 hours of intravenously maintained euglycemic hyperinsulinemia from 9 insulin-resistant and 11 insulin-sensitive females. Gene expression was measured using Affymetrix HG U133 Plus 2 microarrays and qRT-PCR. Microarray data and pathway analyses were performed with Chipster v1.4.2 and by using in-house developed nonparametric pathway analysis software.</p> <p>Results</p> <p>The most prominent difference in gene expression of the insulin-resistant group during hyperinsulinemia was reduced transcription of nuclear genes involved in mitochondrial respiration (mitochondrial respiratory chain, GO:0001934). Inflammatory pathways with complement components (inflammatory response, GO:0006954) and cytokines (chemotaxis, GO:0042330) were strongly up-regulated in insulin-resistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia. Furthermore, differences were observed in genes contributing to fatty acid, cholesterol and triglyceride metabolism (FATP2, ELOVL6, PNPLA3, SREBF1) and in genes involved in regulating lipolysis (ANGPTL4) between the insulin-resistant and -sensitive subjects especially during hyperinsulinemia.</p> <p>Conclusions</p> <p>The major finding of this study was lower expression of mitochondrial respiratory pathway and defective induction of lipid metabolism pathways by insulin in insulin-resistant subjects. Moreover, the study reveals several novel genes whose aberrant regulation is associated with the obese insulin-resistant phenotype.</p

Intraputamenal cerebral dopamine neurotrophic factor in Parkinson's disease: a randomized, double‐blind, multicenter phase 1 trial

Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone‐anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo‐controlled, double‐blind, 6‐month main study followed by an active‐treatment 6‐month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE‐PE2I. Results: Drug‐related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating.

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [11C]carfentanil and [18F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BPND) for [11C]carfentanil and influx rate constant (Ki) values for [18F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [11C]carfentanil BPND in multiple subcortical and cortical brain regions and in striatal [18F]fluorodopa Ki compared with controls. In PG patients, [11C]carfentanil BPND was reduced in the anterior cingulate with no differences in [18F]fluorodopa Ki compared with controls. In the nucleus accumbens, a key region involved in reward processing, [11C]Carfentanil BPND was 30-34% lower and [18F]fluorodopa Ki was 20% lower in BED compared with PG and controls (p<0.002). BED and PG are thus dissociable as a function of dopaminergic and opioidergic neurotransmission. Compared with PG, BED patients show widespread losses of mu-opioid receptor availability together with presynaptic dopaminergic defects. These findings highlight the heterogeneity underlying the subtypes of addiction and indicate differential mechanisms in the expression of pathological behaviors and responses to treatment.This study was supported by the Academy of Finland (grant #256836), the Finnish Medical Foundation, the Finnish Alcohol Research Foundation and the Turku University Central Hospital (EVO grants). VV was supported by a Wellcome Trust Fellowship (093705/10/Z)

Data from: Long-term test–retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [11C]raclopride and high-resolution PET

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies

Data from: Long-term test–retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [11C]raclopride and high-resolution PET

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies

DICOM data part 2

Combine xaa (part 1) and xab (part 2) to obtain a zip-file of size 1.67 GB. The zip-file contains anonymized DICOM PET and MRI data from 7 subjects in their respective folders named C01-C07

Data from: Long-term test–retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [11C]raclopride and high-resolution PET

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies