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Aqel S, Ahmad J, Saleh I, Fathima A, Al Thani AA, Mohamed WMY, Shaito AA. Advances in Huntington's Disease Biomarkers: A 10-Year Bibliometric Analysis and a Comprehensive Review. BIOLOGY 2025; 14:129. [PMID: 40001897 PMCID: PMC11852324 DOI: 10.3390/biology14020129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025]
Abstract
Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington's disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD's heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers- including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers- are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies.
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Affiliation(s)
- Sarah Aqel
- Medical Research Center, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar;
| | - Jamil Ahmad
- Medical Education, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar;
| | - Iman Saleh
- Biological Science Program, Department of Biological and Environmental Sciences, College of Art and Science, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Aseela Fathima
- Biomedical Research Center (BRC), QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar; (A.F.); (A.A.A.T.)
- Department of Biomedical Sciences, College of Health Sciences, QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar
| | - Asmaa A. Al Thani
- Biomedical Research Center (BRC), QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar; (A.F.); (A.A.A.T.)
- Department of Biomedical Sciences, College of Health Sciences, QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar
| | - Wael M. Y. Mohamed
- Department of Basic Medical Sciences, Kulliyyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan 50728, Malaysia;
- Clinical Pharmacology Department, Menoufia Medical School, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Abdullah A. Shaito
- Biomedical Research Center (BRC), QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar; (A.F.); (A.A.A.T.)
- Department of Biomedical Sciences, College of Health Sciences, QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar
- College of Medicine, QU Health Sector, Qatar University, Doha P.O. Box 2713, Qatar
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Alves F, Lane D, Nguyen TPM, Bush AI, Ayton S. In defence of ferroptosis. Signal Transduct Target Ther 2025; 10:2. [PMID: 39746918 PMCID: PMC11696223 DOI: 10.1038/s41392-024-02088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/10/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025] Open
Abstract
Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.
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Affiliation(s)
- Francesca Alves
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Darius Lane
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
| | | | - Ashley I Bush
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
| | - Scott Ayton
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
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Chen H, Li J, Huang Z, Fan X, Wang X, Chen X, Guo H, Liu H, Li S, Yu S, Li H, Huang X, Ma X, Deng X, Wang C, Liu Y. Dopaminergic system and neurons: Role in multiple neurological diseases. Neuropharmacology 2024; 260:110133. [PMID: 39197818 DOI: 10.1016/j.neuropharm.2024.110133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/24/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024]
Abstract
The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases.
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Affiliation(s)
- Heng Chen
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jieshu Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhixing Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoxiao Fan
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaofei Wang
- Beijing Normal University, Beijing, 100875, China
| | - Xing Chen
- University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Haitao Guo
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Hao Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shuqi Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shaojun Yu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Honghong Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xinyu Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xuehua Ma
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xinqi Deng
- Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Chunguo Wang
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Yonggang Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China.
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Williams GK, Akkermans J, Lawson M, Syta P, Staelens S, Adhikari MH, Morton AJ, Nitzsche B, Boltze J, Christou C, Bertoglio D, Ahamed M. Imaging Glucose Metabolism and Dopaminergic Dysfunction in Sheep ( Ovis aries) Brain Using Positron Emission Tomography Imaging Reveals Abnormalities in OVT73 Huntington's Disease Sheep. ACS Chem Neurosci 2024; 15:4082-4091. [PMID: 39420554 DOI: 10.1021/acschemneuro.4c00561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disease that causes cognitive, movement, behavioral, and sleep disturbances, which over time result in progressive disability and eventually death. Clinical translation of novel therapeutics and imaging probes could be accelerated by additional testing in well-characterized large animal models of HD. The major goal of our preliminary cross-sectional study is to demonstrate the feasibility and utility of the unique transgenic sheep model of HD (OVT73) in positron emission tomography (PET) imaging. PET imaging studies were performed in healthy merino sheep (6 year old, n = 3) and OVT73 HD sheep (5.5 year old, n = 3, and 11 year old, n = 3). Region-of-interest and brain atlas labels were defined for regional analyses by using a sheep brain template. [18F]fluorodeoxyglucose ([18F]FDG) was employed to compare the regional brain glucose metabolism and variations in FDG uptake between control and HD sheep. We also used [18F]fluoro-3,4-dihydroxyphenylalanine ([18F]FDOPA) to compare the extent of striatal dysfunction and evaluated the binding potential (BPND) in key brain regions between the groups. Compared with healthy controls and 11 year old HD sheep, the 5.5 year old HD sheep exhibited significantly increased [18F]FDG uptake in several cortical and subcortical brain regions (P < 0.05-0.01). No difference in [18F]FDG uptake was observed between healthy controls and 11 year old HD sheep. Analysis of the [18F]FDOPA BPND parametric maps revealed clusters of reduced binding potential in the 5.5 year old and 11 year old HD sheep compared to the 6 year old control sheep. In this first-of-its-kind study, we showed the usefulness and validity of HD sheep model in imaging cerebral glucose metabolism and dopamine uptake using PET imaging. The identification of discrete patterns of metabolic abnormality using [18F]FDG and decline of [18F]FDOPA uptake may provide a useful means of quantifying early HD-related changes in these models, particularly in the transition from presymptomatic to early symptomatic phases of HD.
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Affiliation(s)
- Georgia K Williams
- Preclinical, Imaging, and Research Laboratories (PIRL), South Australian Health and Medical Research Institute (SAHMRI), Gilles Plains, Adelaide 5086, Australia
- National Imaging Facility, SAHMRI, Adelaide 5000, Australia
| | - Jordy Akkermans
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Antwerp 2160, Belgium
- μNeuro Center for Excellence, University of Antwerp, Antwerp 2160, Belgium
| | - Matt Lawson
- Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, South Australia
| | - Patryk Syta
- Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, South Australia
| | - Steven Staelens
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Antwerp 2160, Belgium
- μNeuro Center for Excellence, University of Antwerp, Antwerp 2160, Belgium
| | - Mohit H Adhikari
- μNeuro Center for Excellence, University of Antwerp, Antwerp 2160, Belgium
- Bio-Imaging Lab, University of Antwerp, Antwerp 2160, Belgium
| | - A Jennifer Morton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, U.K
| | - Björn Nitzsche
- Department of Nuclear Medicine, University Hospital Leipzig, Stephanstr. 11, Leipzig 04103, Germany
- Faculty of Veterinary Medicine, Institute of Anatomy, Histology and Embryology, University of Leipzig, An den Tierkliniken 43, Leipzig 04103, Germany
| | - Johannes Boltze
- School of Life Sciences, University of Warwick, Coventry CV4 7AL, U.K
| | - Chris Christou
- Preclinical, Imaging, and Research Laboratories (PIRL), South Australian Health and Medical Research Institute (SAHMRI), Gilles Plains, Adelaide 5086, Australia
- National Imaging Facility, SAHMRI, Adelaide 5000, Australia
| | - Daniele Bertoglio
- μNeuro Center for Excellence, University of Antwerp, Antwerp 2160, Belgium
- Bio-Imaging Lab, University of Antwerp, Antwerp 2160, Belgium
| | - Muneer Ahamed
- Preclinical, Imaging, and Research Laboratories (PIRL), South Australian Health and Medical Research Institute (SAHMRI), Gilles Plains, Adelaide 5086, Australia
- National Imaging Facility, SAHMRI, Adelaide 5000, Australia
- Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, South Australia
- Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2050, Australia
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Smolobochkin A, Gazizov A, Appazov N, Sinyashin O, Burilov A. Progress in the Stereoselective Synthesis Methods of Pyrrolidine-Containing Drugs and Their Precursors. Int J Mol Sci 2024; 25:11158. [PMID: 39456938 PMCID: PMC11508981 DOI: 10.3390/ijms252011158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/11/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
The presented review systematizes and summarizes the data on the synthesis of pyrrolidine derivatives, which are precursors for obtaining drugs. Based on the analysis of published data, the most promising directions in the synthesis of biologically active compounds containing a pyrrolidine ring are identified. Stereoselective synthesis methods are classified based on the source of the pyrrolidine ring. The first group includes methods that use a pyrrolidine ring as the starting compound. The second group combines stereoselective methods of cyclization of acyclic starting compounds, which lead to optically pure pyrrolidine derivatives.
