Molecular Imaging Studies Research Articles

Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

BackgroundAbnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity. ObjectiveWe studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity. MethodsWe recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers. ResultsWe found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient. ConclusionFrequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.

Radioanalytical Techniques to Quantitatively Assess the Biological Uptake and In Vivo Behavior of Hazardous Substances.

Concern about environmental exposure to hazardous substances has grown over the past several decades, because these substances have adverse effects on human health. Methods used to monitor the biological uptake of hazardous substances and their spatiotemporal behavior in vivo must be accurate and reliable. Recent advances in radiolabeling chemistry and radioanalytical methodologies have facilitated the quantitative analysis of toxic substances, and whole-body imaging can be achieved using nuclear imaging instruments. Herein, we review recent literature on the radioanalytical methods used to study the biological distribution, changes in the uptake and accumulation of hazardous substances, including industrial chemicals, nanomaterials, and microorganisms. We begin with an overview of the radioisotopes used to prepare radiotracers for in vivo experiments. We then summarize the results of molecular imaging studies involving radiolabeled toxins and their quantitative assessment. We conclude the review with perspectives on the use of radioanalytical methods for future environmental research.

Spatially Fractionated Radiation Therapy Using Lattice Radiation in Far-advanced Bulky Cervical Cancer: A Clinical and Molecular Imaging and Outcome Study.

Spatially fractionated radiation therapy (SFRT) has shown promise in generating high tumor response and local control in the treatment of various palliative and locally advanced bulky tumors. SFRT has not yet been studied systematically in cancer of the cervix. Here we report the first series of patients receiving SFRT for advanced/bulky cervical cancer. Ten patients with far-advanced bulky cervical cancer, stage IIIB-IVA (seven squamous cell and three adeno/adenosquamous carcinomas) received lattice radiation therapy (LRT), a variant of SFRT. The LRT regimen consisted of a dose of 24 Gy in three fractions, given to an average of five high-dose spheres within the gross tumor volume (GTV). The dose in the peripheral GTV was limited to 9 Gy in three fractions, using the volumetric modulated arc therapy (VMAT) technique. LRT was followed subsequently by conventionally fractionated external beam irradiation to 44.28 Gy (range: 39.60-45.00 Gy in 1.8 Gy fractions). All patients received concurrent cisplatin chemotherapy. Tumor response was assessed clinically, by morphological imaging (CT, MRI) and 18FDG PET/CT. Tumor control and survival rates were estimated using Kaplan-Meier analysis. All patients had local control at a median follow-up of 16 months (1-77). The two-year disease-specific survival rate was 53.3%. All cancer deaths were due to metastatic failure with local control maintained. Among the three patients who died of disease, all had adeno- or adenosquamous carcinoma histology, and no deaths from disease occurred among the patients with squamous cell carcinoma (P = 0.010). There were no grade ≥3 short-term or long-term treatment-related complications. Intra-treatment morphological tumor regression was highly variable (mean: 54%, range: 6-91%). After therapy, the complete metabolic response was 88.9% (8/9), and one patient out of the nine patients with post-treatment PET-CT had partial response (11.1%). Our preliminary data suggest that LRT-based SFRT is well tolerated in patients with far-advanced bulky cervical cancer and results in favorable tumor responses and high local control. These observations confirm prior reports of favorable tumor control and toxicity outcomes with SFRT in other advanced/bulky malignancies. Our findings are corroborated by high molecular-imaging-based tumor response. These encouraging hypothesis-generating results require cautious interpretation and confirmation with larger patient cohorts, preferably through a multi-institutional controlled randomized clinical trial.

Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?

Emerging evidence demonstrates the critical role of the immune response in the mechanisms relating to mood disorders, such as major depression (MDD) and bipolar disorder (BD). This has cast a spotlight on a specialized branch committed to the research of dynamics of the fine interaction between emotion (or affection) and immune response, which has been termed as “affective immunology.” Inflammatory cytokines and gut microbiota are actively involved in affective immunology. Furthermore, abnormalities of the astrocytes and microglia have been observed in mood disorders from both postmortem and molecular imaging studies; however, the underlying mechanisms remain elusive. Notably, the crosstalk between astrocyte and microglia acts as a mutual and pivotal intermediary factor modulating the immune response posed by inflammatory cytokines and gut microbiota. In this study, we propose the “altered astrocyte-microglia crosstalk (AAMC)” hypothesis which suggests that the astrocyte-microglia crosstalk regulates emotional alteration through mediating immune response, and thus, contributing to the development of mood disorders.

