Current status of PET imaging in Huntington’s disease

Eur J Nucl Med Mol Imaging (2016) 43:1171–1182 DOI 10.1007/s00259-016-3324-6 REVIEW ARTICLE Current status of PET imaging in Huntington’s disease Gennaro Pagano 1 & Flavia Niccolini 1 & Marios Politis 1 Received: 22 September 2015 / Accepted: 25 January 2016 / Published online: 22 February 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Purpose To review the developments of recent decades and the current status of PET molecular imaging in Huntington’s disease (HD). Methods A systematic review of PET studies in HD was performed. The MEDLINE, Web of Science, Cochrane and Scopus databases were searched for articles in all languages published up to 19 August 2015 using the major medical subject heading BHuntington Disease^ combined with text and key words BHuntington Disease^, BNeuroimaging^ and BPET^. Only peer-reviewed, primary research studies in HD patients and premanifest HD carriers, and studies in which clinical features were described in association with PET neuroimaging results, were included in this review. Reviews, case reports and nonhuman studies were excluded. Results A total of 54 PET studies were identified and analysed in this review. Brain metabolism ([18F]FDG and [15O]H2O), presynaptic ([18F]fluorodopa, [11C]β-CIT and [11C]DTBZ) and postsynaptic ([ 11 C]SCH22390, [ 11 C]FLB457 and [11C]raclopride) dopaminergic function, phosphodiesterases ([18F]JNJ42259152, [18F]MNI-659 and [11C]IMA107), and adenosine ([18F]CPFPX), cannabinoid ([18F]MK-9470), opioid ([11C]diprenorphine) and GABA ([11C]flumazenil) receptors were evaluated as potential biomarkers for monitoring disease progression and for assessing the development and efficacy of novel disease-modifying drugs in premanifest * Marios Politis 1 Neurodegeneration Imaging Group, Department of Basic & Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, 125 Coldharbour Lane, Camberwell, London SE5 9NU, UK HD carriers and HD patients. PET studies evaluating brain restoration and neuroprotection were also identified and described in detail. Conclusion Brain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression. However, no single technique may be currently considered an optimal biomarker and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD. Keywords Huntington’s disease . Premanifest Huntington’s disease gene carriers . Neurodegeneration imaging . Positron emission tomography Introduction Huntington’s disease (HD) is an autosomal dominant monogenic neurodegenerative disease with a prevalence of 0.4 – 5.7 per 100,000 worldwide [1]. HD is caused by an expanded CAG trinucleotide repeat sequence in the huntingtin gene on chromosome 4, which leads to the formation of intranuclear inclusions of mutated huntingtin in the brain, resulting in loss of GABAergic medium spiny neurons (MSNs) in the striatum and in cortical areas [2]. HD is clinically characterized by motor symptoms (chorea and parkinsonism), cognitive symptoms (slowed mentation, attention, mental flexibility, planning and emotion recognition) and psychiatric symptoms (depression, apathy, impulsivity, irritability, disinhibition and psychosis), with a progressive course and a typical onset in adult middle age (40 – 55 years) [3]. The age at onset is inversely correlated with the size of the CAG repeat expansion [4]. This allows us to predict the motor onset [5] and classify the disease in stages such as premanifest HD (before motor onset) and 1172 manifest HD (after motor onset) [6] providing a tremendous opportunity to investigate subclinical and pathological changes in asymptomatic HD gene carriers. This offers a therapeutic window for potential preventive treatments aiming to delay the clinical onset of HD. The mechanisms underlying the progressive neurodegeneration in HD are still unclear and, currently, there is no single proven biomarker that allows us to monitor disease progression and assess the efficacy of novel disease-modifying drugs. The lack of biomarkers may be related to the fact that HD pathology causes only minor brain alterations in early stages [7]. Molecular imaging techniques are able to identify subtle alterations at the nanomolecular level and this is a prerequisite to understanding minimal changes in brain activity [8, 9]. PET molecular probes bind a target, such as a receptor, a transporter or an enzyme, with high specificity and power of resolution [10]. PET molecular imaging has revolutionized the ability to gain insights into human brain biology and beyond this to understand the physiology and pathophysiology of neurological diseases [11]. PET radiotracers have provided invaluable insights into the natural history of HD and have been used to measure brain metabolism, dopaminergic function, neuroinflammation, phosphodiesterases and other targets in HD [12]. They have contributed to the identification of disease characteristics at different stages mainly in cross-sectional studies but also in some longitudinal studies. This review describes the developments during recent decades and current applications of PET molecular imaging techniques in HD. Methods Search strategy The MEDLINE, Web of Science, Cochrane CENTRAL and Scopus databases were searched for articles in all languages published up to 19 August 2015. Studies were identified and evaluated by two of the authors (G.P. and F.N.) using the major medical subject heading BHuntington Disease^ combined with text and key words BHuntington Disease^, BNeuroimaging^ and BPET^. Additional eligible studies were identified by screening the reference lists of the studies found. Inclusion criteria Studies were excluded if the title and/or abstract was not appropriate for the aim of the review. The full text of eligible studies and of studies whose relevance was uncertain were obtained. Selected studies were eligible if they met the following criteria: (1) peer-reviewed, primary research studies, (2) studies including HD patients, (3) studies including a Eur J Nucl Med Mol Imaging (2016) 43:1171–1182 description of the clinical features of the HD patients in association with neuroimaging results, and (4) studies including PET neuroimaging. Reviews, case reports and nonhuman studies were excluded. Results Of 944 articles identified by the initial search, 86 were retrieved for more detailed evaluation, and 54 PET studies were finally identified and analysed in this review. The results of 32 of the main studies are summarized in Table 1. Brain metabolism [15O]H2O and [18F]FDG have been used as markers of cerebral blood flow and cerebral glucose metabolism providing an index of neuronal integrity and the functional state of neurons [13 (...truncated)