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Affiliation(s)
- Andrey Smolobochkin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Almir Gazizov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Nurbol Appazov
- Laboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, Aiteke bi Str., 29A, Kyzylorda 120014, Kazakhstan
| | - Oleg Sinyashin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Alexander Burilov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
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Dell’Angelica D, Singh K, Colwell CS, Ghiani CA. Circadian Interventions in Preclinical Models of Huntington's Disease: A Narrative Review. Biomedicines 2024; 12:1777. [PMID: 39200241 PMCID: PMC11351982 DOI: 10.3390/biomedicines12081777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/25/2024] [Accepted: 07/25/2024] [Indexed: 09/02/2024] Open
Abstract
Huntington's Disease (HD) is a neurodegenerative disorder caused by an autosomal-dominant mutation in the huntingtin gene, which manifests with a triad of motor, cognitive and psychiatric declines. Individuals with HD often present with disturbed sleep/wake cycles, but it is still debated whether altered circadian rhythms are intrinsic to its aetiopathology or a consequence. Conversely, it is well established that sleep/wake disturbances, perhaps acting in concert with other pathophysiological mechanisms, worsen the impact of the disease on cognitive and motor functions and are a burden to the patients and their caretakers. Currently, there is no cure to stop the progression of HD, however, preclinical research is providing cementing evidence that restoring the fluctuation of the circadian rhythms can assist in delaying the onset and slowing progression of HD. Here we highlight the application of circadian-based interventions in preclinical models and provide insights into their potential translation in clinical practice. Interventions aimed at improving sleep/wake cycles' synchronization have shown to improve motor and cognitive deficits in HD models. Therefore, a strong support for their suitability to ameliorate HD symptoms in humans emerges from the literature, albeit with gaps in our knowledge on the underlying mechanisms and possible risks associated with their implementation.
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Affiliation(s)
- Derek Dell’Angelica
- Department of Psychiatry and Biobehavioural Sciences, Semel Institute for Neuroscience and Human Behaviour, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA; (D.D.); (K.S.); (C.S.C.)
| | - Karan Singh
- Department of Psychiatry and Biobehavioural Sciences, Semel Institute for Neuroscience and Human Behaviour, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA; (D.D.); (K.S.); (C.S.C.)
| | - Christopher S. Colwell
- Department of Psychiatry and Biobehavioural Sciences, Semel Institute for Neuroscience and Human Behaviour, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA; (D.D.); (K.S.); (C.S.C.)
| | - Cristina A. Ghiani
- Department of Psychiatry and Biobehavioural Sciences, Semel Institute for Neuroscience and Human Behaviour, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA; (D.D.); (K.S.); (C.S.C.)
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA
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Chen Y, Sun J, Tao J, Sun T. Treatments and regulatory mechanisms of acoustic stimuli on mood disorders and neurological diseases. Front Neurosci 2024; 17:1322486. [PMID: 38249579 PMCID: PMC10796816 DOI: 10.3389/fnins.2023.1322486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/13/2023] [Indexed: 01/23/2024] Open
Abstract
Acoustic stimuli such as music or ambient noise can significantly affect physiological and psychological health in humans. We here summarize positive effects of music therapy in premature infant distress regulation, performance enhancement, sleep quality control, and treatment of mental disorders. Specifically, music therapy exhibits promising effects on treatment of neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). We also highlight regulatory mechanisms by which auditory intervention affects an organism, encompassing modulation of immune responses, gene expression, neurotransmitter regulation and neural circuitry. As a safe, cost-effective and non-invasive intervention, music therapy offers substantial potential in treating a variety of neurological conditions.
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Affiliation(s)
- Yikai Chen
- Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, China
| | - Julianne Sun
- Xiamen Institute of Technology Attached School, Xiamen, China
| | - Junxian Tao
- Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, China
| | - Tao Sun
- Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, China
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Pfalzer AC, Shiino S, Silverman J, Codreanu SG, Sherrod SD, McLean JA, Claassen DO. Alterations in Cerebrospinal Fluid Urea Occur in Late Manifest Huntington's Disease. J Huntingtons Dis 2024; 13:103-111. [PMID: 38461512 PMCID: PMC11238568 DOI: 10.3233/jhd-231511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Background Huntington's disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. However, the relationship between disease course and urea elevations, along with the molecular mechanisms responsible for these disturbances remain unknown. Objective To better understand the molecular disturbances and timing of urea cycle metabolism across different stages in HD. Methods We completed a global metabolomic profile of cerebrospinal fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late manifest (LATE) HD participants, and compared to controls. Results Approximately 500 metabolites were significantly altered in PRE participants compared to controls, although no significant differences in CSF urea or urea metabolites were observed. CSF urea was significantly elevated in LATE participants only. There were no changes in the urea metabolites citrulline, ornithine, and arginine. Conclusions Overall, our study confirms that CSF elevations occur late in the HD course, and these changes may reflect accumulating deficits in cellular energy metabolism.
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Affiliation(s)
- Anna C. Pfalzer
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shuhei Shiino
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James Silverman
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Simona G. Codreanu
- Department of Chemistry and Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA
| | - Stacy D. Sherrod
- Department of Chemistry and Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA
| | - John A. McLean
- Department of Chemistry and Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA
| | - Daniel O. Claassen
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
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Hobbs NZ, Papoutsi M, Delva A, Kinnunen KM, Nakajima M, Van Laere K, Vandenberghe W, Herath P, Scahill RI. Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group. J Huntingtons Dis 2024; 13:163-199. [PMID: 38788082 PMCID: PMC11307036 DOI: 10.3233/jhd-240016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 05/26/2024]
Abstract
Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.
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Affiliation(s)
- Nicola Z. Hobbs
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
| | - Marina Papoutsi
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
- IXICO plc, London, UK
| | - Aline Delva
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
| | | | | | - Koen Van Laere
- Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Belgium
- Division of Nuclear Medicine, University Hospitals Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
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10
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Campesan S, Del Popolo I, Marcou K, Straatman-Iwanowska A, Repici M, Boytcheva KV, Cotton VE, Allcock N, Rosato E, Kyriacou CP, Giorgini F. Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila. Neurobiol Dis 2023; 185:106236. [PMID: 37495179 DOI: 10.1016/j.nbd.2023.106236] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/06/2023] [Accepted: 07/22/2023] [Indexed: 07/28/2023] Open
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder.
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Affiliation(s)
- Susanna Campesan
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.
| | - Ivana Del Popolo
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Kyriaki Marcou
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Anna Straatman-Iwanowska
- Electron Microscopy Facility, Core Biotechnology Services, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, Leicestershire, UK
| | - Mariaelena Repici
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK; School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Kalina V Boytcheva
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Victoria E Cotton
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Natalie Allcock
- Electron Microscopy Facility, Core Biotechnology Services, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, Leicestershire, UK
| | - Ezio Rosato
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Charalambos P Kyriacou
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Flaviano Giorgini
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.
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van Eimeren T, Giehl K, Reetz K, Sampaio C, Mestre TA. Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development. Parkinsonism Relat Disord 2023; 114:105488. [PMID: 37407343 DOI: 10.1016/j.parkreldis.2023.105488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/05/2023] [Accepted: 06/10/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND A critical challenge for Huntington's disease (HD) clinical trials in disease modification is the definition of endpoints that can capture change when clinical signs are subtle/non-existent. Reliable biomarkers are therefore urgently needed to facilitate drug development by allowing the enrichment of clinical trial populations and providing measures of benefit that can support the establishment of efficacy. METHODS By systematically examining the published literature on HD neuroimaging biomarker studies, we sought to advance knowledge to guide the validation of neuroimaging biomarkers. We started by reviewing both cross-sectional and longitudinal studies and then conducted an in-depth review to make quantitative comparisons between biomarkers using data only from longitudinal studies with samples sizes larger than ten participants in PET studies or 30 participants in MRI studies. RESULTS From a total of 2202 publications initially identified, we included 32 studies, 19 of which underwent in-depth comparative review. The majority of included studies used various MRI-based methods (manual to automatic) to longitudinally assess either the volume of the putamen or the caudate, which have been shown to undergo significant structural change during HD natural history. CONCLUSION Despite the impressively large number of neuroimaging biomarker studies, only a small number of adequately designed studies met our criteria. Among these various biomarkers, MRI-based volumetric analyses of the caudate and putamen are currently the best validated for use in the disease phase before clinical motor diagnosis. A biomarker that can be used to demonstrate a disease-modifying effect is still missing.
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Affiliation(s)
- Thilo van Eimeren
- University of Cologne, Faculty of Medicine, Department of Nuclear Medicine, Cologne, Germany; University of Cologne, Faculty of Medicine, Department of Neurology, Cologne, Germany.
| | - Kathrin Giehl
- University of Cologne, Faculty of Medicine, Department of Nuclear Medicine, Cologne, Germany; Research Center Jülich, Institute for Neuroscience and Medicine (INM-2), Jülich, Germany
| | - Kathrin Reetz
- University of Aachen, Department of Neurology, Aachen, Germany
| | | | - Tiago A Mestre
- University of Ottawa, Department of Medicine, Division of Neurology, The Ottawa Hospital Research Institute, Parkinson's Disease and Movement Disorders Center, Canada
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Jiang A, Handley RR, Lehnert K, Snell RG. From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research. Int J Mol Sci 2023; 24:13021. [PMID: 37629202 PMCID: PMC10455900 DOI: 10.3390/ijms241613021] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Huntington's disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington's disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.
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Affiliation(s)
- Andrew Jiang
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand; (R.R.H.); (K.L.); (R.G.S.)