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

ObjectiveSex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register‐based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5‐HT4R) brain imaging.Methods[11C]SB207145‐PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5‐HT4R binding in a latent variable model based on 5‐HT4R binding across cortical and subcortical regions.ResultsWe demonstrate that OC users have 9–12% lower global brain 5‐HT4R binding potential compared to non‐users. Univariate region‐based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (−12.8% (95% CI [−21.0; −3.9], P corrected = 0.03).ConclusionWe show that women who use OCs have markedly lower brain 5‐HT4R binding relative to non‐users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5‐HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

Superhydrophilic fluorinated polymer and nanogel for high-performance 19F magnetic resonance imaging

19F magnetic resonance imaging (19F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, 19F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable 19F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high 19F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and 19F MRS-based quantitative determination in complex biological fluids, and intense 19F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivo19F MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense 19F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance 19F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.

Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci.

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.

Importance of attenuation correction in PET/MR image quantification: Methods and applications

The generation of accurate attenuation correction (AC) maps is a basic step to allow for quantitative PET/MR imaging. However, generating MR-based AC maps is a challenge because there is no direct relationship between the PET attenuation coefficients (μ) and the intensity of the MR signal, contrary to what happens with the intensity of CT images. In fact, ignoring the bone causes a distorted and biased distribution of the calculated SUV values. To solve this problem, several MR-based AC methods have been proposed in the literature. In this paper we describe how these methods work, and the challenge they faced to translate into full body applications. Currently, in research environments, the accuracy of AC methods is no longer a limiting factor to solve in order to carry out quantitative in vivo molecular imaging studies. However, many of these methods present a series of limitations for their real implementation in the clinical practice due to insufficient clinical validation and the difficulty of their implementation in a real environment (as described in the examples of clinical applications). Thus, we need the PET/MR community to work on the standardization of the use and assessment of different AC methods. In this scenario, the opening and access by vendors to the implementation of new AC methods in their PET/MR scanners plays a crucial role.

Importancia de la corrección de atenuación en la cuantificación de imagen PET/RM: métodos y aplicaciones

The generation of accurate attenuation correction (AC) maps is a basic step to allow for quantitative PET/MR imaging. However, generating MR-based AC maps is a challenge because there is no direct relationship between the PET attenuation coefficients (μ) and the intensity of the MR signal, contrary to what happens with the intensity of CT images. In fact, ignoring the bone causes a distorted and biased distribution of the calculated SUV values. To solve this problem, several MR-based AC methods have been proposed in the literature. In this paper we describe how these methods work, and the challenge they faced to translate into full body applications. Currently, in research environments, the accuracy of AC methods is no longer a limiting factor to solve in order to carry out quantitative in vivo molecular imaging studies. However, many of these methods present a series of limitations for their real implementation in the clinical practice due to insufficient clinical validation and the difficulty of their implementation in a real environment (as described in the examples of clinical applications). Thus, we need the PET/MR community to work on the standardization of the use and assessment of different AC methods. In this scenario, the opening and access by vendors to the implementation of new AC methods in their PET/MR scanners plays a crucial role.

Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides.

Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d‐Ala‐d‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.

A general 11C-labeling approach enabled by fluoride-mediated desilylation of organosilanes

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.

Dopamine Transporter, Age, and Motor Complications in Parkinson's Disease: A Clinical and Single-Photon Emission Computed Tomography Study.

Previous molecular imaging studies comparing dopamine function in vivo between early-onset PD and late-onset PD patients have shown contradictory results, presumably attributable to the aging-related decline in nigrostriatal function. (1) To investigate baseline dopamine transporter availability in early-onset PD (<55 years) and late-onset PD (>70 years) patients, z-scores values of putamen and caudate [123 I]-ioflupane uptake were calculated using the respective age-matched controls in order to correct for early presynaptic compensatory mechanisms and age-related dopamine neuron loss; (2) to examine the associations of such baseline single-photon emission computed tomography measures with the emergence of late-disease motor complications. In this retrospective study, 105 de novo PD patients who underwent [123 I]-ioflupane single-photon emission computed tomography at time of diagnosis were divided into three tertile groups according to age at disease onset (35 early-onset PD and 40 late-onset PD patients). Z-scores were compared between the two groups, and their predictive power for motor complications (during a mean follow-up of 7 years) was evaluated using Cox proportional hazard models. Despite a less-severe motor phenotype, early-onset PD patients exhibited more reduced [123 I]-ioflupane binding in the putamen and had a higher and earlier risk for developing motor complications than those with late-onset PD. Lower [123 I]-Ioflupane uptake in the putamen and caudate increased the risk of motor complications. Our findings indicate that a lower dopamine transporter binding in early-onset PD predicts the later development of motor complications, but it is not related to severity of motor symptoms, suggesting age-related differences in striatal compensatory mechanisms in PD. © 2020 International Parkinson and Movement Disorder Society.