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Delva A, Van Laere K, Vandenberghe W. Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease. Mov Disord 2023; 38:1515-1526. [PMID: 37382295 DOI: 10.1002/mds.29501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/03/2023] [Accepted: 05/18/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Development of disease-modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11 C-UCB-J, a radioligand for the brain-wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18 F-fludeoxyglucose (18 F-FDG) PET, but longitudinal 11 C-UCB-J PET data have not been reported. The aim of this study was to compare the sensitivity of 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI for detection of longitudinal changes in early HD. METHODS Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within-group and between-group longitudinal clinical and imaging changes were assessed. RESULTS The HD group showed significant 2-year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (-4.5% ± 3.8%), putamen (-3.6% ± 3.5%), pallidum (-3.0% ± 2.7%), and frontal cortex (-2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (-2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions. CONCLUSIONS Volumetric MRI may be more sensitive than 11 C-UCB-J PET and 18 F-FDG PET for detection of 2-year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Aline Delva
- Department of Neurosciences, KU Leuven, Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Koen Van Laere
- Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
- Division of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurosciences, KU Leuven, Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium
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14
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Fernández-Moncada I, Eraso-Pichot A, Tor TD, Fortunato-Marsol B, Marsicano G. An enquiry to the role of CB1 receptors in neurodegeneration. Neurobiol Dis 2023:106235. [PMID: 37481040 DOI: 10.1016/j.nbd.2023.106235] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/27/2023] [Accepted: 07/20/2023] [Indexed: 07/24/2023] Open
Abstract
Neurodegenerative disorders are debilitating conditions that impair patient quality of life and that represent heavy social-economic burdens to society. Whereas the root of some of these brain illnesses lies in autosomal inheritance, the origin of most of these neuropathologies is scantly understood. Similarly, the cellular and molecular substrates explaining the progressive loss of brain functions remains to be fully described too. Indeed, the study of brain neurodegeneration has resulted in a complex picture, composed of a myriad of altered processes that include broken brain bioenergetics, widespread neuroinflammation and aberrant activity of signaling pathways. In this context, several lines of research have shown that the endocannabinoid system (ECS) and its main signaling hub, the type-1 cannabinoid (CB1) receptor are altered in diverse neurodegenerative disorders. However, some of these data are conflictive or poorly described. In this review, we summarize the findings about the alterations in ECS and CB1 receptors signaling in three representative brain illnesses, the Alzheimer's, Parkinson's and Huntington's diseases, and we discuss the relevance of these studies in understanding neurodegeneration development and progression, with a special focus on astrocyte function. Noteworthy, the analysis of ECS defects in neurodegeneration warrant much more studies, as our conceptual understanding of ECS function has evolved quickly in the last years, which now include glia cells and the subcellular-specific CB1 receptors signaling as critical players of brain functions.
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Affiliation(s)
| | - Abel Eraso-Pichot
- Université de Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux, France
| | - Tommaso Dalla Tor
- Université de Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux, France; Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95124, Italy
| | | | - Giovanni Marsicano
- Université de Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux, France.
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15
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Jurcau A, Jurcau CM. Mitochondria in Huntington's disease: implications in pathogenesis and mitochondrial-targeted therapeutic strategies. Neural Regen Res 2023; 18:1472-1477. [PMID: 36571344 PMCID: PMC10075114 DOI: 10.4103/1673-5374.360289] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Huntington's disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4. Compelling evidence implicates impaired mitochondrial energetics, altered mitochondrial biogenesis and quality control, disturbed mitochondrial trafficking, oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder. Unfortunately, conventional mitochondrial-targeted molecules, such as cysteamine, creatine, coenzyme Q10, or triheptanoin, yielded negative or inconclusive results. However, future therapeutic strategies, aiming to restore mitochondrial biogenesis, improving the fission/fusion balance, and improving mitochondrial trafficking, could prove useful tools in improving the phenotype of Huntington's disease and, used in combination with genome-editing methods, could lead to a cure for the disease.
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Affiliation(s)
- Anamaria Jurcau
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea; Neurology 3 Ward, Clinical Emergency Hospital, Oradea, Romania
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16
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Timmers ER, Klamer MR, Marapin RS, Lammertsma AA, de Jong BM, Dierckx RAJO, Tijssen MAJ. [ 18F]FDG PET in conditions associated with hyperkinetic movement disorders and ataxia: a systematic review. Eur J Nucl Med Mol Imaging 2023; 50:1954-1973. [PMID: 36702928 PMCID: PMC10199862 DOI: 10.1007/s00259-023-06110-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 01/05/2023] [Indexed: 01/28/2023]
Abstract
PURPOSE To give a comprehensive literature overview of alterations in regional cerebral glucose metabolism, measured using [18F]FDG PET, in conditions associated with hyperkinetic movement disorders and ataxia. In addition, correlations between glucose metabolism and clinical variables as well as the effect of treatment on glucose metabolism are discussed. METHODS A systematic literature search was performed according to PRISMA guidelines. Studies concerning tremors, tics, dystonia, ataxia, chorea, myoclonus, functional movement disorders, or mixed movement disorders due to autoimmune or metabolic aetiologies were eligible for inclusion. A PubMed search was performed up to November 2021. RESULTS Of 1240 studies retrieved in the original search, 104 articles were included. Most articles concerned patients with chorea (n = 27), followed by ataxia (n = 25), dystonia (n = 20), tremor (n = 8), metabolic disease (n = 7), myoclonus (n = 6), tics (n = 6), and autoimmune disorders (n = 5). No papers on functional movement disorders were included. Altered glucose metabolism was detected in various brain regions in all movement disorders, with dystonia-related hypermetabolism of the lentiform nuclei and both hyper- and hypometabolism of the cerebellum; pronounced cerebellar hypometabolism in ataxia; and striatal hypometabolism in chorea (dominated by Huntington disease). Correlations between clinical characteristics and glucose metabolism were often described. [18F]FDG PET-showed normalization of metabolic alterations after treatment in tremors, ataxia, and chorea. CONCLUSION In all conditions with hyperkinetic movement disorders, hypo- or hypermetabolism was found in multiple, partly overlapping brain regions, and clinical characteristics often correlated with glucose metabolism. For some movement disorders, [18F]FDG PET metabolic changes reflected the effect of treatment.
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Affiliation(s)
- Elze R Timmers
- Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
- Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Marrit R Klamer
- Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
- Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Ramesh S Marapin
- Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
- Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Adriaan A Lammertsma
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen (UMCG), University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Bauke M de Jong
- Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen (UMCG), University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Marina A J Tijssen
- Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
- Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, the Netherlands.
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17
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Weil EL, Nakawah MO, Masdeu JC. Advances in the neuroimaging of motor disorders. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:359-381. [PMID: 37562878 DOI: 10.1016/b978-0-323-98818-6.00039-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Neuroimaging is a valuable adjunct to the history and examination in the evaluation of motor system disorders. Conventional imaging with computed tomography or magnetic resonance imaging depicts important anatomic information and helps to identify imaging patterns which may support diagnosis of a specific motor disorder. Advanced imaging techniques can provide further detail regarding volume, functional, or metabolic changes occurring in nervous system pathology. This chapter is an overview of the advances in neuroimaging with particular emphasis on both standard and less well-known advanced imaging techniques and findings, such as diffusion tensor imaging or volumetric studies, and their application to specific motor disorders. In addition, it provides reference to emerging imaging biomarkers in motor system disorders such as Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease, and briefly reviews the neuroimaging findings in different causes of myelopathy and peripheral nerve disorders.
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Affiliation(s)
- Erika L Weil
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States; Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Houston, TX, United States.
| | - Mohammad Obadah Nakawah
- Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Houston, TX, United States; Department of Neurology, Weill Cornell Medicine, New York, NY, United States
| | - Joseph C Masdeu
- Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Houston, TX, United States; Department of Neurology, Weill Cornell Medicine, New York, NY, United States
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18
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Kim H, Gomez-Pastor R. HSF1 and Its Role in Huntington's Disease Pathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1410:35-95. [PMID: 36396925 PMCID: PMC12001818 DOI: 10.1007/5584_2022_742] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
PURPOSE OF REVIEW Heat shock factor 1 (HSF1) is the master transcriptional regulator of the heat shock response (HSR) in mammalian cells and is a critical element in maintaining protein homeostasis. HSF1 functions at the center of many physiological processes like embryogenesis, metabolism, immune response, aging, cancer, and neurodegeneration. However, the mechanisms that allow HSF1 to control these different biological and pathophysiological processes are not fully understood. This review focuses on Huntington's disease (HD), a neurodegenerative disease characterized by severe protein aggregation of the huntingtin (HTT) protein. The aggregation of HTT, in turn, leads to a halt in the function of HSF1. Understanding the pathways that regulate HSF1 in different contexts like HD may hold the key to understanding the pathomechanisms underlying other proteinopathies. We provide the most current information on HSF1 structure, function, and regulation, emphasizing HD, and discussing its potential as a biological target for therapy. DATA SOURCES We performed PubMed search to find established and recent reports in HSF1, heat shock proteins (Hsp), HD, Hsp inhibitors, HSF1 activators, and HSF1 in aging, inflammation, cancer, brain development, mitochondria, synaptic plasticity, polyglutamine (polyQ) diseases, and HD. STUDY SELECTIONS Research and review articles that described the mechanisms of action of HSF1 were selected based on terms used in PubMed search. RESULTS HSF1 plays a crucial role in the progression of HD and other protein-misfolding related neurodegenerative diseases. Different animal models of HD, as well as postmortem brains of patients with HD, reveal a connection between the levels of HSF1 and HSF1 dysfunction to mutant HTT (mHTT)-induced toxicity and protein aggregation, dysregulation of the ubiquitin-proteasome system (UPS), oxidative stress, mitochondrial dysfunction, and disruption of the structural and functional integrity of synaptic connections, which eventually leads to neuronal loss. These features are shared with other neurodegenerative diseases (NDs). Currently, several inhibitors against negative regulators of HSF1, as well as HSF1 activators, are developed and hold promise to prevent neurodegeneration in HD and other NDs. CONCLUSION Understanding the role of HSF1 during protein aggregation and neurodegeneration in HD may help to develop therapeutic strategies that could be effective across different NDs.
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Affiliation(s)
- Hyuck Kim
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Rocio Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
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Weiss AR, Bertoglio D, Liguore WA, Brandon K, Templon J, Link J, McBride JL. Reduced D 2 /D 3 Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease. Mov Disord 2023; 38:143-147. [PMID: 36544385 PMCID: PMC9948637 DOI: 10.1002/mds.29271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/04/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Dopamine system dysfunction and altered glucose metabolism are implicated in Huntington's disease (HD), a neurological disease caused by mutant huntingtin (mHTT) expression. OBJECTIVE The aim was to characterize alterations in cerebral dopamine D2 /D3 receptor density and glucose utilization in a newly developed AAV-mediated NHP model of HD that expresses mHTT throughout numerous brain regions. METHODS Positron emission tomography (PET) imaging was performed using [18 F]fallypride to quantify D2 /D3 receptor density and 2-[18 F]fluoro-2-deoxy-d-glucose ([18 F]FDG) to measure cerebral glucose utilization in these HD macaques. RESULTS Compared to controls, HD macaques showed significantly reduced dopamine D2 /D3 receptor densities in basal ganglia (P < 0.05). In addition, HD macaques displayed significant glucose hypometabolism throughout the cortico-basal ganglia network (P < 0.05). CONCLUSIONS [18 F]Fallypride and [18 F]FDG are PET imaging biomarkers of mHTT-mediated disease progression that can be used as noninvasive outcome measures in future therapeutic studies with this AAV-mediated HD macaque model. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Alison R. Weiss
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR
| | - Daniele Bertoglio
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Belgium
| | - William A. Liguore
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR
| | - Kristin Brandon
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR
| | - John Templon
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR
| | - Jeanne Link
- Center for Radiochemistry Research, Oregon Health and Science University, Portland, OR
| | - Jodi L. McBride
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR
- Dept. of Behavioral Neuroscience, Oregon National Primate Research Center, Beaverton, OR
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Taghian T, Gallagher J, Batcho E, Pullan C, Kuchel T, Denney T, Perumal R, Moore S, Muirhead R, Herde P, Johns D, Christou C, Taylor A, Passler T, Pulaparthi S, Hall E, Chandra S, O’Neill CA, Gray-Edwards H. Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach. J Huntingtons Dis 2022; 11:391-406. [PMID: 36189602 PMCID: PMC9837686 DOI: 10.3233/jhd-220526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. OBJECTIVE AND METHODS Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. RESULTS Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. CONCLUSION This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.
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Affiliation(s)
- Toloo Taghian
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA,
Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jillian Gallagher
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA
| | - Erin Batcho
- Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA
| | - Caitlin Pullan
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Tim Kuchel
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Thomas Denney
- Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA
| | - Raj Perumal
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Shamika Moore
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Robb Muirhead
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Paul Herde
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Daniel Johns
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Chris Christou
- South Australian Health and Medical Research Institute, Gillies Plains, SA, Australia
| | - Amanda Taylor
- Department of Clinical Sciences, Auburn University, Auburn, AL, USA
| | - Thomas Passler
- Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA
| | - Sanjana Pulaparthi
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA
| | - Erin Hall
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sundeep Chandra
- Sana Biotechnology, South San Francisco, CA, USA,Bio Marin Pharmaceutical Inc., San Rafael, CA, USA
| | | | - Heather Gray-Edwards
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA,
Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA,Correspondence to: Heather L. Gray-Edwards, DVM, PhD, University of Massachusetts Medical School, Department of Radiology and Horae Gene Therapy Center, 368 Plantation Street, ASC6-2055, Worcester, MA 01605, USA. Tel.: +1 508 856 4051; Fax: +1 508 856 1552; E-mail:
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21
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Singh A, Agrawal N. Metabolism in Huntington's disease: a major contributor to pathology. Metab Brain Dis 2022; 37:1757-1771. [PMID: 34704220 DOI: 10.1007/s11011-021-00844-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/15/2021] [Indexed: 01/01/2023]
Abstract
Huntington's disease (HD) is a progressively debilitating neurodegenerative disease exhibiting autosomal-dominant inheritance. It is caused by an unstable expansion in the CAG repeat tract of HD gene, which transforms the disease-specific Huntingtin protein (HTT) to a mutant form (mHTT). The profound neuronal death in cortico-striatal circuits led to its identification and characterisation as a neurodegenerative disease. However, equally disturbing are the concomitant whole-body manifestations affecting nearly every organ of the diseased individuals, at varying extents. Altered central and peripheral metabolism of energy, proteins, nucleic acids, lipids and carbohydrates encompass the gross pathology of the disease. Intense fluctuation of body weight, glucose homeostasis and organ-specific subcellular abnormalities are being increasingly recognised in HD. Many of these metabolic abnormalities exist years before the neuropathological manifestations such as chorea, cognitive decline and behavioural abnormalities develop, and prove to be reliable predictors of the disease progression. In this review, we provide a consolidated overview of the central and peripheral metabolic abnormalities associated with HD, as evidenced from clinical and experimental studies. Additionally, we have discussed the potential of metabolic biomolecules to translate into efficient biomarkers for the disease onset as well as progression. Finally, we provide a brief outlook on the efficacy of existing therapies targeting metabolic remediation. While it is clear that components of altered metabolic pathways can mark many aspects of the disease, it is only conceivable that combinatorial therapies aiming for neuronal protection in consort with metabolic upliftment will prove to be more efficient than the existing symptomatic treatment options.
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Affiliation(s)
- Akanksha Singh
- Department of Zoology, University of Delhi, New Delhi, 110007, India
| | - Namita Agrawal
- Department of Zoology, University of Delhi, New Delhi, 110007, India.
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22
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Phillips MCL, McManus EJ, Brinkhuis M, Romero-Ferrando B. Time-Restricted Ketogenic Diet in Huntington's Disease: A Case Study. Front Behav Neurosci 2022; 16:931636. [PMID: 35967897 PMCID: PMC9372583 DOI: 10.3389/fnbeh.2022.931636] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder with limited treatment options. Substantial evidence implicates mitochondria dysfunction in brain and skeletal muscle in the pathogenesis of HD. Metabolic strategies, such as fasting and ketogenic diets, theoretically enhance brain and muscle metabolism and mitochondria function, which may improve the clinical symptoms of HD. We report the case of a 41-year-old man with progressive, deteriorating HD who pursued a time-restricted ketogenic diet (TRKD) for 48 weeks. Improvements were measured in his motor symptoms (52% improvement from baseline), activities of daily living (28% improvement), composite Unified HD Rating Scale (cUHDRS) score (20% improvement), HD-related behavior problems (apathy, disorientation, anger, and irritability improved by 50–100%), and mood-related quality of life (25% improvement). Cognition did not improve. Weight remained stable and there were no significant adverse effects. This case study is unique in that a patient with progressive, deteriorating HD was managed with a TRKD, with subsequent improvements in his motor symptoms, activities of daily living, cUHDRS score, most major HD-related behavior problems, and quality of life. Our patient remains dedicated to his TRKD, which continues to provide benefit for him and his family.