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes.

The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

Traditional approaches to studying Alzheimer’s disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased Aβ42 and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening.

Feasibility Study of MRI Muscles Molecular Imaging in Evaluation of Early Post-Mortem Interval

Estimating early postmortem interval (EPI) is a difficult task in daily forensic activity due to limitations of accurate and reliable methods. The aim of the present work is to describe a novel approach in the estimation of EPI based on quantitative magnetic resonance molecular imaging (qMRMI) using a pig phantom since post-mortem degradation of pig meat is similar to that of human muscles. On a pig phantom maintained at 20° degree, using a 1.5 T MRI scanner we performed 10 scans (every 4 hours) monitoring apparent diffusion coefficient (ADC), fractional anisotropy (FA) magnetization transfer ration (MTR), tractography and susceptibility weighted changes in muscles until 36 hours after death. Cooling of the phantom during the experiment was recorded. Histology was also obtained. Pearson’s Test was carried out for time correlation between post-mortem interval and MRI data. We found a significative inverse correlation between ADC, FA, MT values and PMI. Our preliminary data shows that post-mortem qMRMI is a potential powerful tool in accurately determining EPI and is worth of further investigation.

Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies.

Background: The LRP1 (CR9) domain and, in particular, the sequence Gly1127-Cys1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL). We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis.Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier. IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group. Anti-P3 antibody levels were determined by ELISA. Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography). Studies treating human macrophages (hMΦ) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells.Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile. HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hMΦ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression. These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hMΦ and hcVSMC exposed to the P3 rabbit serums. Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta. PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group.Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits. The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature.

Nanobodies as versatile tools: A focus on targeted tumor therapy, tumor imaging and diagnostics.

Monoclonal antibodies and vaccines have widely been studied for the immunotherapy of cancer, though their large size appears to limit their functionality in solid tumors, in large part due to unique properties of tumor microenvironment. Smaller formats of antibodies have been developed to throw such restrictions. These small format antibodies include antigen binding fragments, single-chain variable fragments, single variable domain of camelid antibody (so-called nanobody (Nb) or VHH). Since their serendipitous discovery, nanobodies have been studies at length in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes out performing monoclonal antibodies. In addition, these small camelid heavy-chain antibodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. In this review, we shed light on the current status of nanobodies in diagnosis and imaging of tumor and exploiting nanobodies revert immunosuppressive events, modulation of immune checkpoints, and as deliverers of drugs for targeted tumor therapy.

ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.

Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.

A KP-based Molecular Imaging Study of Individualized Diagnosis and Treatment for Major Depressive Disorder

A KP-based Molecular Imaging Study of Individualized Diagnosis and Treatment for Major Depressive Disorder

Lower midbrain dopamine transporter availability in depressed patients: Report from high-resolution PET imaging

BackgroundA reduced presynaptic dopamine neurotransmission has long been implicated in major depressive disorder (MDD). However, molecular imaging studies that assessed the dopamine transporter (DAT) availability have led to inconsistent results, partly due to methodological considerations, and to exclusive focus on the striatum, precluding findings in extra-striatal regions. MethodsHerein, we leveraged our database of high-resolution Positron Emission Tomography (PET) images acquired with a highly selective radiotracer, [11C]PE2I, to assess striatal and extra-striatal DAT availability in eight patients treated for depression compared to twenty-four healthy controls. ResultsStatistical parametric mapping and voxel-based analyses of PET images detected a significant lower DAT availability in depressed patients within the superior part of the midbrain (right, pFWE = 0.002; left, pFWE = 0.006), a region including the ventral tegmental area and the substantia nigra from where the mesocorticolimbic and nigrostriatal dopamine pathways originate. A similar difference was found in the right dorsal putamen (pFWE = 0.012). LimitationsThe statistical power was limited to detect only large effects, due to the size of the patients’ sample. ConclusionsThe findings support the hypothesis that a reduced presynaptic dopamine function plays a role in the pathophysiology of depression, and that extra-striatal dopamine function should be further investigated.