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Affiliation(s)
- Matthew C. L. Phillips
- Department of Neurology, Waikato Hospital, Hamilton, New Zealand
- *Correspondence: Matthew C. L. Phillips
| | | | - Martijn Brinkhuis
- Mental Health Services for Older People, Tauranga Hospital, Tauranga, New Zealand
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23
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Moldovean SN, Timaru DG, Chiş V. All-Atom Molecular Dynamics Investigations on the Interactions between D2 Subunit Dopamine Receptors and Three 11C-Labeled Radiopharmaceutical Ligands. Int J Mol Sci 2022; 23:ijms23042005. [PMID: 35216115 PMCID: PMC8880249 DOI: 10.3390/ijms23042005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 11/24/2022] Open
Abstract
The D2 subunit dopamine receptor represents a key factor in modulating dopamine release. Moreover, the investigated radiopharmaceutical ligands used in positron emission tomography imaging techniques are known to bind D2 receptors, allowing for dopaminergic pathways quantification in the living human brain. Thus, the biophysical characterization of these radioligands is expected to provide additional insights into the interaction mechanisms between the vehicle molecules and their targets. Using molecular dynamics simulations and QM calculations, the present study aimed to investigate the potential positions in which the D2 dopamine receptor would most likely interact with the three distinctive synthetic 11C-labeled compounds (raclopride (3,5-dichloro-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2-hydroxy-6-methoxybenzamide)—RACL, FLB457 (5-bromo-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2,3-dimethoxybenzamide)—FLB457 and SCH23390 (R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine)—SCH)), as well as to estimate the binding affinities of the ligand-receptor complexes. A docking study was performed prior to multiple 50 ns molecular dynamics productions for the ligands situated at the top and bottom interacting pockets of the receptor. The most prominent motions for the RACL ligand were described by the high fluctuations of the peripheral aliphatic -CH3 groups and by its C-Cl aromatic ring groups. In good agreement with the experimental data, the D2 dopamine receptor-RACL complex showed the highest interacting patterns for ligands docked at the receptor’s top position.
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Affiliation(s)
- Sanda Nastasia Moldovean
- Faculty of Physics, Babeş-Bolyai University, 400084 Cluj-Napoca, Romania; (S.N.M.); (D.-G.T.)
- Biomolecular Modeling and Computational Spectroscopy Laboratory, Institute for Research, Development and Innovation in Applied Natural Sciences, Babeş-Bolyai University, 400327 Cluj-Napoca, Romania
| | - Diana-Gabriela Timaru
- Faculty of Physics, Babeş-Bolyai University, 400084 Cluj-Napoca, Romania; (S.N.M.); (D.-G.T.)
| | - Vasile Chiş
- Faculty of Physics, Babeş-Bolyai University, 400084 Cluj-Napoca, Romania; (S.N.M.); (D.-G.T.)
- Biomolecular Modeling and Computational Spectroscopy Laboratory, Institute for Research, Development and Innovation in Applied Natural Sciences, Babeş-Bolyai University, 400327 Cluj-Napoca, Romania
- Correspondence:
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24
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Harris KL, Mason SL, Vallin B, Barker RA. Reduced expression of dopamine D2 receptors on astrocytes in R6/1 HD mice and HD post-mortem tissue. Neurosci Lett 2022; 767:136289. [PMID: 34637857 PMCID: PMC9188264 DOI: 10.1016/j.neulet.2021.136289] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/05/2021] [Accepted: 10/05/2021] [Indexed: 12/15/2022]
Abstract
Dysfunction of the central dopaminergic system is thought to contribute to some of the clinical features of Huntington's disease (HD), and dopamine (DA) receptor antagonists are commonly used to good effect in its treatment. It is well established that there is an early significant reduction in neuronal D2 receptors in HD, considered to be a compensatory response to increased dopaminergic activity. However, no studies have examined the expression of D2 receptors on astrocytes which is important given that these cells have been shown to play a role in the pathogenesis of HD, as well as express dopamine receptors and modulate DA homeostasis in the normal brain. We therefore sought to investigate the expression of D2 receptors on astrocytes in HD, and found them to be reduced in both the R6/1 HD mouse model, and in human post-mortem brain in comparison to controls, suggesting that astrocytes may be important in DA-dependent aspects of HD. Further studies are needed to determine the functional significance of this finding.
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Affiliation(s)
- Kate L Harris
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Trumpington, Cambridge CB2 0QH, UK.
| | - Sarah L Mason
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Benjamin Vallin
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Roger A Barker
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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25
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Jadiya P, Garbincius JF, Elrod JW. Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling. Acta Neuropathol Commun 2021; 9:124. [PMID: 34233766 PMCID: PMC8262011 DOI: 10.1186/s40478-021-01224-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/27/2021] [Indexed: 02/06/2023] Open
Abstract
The cellular and molecular mechanisms that drive neurodegeneration remain poorly defined. Recent clinical trial failures, difficult diagnosis, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypotheses of neurodegenerative pathogenesis. Recent reports establish that mitochondrial and calcium dysregulation occur early in many neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and others. However, causal molecular evidence of mitochondrial and metabolic contributions to pathogenesis remains insufficient. Here we summarize the data supporting the hypothesis that mitochondrial and metabolic dysfunction result from diverse etiologies of neuropathology. We provide a current and comprehensive review of the literature and interpret that defective mitochondrial metabolism is upstream and primary to protein aggregation and other dogmatic hypotheses of NDDs. Finally, we identify gaps in knowledge and propose therapeutic modulation of mCa2+ exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs.
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Affiliation(s)
- Pooja Jadiya
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, 3500 N Broad St, MERB 949, Philadelphia, PA, 19140, USA
| | - Joanne F Garbincius
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, 3500 N Broad St, MERB 949, Philadelphia, PA, 19140, USA
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, 3500 N Broad St, MERB 949, Philadelphia, PA, 19140, USA.
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26
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Cheong RY, Baldo B, Sajjad MU, Kirik D, Petersén Å. Effects of mutant huntingtin inactivation on Huntington disease-related behaviours in the BACHD mouse model. Neuropathol Appl Neurobiol 2021; 47:564-578. [PMID: 33330988 PMCID: PMC8247873 DOI: 10.1111/nan.12682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/27/2020] [Accepted: 12/14/2020] [Indexed: 01/02/2023]
Abstract
AIMS Huntington disease (HD) is a fatal neurodegenerative disorder with no disease-modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT-lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD-related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model. METHODS We generated mutant BACHD mice with either a widespread or circuit-specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A2A receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele-specific HTT targeting by injections of recombinant adeno-associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4-6 months of age. RESULTS While motor deficits, body weight changes, anxiety and depressive-like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive-like behaviour. However, conditional circuit-wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal-specific deletion in adulthood failed to rescue any of the HD-related behaviours. CONCLUSIONS Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease-modifying therapies for HD.
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Affiliation(s)
- Rachel Y. Cheong
- Translational Neuroendocrine Research UnitDepartment of Experimental Medical ScienceLund UniversityLundSweden
| | - Barbara Baldo
- Translational Neuroendocrine Research UnitDepartment of Experimental Medical ScienceLund UniversityLundSweden
- Present address:
Evotec SEHD Research and Translational SciencesHamburgGermany
| | - Muhammad U. Sajjad
- Translational Neuroendocrine Research UnitDepartment of Experimental Medical ScienceLund UniversityLundSweden
| | - Deniz Kirik
- Brain Repair and Imaging in Neural Systems UnitDepartment of Experimental Medical ScienceLund UniversityLundSweden
| | - Åsa Petersén
- Translational Neuroendocrine Research UnitDepartment of Experimental Medical ScienceLund UniversityLundSweden
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27
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Han R, Liang J, Zhou B. Glucose Metabolic Dysfunction in Neurodegenerative Diseases-New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming. Int J Mol Sci 2021; 22:5887. [PMID: 34072616 PMCID: PMC8198281 DOI: 10.3390/ijms22115887] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 12/11/2022] Open
Abstract
Glucose is the main circulating energy substrate for the adult brain. Owing to the high energy demand of nerve cells, glucose is actively oxidized to produce ATP and has a synergistic effect with mitochondria in metabolic pathways. The dysfunction of glucose metabolism inevitably disturbs the normal functioning of neurons, which is widely observed in neurodegenerative disease. Understanding the mechanisms of metabolic adaptation during disease progression has become a major focus of research, and interventions in these processes may relieve the neurons from degenerative stress. In this review, we highlight evidence of mitochondrial dysfunction, decreased glucose uptake, and diminished glucose metabolism in different neurodegeneration models such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss how hypoxia, a metabolic reprogramming strategy linked to glucose metabolism in tumor cells and normal brain cells, and summarize the evidence for hypoxia as a putative therapy for general neurodegenerative disease.
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Affiliation(s)
- Rongrong Han
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Interdisciplinary Innovation Institute of Medicine and Engineering, Beihang University, Beijing 100191, China; (R.H.); (J.L.)
| | - Jing Liang
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Interdisciplinary Innovation Institute of Medicine and Engineering, Beihang University, Beijing 100191, China; (R.H.); (J.L.)
| | - Bing Zhou
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Interdisciplinary Innovation Institute of Medicine and Engineering, Beihang University, Beijing 100191, China; (R.H.); (J.L.)
- School of Engineering Medicine, Beihang University, Beijing 100191, China
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28
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Klinkmueller P, Kronenbuerger M, Miao X, Bang J, Ultz KE, Paez A, Zhang X, Duan W, Margolis RL, van Zijl PCM, Ross CA, Hua J. Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington's disease. J Cereb Blood Flow Metab 2021; 41:1119-1130. [PMID: 32807001 PMCID: PMC8054727 DOI: 10.1177/0271678x20949286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/30/2020] [Accepted: 07/15/2020] [Indexed: 01/29/2023]
Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO2 during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO2 responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R2 = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO2 response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.
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Affiliation(s)
- Peter Klinkmueller
- Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, USA
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Martin Kronenbuerger
- Division of Movement Disorders, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, University of Greifswald, Greifswald, Germany
| | - Xinyuan Miao
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jee Bang
- Division of Movement Disorders, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kia E Ultz
- Division of Movement Disorders, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Adrian Paez
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xiaoyu Zhang
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wenzhen Duan
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Russell L Margolis
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter CM van Zijl
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher A Ross
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jun Hua
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Neurosection, Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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29
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Abstract
Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.
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30
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Goud NS, Bhattacharya A, Joshi RK, Nagaraj C, Bharath RD, Kumar P. Carbon-11: Radiochemistry and Target-Based PET Molecular Imaging Applications in Oncology, Cardiology, and Neurology. J Med Chem 2021; 64:1223-1259. [PMID: 33499603 DOI: 10.1021/acs.jmedchem.0c01053] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The positron emission tomography (PET) molecular imaging technique has gained its universal value as a remarkable tool for medical diagnosis and biomedical research. Carbon-11 is one of the promising radiotracers that can report target-specific information related to its pharmacology and physiology to understand the disease status. Currently, many of the available carbon-11 (t1/2 = 20.4 min) PET radiotracers are heterocyclic derivatives that have been synthesized using carbon-11 inserted different functional groups obtained from primary and secondary carbon-11 precursors. A spectrum of carbon-11 PET radiotracers has been developed against many of the upregulated and emerging targets for the diagnosis, prognosis, prediction, and therapy in the fields of oncology, cardiology, and neurology. This review focuses on the carbon-11 radiochemistry and various target-specific PET molecular imaging agents used in tumor, heart, brain, and neuroinflammatory disease imaging along with its associated pathology.
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Affiliation(s)
- Nerella Sridhar Goud
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - Ahana Bhattacharya
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - Raman Kumar Joshi
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - Chandana Nagaraj
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - Rose Dawn Bharath
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - Pardeep Kumar
- Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
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31
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Onyango IG, Bennett JP, Stokin GB. Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases. Neural Regen Res 2021; 16:1467-1482. [PMID: 33433460 PMCID: PMC8323696 DOI: 10.4103/1673-5374.303007] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.
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Affiliation(s)
- Isaac G Onyango
- Center for Translational Medicine, International Clinical Research Centre (ICRC), St. Anne's University Hospital, Brno, Czech Republic
| | - James P Bennett
- Neurodegeneration Therapeutics, 3050A Berkmar Drive, Charlottesville, VA, USA
| | - Gorazd B Stokin
- Center for Translational Medicine, International Clinical Research Centre (ICRC), St. Anne's University Hospital, Brno, Czech Republic
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32
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Molnar MJ, Molnar V, Fedor M, Csehi R, Acsai K, Borsos B, Grosz Z. Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment. Front Psychiatry 2021; 12:825532. [PMID: 35222108 PMCID: PMC8866559 DOI: 10.3389/fpsyt.2021.825532] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/22/2021] [Indexed: 11/13/2022] Open
Abstract
In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5-3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.
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Affiliation(s)
- Maria Judit Molnar
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University Budapest, Budapest, Hungary
| | - Viktor Molnar
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University Budapest, Budapest, Hungary
| | - Mariann Fedor
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University Budapest, Budapest, Hungary
| | - Reka Csehi
- Global Medical Division, Richter Gedeon Plc., Budapest, Hungary
| | - Karoly Acsai
- Global Medical Division, Richter Gedeon Plc., Budapest, Hungary
| | - Beata Borsos
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University Budapest, Budapest, Hungary
| | - Zoltan Grosz
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University Budapest, Budapest, Hungary
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33
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Tabrizi SJ, Flower MD, Ross CA, Wild EJ. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol 2020; 16:529-546. [PMID: 32796930 DOI: 10.1038/s41582-020-0389-4] [Citation(s) in RCA: 297] [Impact Index Per Article: 59.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2020] [Indexed: 12/11/2022]
Abstract
Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.
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Affiliation(s)
- Sarah J Tabrizi
- Huntington's Disease Centre, University College London, London, UK. .,Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK. .,UK Dementia Research Institute, University College London, London, UK.
| | - Michael D Flower
- Huntington's Disease Centre, University College London, London, UK.,Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.,UK Dementia Research Institute, University College London, London, UK
| | - Christopher A Ross
- Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward J Wild
- Huntington's Disease Centre, University College London, London, UK.,Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK
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Mitelman SA, Buchsbaum MS, Christian BT, Merrill BM, Buchsbaum BR, Mukherjee J, Lehrer DS. Positive association between cerebral grey matter metabolism and dopamine D 2/D 3 receptor availability in healthy and schizophrenia subjects: An 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography study. World J Biol Psychiatry 2020; 21:368-382. [PMID: 31552783 DOI: 10.1080/15622975.2019.1671609] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objectives: Overlapping decreases in extrastriatal dopamine D2/D3-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.Methods: To ascertain this, we used two consecutive 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between 18F-fluorodeoxyglucose uptake and 18F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.Results:18F-fluorodeoxyglucose uptake and 18F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D2/D3-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.
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Affiliation(s)
- Serge A Mitelman
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City,NY, USA.,Department of Psychiatry, Division of Child and Adolescent Psychiatry, Elmhurst Hospital Center, Elmhurst, IL, USA
| | - Monte S Buchsbaum
- Departments of Psychiatry and Radiology, University of California, San Diego, CA, USA.,Department of Psychiatry and Human Behavior, University of California, Irvine School of Medicine, Orange, CA, USA
| | - Bradley T Christian
- Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA
| | - Brian M Merrill
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
| | - Bradley R Buchsbaum
- The Rotman Research Institute, Baycrest Centre for Geriatric Care and Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Jogeshwar Mukherjee
- Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine School of Medicine, Irvine, CA, USA
| | - Douglas S Lehrer
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
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Muddapu VR, Dharshini SAP, Chakravarthy VS, Gromiha MM. Neurodegenerative Diseases - Is Metabolic Deficiency the Root Cause? Front Neurosci 2020; 14:213. [PMID: 32296300 PMCID: PMC7137637 DOI: 10.3389/fnins.2020.00213] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 02/26/2020] [Indexed: 01/31/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis, are a prominent class of neurological diseases currently without a cure. They are characterized by an inexorable loss of a specific type of neurons. The selective vulnerability of specific neuronal clusters (typically a subcortical cluster) in the early stages, followed by the spread of the disease to higher cortical areas, is a typical pattern of disease progression. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Efforts to treat these diseases are often limited by the fact that they tend to address any one of the above pathological changes while ignoring others. Lack of clarity regarding a possible root cause that underlies all the above pathologies poses a significant challenge. In search of an integrative theory for neurodegenerative pathology, we hypothesize that metabolic deficiency in certain vulnerable neuronal clusters is the common underlying thread that links many dimensions of the disease. The current review aims to present an outline of such an integrative theory. We present a new perspective of neurodegenerative diseases as metabolic disorders at molecular, cellular, and systems levels. This helps to understand a common underlying mechanism of the many facets of the disease and may lead to more promising disease-modifying therapeutic interventions. Here, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and also the involvement of glia and vascular dysfunctions. Any failure in satisfaction of the metabolic demand by the neurons triggers a chain of events that precipitate various manifestations of neurodegenerative pathology.
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Affiliation(s)
- Vignayanandam Ravindernath Muddapu
- Laboratory for Computational Neuroscience, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - S. Akila Parvathy Dharshini
- Protein Bioinformatics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - V. Srinivasa Chakravarthy
- Laboratory for Computational Neuroscience, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - M. Michael Gromiha
- Protein Bioinformatics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
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Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells. Mol Neurobiol 2019; 57:1570-1593. [PMID: 31797328 DOI: 10.1007/s12035-019-01824-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/24/2019] [Indexed: 12/14/2022]
Abstract
Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.
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Koch ET, Raymond LA. Dysfunctional striatal dopamine signaling in Huntington's disease. J Neurosci Res 2019; 97:1636-1654. [PMID: 31304622 DOI: 10.1002/jnr.24495] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/06/2019] [Accepted: 06/26/2019] [Indexed: 12/17/2022]
Abstract
Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.
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Affiliation(s)
- Ellen T Koch
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.,Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada
| | - Lynn A Raymond
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.,Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
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Peralta C, Biafore F, Depetris TS, Bastianello M. Recent Advancement and Clinical Implications of 18FDG-PET in Parkinson's Disease, Atypical Parkinsonisms, and Other Movement Disorders. Curr Neurol Neurosci Rep 2019; 19:56. [PMID: 31256288 DOI: 10.1007/s11910-019-0966-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE OF REVIEW The molecular imaging field has been very instrumental in identifying the multiple network interactions that compose the human brain. The cerebral glucose metabolism is associated with neural function. 18F-fluoro-deoxyglucose-PET (FDG-PET) studies reflect brain metabolism in a pattern-specific manner. This article reviews FDG-PET studies in Parkinson's disease (PD), atypical parkinsonism (AP), Huntington's disease (HD), and dystonia. RECENT FINDINGS The metabolic pattern of PD, disease progression, non-motor symptoms such as fatigue, depression, apathy, impulse control disorders, and cognitive impairment, and the risk of progression to dementia have been identified with FDG-PET studies. In prodromal PD, the REM sleep behavior disorder-related covariance pattern has been described. In AP, FDG-PET studies have demonstrated to be superior to D2/D3 SPECT in differentiating PD from AP. The metabolic patterns of HD and dystonia have also been described. FDG-PET studies are an excellent tool to identify patterns of brain metabolism.
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Affiliation(s)
- Cecilia Peralta
- Department of Neurology, CEMIC University Hospital, Elias Galván 4102, C1431FWO, Buenos Aires, Argentina.
| | - Federico Biafore
- Department of Biostatistics, School of Science and Technology, National University of San Martín, Campus Miguelete, 25 de Mayo y Francia, Buenos Aires, Argentina
| | - Tamara Soto Depetris
- Department of Neurology, CEMIC University Hospital, Elias Galván 4102, C1431FWO, Buenos Aires, Argentina
| | - Maria Bastianello
- Department of Molecular and Metabolic Imaging, CEMIC University Hospital, Elias Galván, 4102, Buenos Aires, Argentina
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Intihar TA, Martinez EA, Gomez-Pastor R. Mitochondrial Dysfunction in Huntington's Disease; Interplay Between HSF1, p53 and PGC-1α Transcription Factors. Front Cell Neurosci 2019; 13:103. [PMID: 30941017 PMCID: PMC6433789 DOI: 10.3389/fncel.2019.00103] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 02/28/2019] [Indexed: 12/20/2022] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the huntingtin (HTT) gene, causing the protein to misfold and aggregate. HD progression is characterized by motor impairment and cognitive decline associated with the preferential loss of striatal medium spiny neurons (MSNs). The mechanisms that determine increased susceptibility of MSNs to mutant HTT (mHTT) are not fully understood, although there is abundant evidence demonstrating the importance of mHTT mediated mitochondrial dysfunction in MSNs death. Two main transcription factors, p53 and peroxisome proliferator co-activator PGC-1α, have been widely studied in HD for their roles in regulating mitochondrial function and apoptosis. The action of these two proteins seems to be interconnected. However, it is still open to discussion whether p53 and PGC-1α dependent responses directly influence each other or if they are connected via a third mechanism. Recently, the stress responsive transcription factor HSF1, known for its role in protein homeostasis, has been implicated in mitochondrial function and in the regulation of PGC-1α and p53 levels in different contexts. Based on previous reports and our own research, we discuss in this review the potential role of HSF1 in mediating mitochondrial dysfunction in HD and propose a unifying mechanism that integrates the responses mediated by p53 and PGC-1α in HD via HSF1.
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Affiliation(s)
- Taylor A. Intihar
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Elisa A. Martinez
- Department of Biochemistry and Molecular Biology, Dickinson College, Carlisle, PA, United States
| | - Rocio Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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Aldana BI. Microglia-Specific Metabolic Changes in Neurodegeneration. J Mol Biol 2019; 431:1830-1842. [PMID: 30878483 DOI: 10.1016/j.jmb.2019.03.006] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
Abstract
The high energetic demand of the brain deems this organ rather sensitive to changes in energy supply. Therefore, even minor alterations in energy metabolism may underlie detrimental disturbances in brain function, contributing to the generation and progression of neurodegenerative diseases. Considerable evidence supports the key role of deficits in cerebral energy metabolism, particularly hypometabolism of glucose and mitochondrial dysfunction, in the pathophysiology of brain disorders. Major breakthroughs in the field of bioenergetics and neurodegeneration have been achieved through the use of in vitro and in vivo models of disease as well as sophisticated neuroimaging techniques in patients, yet these have been mainly focused on neuron and astrocyte function. Remarkably, the subcellular metabolic mechanisms linked to neurodegeneration that operate in other crucial brain cell types such as microglia have remain obscured, although they are beginning to be unraveled. Microglia, the brain-resident immune sentinels, perform a diverse range of functions that require a high-energy expenditure, namely, their role in brain development, maintenance of the neural environment, response to injury and infection, and activation of repair programs. Interestingly, another key mechanism underlying several neurodegenerative diseases is neuroinflammation, which can be associated with chronic microglia activation. Considering that many brain disorders are accompanied by changes in brain energy metabolism and sustained inflammation, and that energy metabolism has a strong influence on the inflammatory responses of microglia, the emerging significance of microglial energy metabolism in neurodegeneration is highlighted in this review.
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Affiliation(s)
- Blanca I Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
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41
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Jamwal S, Kumar P. Insight Into the Emerging Role of Striatal Neurotransmitters in the Pathophysiology of Parkinson's Disease and Huntington's Disease: A Review. Curr Neuropharmacol 2019; 17:165-175. [PMID: 29512464 PMCID: PMC6343208 DOI: 10.2174/1570159x16666180302115032] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 11/06/2017] [Accepted: 02/28/2018] [Indexed: 12/05/2022] Open
Abstract
Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson's disease and Huntington's disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson's disease and Huntington's disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson's disease and Huntington's disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.
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Affiliation(s)
| | - Puneet Kumar
- Address correspondence to this author at the Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Panjab, India; E-mail:
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Jędrak P, Mozolewski P, Węgrzyn G, Więckowski MR. Mitochondrial alterations accompanied by oxidative stress conditions in skin fibroblasts of Huntington's disease patients. Metab Brain Dis 2018; 33:2005-2017. [PMID: 30120672 PMCID: PMC6244791 DOI: 10.1007/s11011-018-0308-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/12/2018] [Indexed: 01/08/2023]
Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder manifesting as progressive impairment of motor function and different neuropsychiatric symptoms caused by an expansion of CAG repeats in huntingtin gene (HTT). Mitochondrial dysfunction and bioenergetic defects can contribute to the course of the disease, however, the molecular mechanism underlying this process is still largely unknown. In this study, we aimed to determine several mitochondrial parameters in HD fibroblasts and assess their relevance to the disease progression as well as to value mitochondrial pathology in peripheral cells as disease potential biomarker. We showed that HD fibroblasts demonstrate significantly lower growth rate compared to control fibroblasts despite the lack of cell cycle perturbations. In order to investigate mitochondrial contribution to cell growth differences between HD and healthy cells, we provided insight into various mitochondrial parameters. Conducted experiments have revealed a significant reduction of the ATP level in HD fibroblasts accompanied by a decrease in mitochondrial metabolic activity in relation to the cells from healthy donors. Importantly, there were no differences in the mitochondrial membrane potential (mtΔΨ) and OXPHOS complexes' levels. Slightly increased level of mitochondrial superoxide (mt. O2•-), but not cytosolic reactive oxygen species (cyt. ROS), has been demonstrated. We have also observed significantly elevated levels of some antioxidant enzymes (SOD2 and GR) which may serve as an indicator of antioxidant defense system in HD patients. Thus, we suggest that mitochondrial alterations in skin fibroblasts of Huntington's disease patients might be helpful in searching for novel disease biomarkers.
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Affiliation(s)
- Paulina Jędrak
- Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Paweł Mozolewski
- Department of Medical Biology and Genetics, University of Gdańsk, Gdańsk, Poland
| | - Grzegorz Węgrzyn
- Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland.
| | - Mariusz R Więckowski
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093, Warsaw, Poland.
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Lois C, González I, Izquierdo-García D, Zürcher NR, Wilkens P, Loggia ML, Hooker JM, Rosas HD. Neuroinflammation in Huntington's Disease: New Insights with 11C-PBR28 PET/MRI. ACS Chem Neurosci 2018; 9:2563-2571. [PMID: 29719953 DOI: 10.1021/acschemneuro.8b00072] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Huntington's disease is a devastating neurodegenerative genetic disorder that causes progressive motor dysfunction, emotional disturbances, and cognitive impairment. Unfortunately, there is no treatment to cure or slow the progression of the disease. Neuroinflammation is one hallmark of Huntington's disease, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. The relationship between neuroinflammation markers and the disease pathology is still poorly understood. To improve our understanding of neuroinflammation in Huntington's disease, we measured translocator protein (TSPO) expression using 11C-PBR28 and simultaneous PET/MRI. Standardized-uptake-value ratios, normalized by whole brain uptake, were calculated for data acquired 60-90 min after radiotracer administration. We identified distinct patterns of regional neuroinflammation (as defined by TSPO overexpression relative to a control group) in the basal ganglia of Huntington's disease patients. These patterns were observed at the individual level in all patients, with region of interest analysis confirming significant differences between patients and the control group in the putamen and the pallidum. Additionally, we observed further distinct regional and subregional signatures, which may provide insights into phenotypical variability. For example, in certain Huntington's disease patients, we observed in vivo elevation of the level of TSPO binding in subnuclei in the thalamus and brainstem that have been previously associated with visual function, motor function, and motor coordination. Our main result is an objective score, based solely on 11C-PBR28 measurements, that correlates well with measurements of brain atrophy. We conclude that PET/MR imaging using 11C-PBR28 provides a high signal-to-background ratio and has the potential to be used to assess Huntington's disease progression. Our results suggest 11C-PBR28 might prove useful in clinical trials evaluating therapies targeting neuroinflammation.
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Affiliation(s)
- Cristina Lois
- Department of
Radiology, Gordon Center for Medical Imaging, Massachusetts General
Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
- Department of
Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
- Madrid-MIT M+Visión Consortium, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Iván González
- Department of
Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - David Izquierdo-García
- Department of
Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Nicole R. Zürcher
- Department of
Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Paul Wilkens
- Department of
Neurology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Marco L. Loggia
- Department of
Anesthesiology, Athinoula A. Martinos Center for Biomedical Imaging,
Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Jacob M. Hooker
- Department of
Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - H. Diana Rosas
- Department of
Neurology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
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Molecular Imaging in Huntington's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 142:289-333. [PMID: 30409256 DOI: 10.1016/bs.irn.2018.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non-invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD.
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Abstract
Even before the success of combined positron emission tomography and computed tomography (PET/CT), the neuroimaging community was conceiving the idea to integrate the positron emission tomography (PET), with very high molecular quantitative data but low spatial resolution, and magnetic resonance imaging (MRI), with high spatial resolution. Several technical limitations have delayed the use of a hybrid scanner in neuroimaging studies, including the full integration of the PET detector ring within the MRI system, the optimization of data acquisition, and the implementation of reliable methods for PET attenuation, motion correction, and joint image reconstruction. To be valid and useful in clinical and research settings, this instrument should be able to simultaneously acquire PET and MRI, and generate quantitative parametric PET images comparable to PET-CT. While post hoc co-registration of combined PET and MRI data acquired separately became the most reliable technique for the generation of "fused" PET-MRI images, only hybrid PET-MRI approach allows merging these measurements naturally and correlating them in a temporal manner. Furthermore, hybrid PET-MRI represents the most accurate tool to investigate in vivo the interplay between molecular and functional aspects of brain pathophysiology. Hybrid PET-MRI technology is still in the early stages in the movement disorders field, due to the limited availability of scanners with integrated optimized methodological models. This technology is ideally suited to investigate interactions between resting-state functional/arterial spin labeling MRI and [18F]FDG PET glucose metabolism in the evaluation of the brain "hubs" particularly vulnerable to neurodegeneration, areas with a high degree of connectivity and associated with an efficient synaptic neurotransmission. In Parkinson's disease, hybrid PET-MRI is also the ideal instrument to deeper explore the relationship between resting-state functional MRI and dopamine release at [11C]raclopride PET challenge, in the identification of early drug-naïve Parkinson's disease patients at higher risk of motor complications and in the evaluation of the efficacy of novel neuroprotective treatment able to restore at the same time the altered resting state and the release of dopamine. In this chapter, we discuss the key methodological aspects of hybrid PET-MRI; the evidence in movement disorders of the key resting-state functional and perfusion MRI; [18F]FDG PET and [11C]raclopride PET challenge studies; the potential advantages of using hybrid PET-MRI to investigate the pathophysiology of movement disorders and neurodegenerative diseases. Future directions of hybrid PET-MRI will be discussed alongside with up-to-date technological innovations on hybrid systems.
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de Natale ER, Wilson H, Pagano G, Politis M. Imaging Transplantation in Movement Disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 143:213-263. [PMID: 30473196 DOI: 10.1016/bs.irn.2018.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell replacement therapy with graft transplantation has been tested as a disease-modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.
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Affiliation(s)
- Edoardo Rosario de Natale
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Heather Wilson
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Gennaro Pagano
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Marios Politis
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
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Fazio P, Paucar M, Svenningsson P, Varrone A. Novel Imaging Biomarkers for Huntington's Disease and Other Hereditary Choreas. Curr Neurol Neurosci Rep 2018; 18:85. [PMID: 30291526 PMCID: PMC6182636 DOI: 10.1007/s11910-018-0890-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF THE REVIEW Imaging biomarkers for neurodegenerative disorders are primarily developed with the goal to aid diagnosis, to monitor disease progression, and to assess the efficacy of disease-modifying therapies in support to clinical outcomes that may either show limited sensitivity or need extended time for their evaluation. This article will review the most recent concepts and findings in the field of neuroimaging applied to Huntington's disease and Huntington-like syndromes. Emphasis will be given to the discussion of potential pharmacodynamic biomarkers for clinical trials in Huntington's disease (HD) and of neuroimaging tools that can be used as diagnostic biomarkers in HD-like syndromes. RECENT FINDINGS Several magnetic resonance (MR) and positron emission tomography (PET) molecular imaging tools have been identified as potential pharmacodynamic biomarkers and others are in the pipeline after preclinical validation. MRI and 18F-fluorodeoxyglucose PET can be considered useful supportive diagnostic tools for the differentiation of other HD-like syndromes. New trials in HD have the primary goal to lower mutant huntingtin (mHTT) protein levels in the brain in order to reduce or alter the progression of the disease. MR and PET molecular imaging markers have been developed as tools to monitor disease progression and to evaluate treatment outcomes of disease-modifying trials in HD. These markers could be used alone or in combination for detecting structural and pharmacodynamic changes potentially associated with the lowering of mHTT.
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Affiliation(s)
- Patrik Fazio
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, R5:02 Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
| | - Martin Paucar
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Per Svenningsson
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Andrea Varrone
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, R5:02 Karolinska University Hospital, SE-171 76, Stockholm, Sweden
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Snowden JS. The Neuropsychology of Huntington's Disease. Arch Clin Neuropsychol 2018; 32:876-887. [PMID: 28961886 DOI: 10.1093/arclin/acx086] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 09/04/2017] [Indexed: 01/24/2023] Open
Abstract
Huntington's disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally. Symptoms emerge at around 40 years, although there is wide variation. A rare juvenile form has onset in childhood or adolescence. The evolution of disease is insidious and structural and functional brain changes may be present more than a decade before symptoms and signs become manifest. The earliest site of pathology is the striatum and neuroimaging measures of striatal change correlate with neurological and cognitive markers of disease. Chorea and other aspects of the movement disorder are the most visible aspect of the disease. However, non-motor features have greatest affect on functional independence and quality of life, so require recognition and management. The evidence-base for non-pharmacological treatments in Huntington's disease is currently limited, but recent intervention studies are encouraging.
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Affiliation(s)
- Julie S Snowden
- Greater Manchester Neuroscience Centre, Salford Royal NHS Trust, Salford, UK.,Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Agosta F, Altomare D, Festari C, Orini S, Gandolfo F, Boccardi M, Arbizu J, Bouwman F, Drzezga A, Nestor P, Nobili F, Walker Z, Pagani M. Clinical utility of FDG-PET in amyotrophic lateral sclerosis and Huntington's disease. Eur J Nucl Med Mol Imaging 2018; 45:1546-1556. [PMID: 29717332 DOI: 10.1007/s00259-018-4033-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
AIM To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. METHODS Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. RESULTS The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. CONCLUSION Relative to other neurodegenerative diseases, the clinical use of FDG-PET in ALS and HD is still in its infancy. Once validated by disease-control studies, FDG-PET might represent a potentially useful biomarker for ALS diagnosis. FDG-PET is presently not justified as a routine investigation to predict conversion to HD, nor to detect evidence of brain dysfunction justifying cognitive decline in ALS and HD.
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Affiliation(s)
- Federica Agosta
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
| | - Daniele Altomare
- LANE - Laboratory of Alzheimer's Neuroimaging & Epidemiology, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Cristina Festari
- LANE - Laboratory of Alzheimer's Neuroimaging & Epidemiology, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Stefania Orini
- Alzheimer Operative Unit, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy
| | - Federica Gandolfo
- Alzheimer Operative Unit, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy
| | - Marina Boccardi
- LANE - Laboratory of Alzheimer's Neuroimaging & Epidemiology, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
- LANVIE (Laboratoire de Neuroimagerie du Vieillissement), Department of Psychiatry, University of Geneva, Geneva, Switzerland.
| | - Javier Arbizu
- Department of Nuclear Medicine, Clinica Universidad de Navarra, University of Navarra, Pamplona, Spain
| | - Femke Bouwman
- Department of Neurology & Alzheimer Center, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
| | - Alexander Drzezga
- Department of Nuclear Medicine, University Hospital of Cologne, University of Cologne and German Center for Neurodegenerative Diseases (DZNE), Cologne, Germany
| | - Peter Nestor
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
- Queensland Brain Institute, University of Queensland and at the Mater Hospital Brisbane, Brisbane, Australia
| | - Flavio Nobili
- Department of Neuroscience (DINOGMI), University of Genoa and Polyclinic San Martino Hospital, Genoa, Italy
| | - Zuzana Walker
- Division of Psychiatry & Essex Partnership University NHS Foundation Trust, University College London, London, UK
| | - Marco Pagani
- Institute of Cognitive Sciences and Technologies, CNR, Rome, Italy
- Department of Nuclear Medicine, Karolinska Hospital Stockholm, Stockholm, Sweden
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