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Drug Development in Alzheimer's Disease: the Contribution of PET and SPECT

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Drug Development in Alzheimer's Disease: the Contribution of PET and SPECT fphar-07-00088 March 29, 2016 Time: 15:21 # 1 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 31 March 2016 doi: 10.3389/fphar.2016.00088 Drug Development in Alzheimer’s Disease: The Contribution of PET and SPECT Lieven D. Declercq1, Rik Vandenberghe2, Koen Van Laere3, Alfons Verbruggen1 and Guy Bormans1* 1 Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, 2 Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium, 3 Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium Clinical trials aiming to develop disease-altering drugs for Alzheimer’s disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders. Edited by: Albert D. Windhorst, PET and SPECT have the ability to provide biomarkers that permit spatial assessment VU University Medical Center, of pathophysiological molecular changes and therefore objectively evaluate and follow Netherlands up therapeutic response, especially in the brain. A number of specific PET/SPECT Reviewed by: biomarkers used in support of emerging clinical therapies in AD are discussed in this Bashir M. Rezk, Southern University at New Orleans, review. USA Carmen Gil, Keywords: Alzheimer’s disease, PET, SPECT, drug development, biomarkers Centro de Investigaciones Biologicas (CIB–CSIC), Spain *Correspondence: INTRODUCTION Guy Bormans [email protected] The worldwide prevalence of AD is estimated at 35 million, a number expected to quadruple by 2050, due to the increasing lifespan of the world population (Brookmeyer et al., 2007). With an Specialty section: unfavorable prognosis and a life expectancy of approximately 8–10 years, AD is becoming one This article was submitted to of the most costly diseases for society (Thies and Bleiler, 2013). In spite of increasing knowledge Experimental Pharmacology and Drug Discovery, a section of the journal Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HTRs, 5-HT receptors; 5-HTT, 5-HT transporter; a-APP, a-amyloid Frontiers in Pharmacology precursor protein; Ab, amyloid beta; ACh, acetylcholine; AChE, acetylcholinesterase; AD, Alzheimer’s disease; ADAS-cog, a b Received: 05 February 2016 Alzheimer’s disease assessment scale-cognitive subscale; ALA, -lipoic acid; APP, amyloid precursor protein; BACE1, -site APP-cleaving enzyme 1; BBB, blood–brain barrier; BPSD, behavioral and psychological symptoms of dementia; BZDs, Accepted: 16 March 2016 benzodiazepines; CBD, corticobasal degeneration; ChAT, choline acetyltransferase; CIBICC, clinician’s interview-based Published: 31 March 2016 impression of change; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computerized tomography; CTI, clinical Citation: trial identifier; D1R, dopamine1-like receptors; DA, dopamine; DAT, dopamine transporter; DLB, dementia with Lewy bodies; Declercq LD, Vandenberghe R, Van ECT, EudraCT-number; EMA, European medicines agency; FDA, food and drug administration; FTD, frontal temporal Laere K, Verbruggen A dementia; GABA, gamma-amino butyric acid; GSK, glycogen synthase kinase; HCs, healthy controls; mAChR, muscarinic acetylcholine receptor; MAPT, microtubule-associated protein tau gene; MCI, mild cognitive impairment; MMSE, mini- and Bormans G (2016) Drug mental state examination; MOAs, monoamine oxidases; MRI, magnetic resonance imaging; nAChRs, nicotinic acetylcholine Development in Alzheimer’s Disease: receptors; NFTs, neurofibrillary tangles; PBR, peripheral benzodiazepine receptor; PET, positron emission tomography; P-gp, The Contribution of PET and SPECT. permeability glycoprotein; PHFs, paired helical filaments; PSP, progressive supranuclear palsy; p-tau, phosphorylated tau; Front. Pharmacol. 7:88. rCBF, regional cerebral blood flow; SERT, 5-HT reuptake transporter; SP, senile plaques; SPE(C)T, single photon emission doi: 10.3389/fphar.2016.00088 (computed) tomography; TSPO, translocator protein; VDAC, voltage dependent anion channel. Frontiers in Pharmacology | www.frontiersin.org 1 March 2016 | Volume 7 | Article 88 fphar-07-00088 March 29, 2016 Time: 15:21 # 2 Declercq et al. Diagnostic Support of Neuroimaging in AD about the genetics, epidemiology, and histopathological features Using highly selective PET- or SPECT radioligands, the true of AD there is, at this moment, only symptomatic treatment biological effect of novel clinical candidates can be established available. However, already at early clinical signs, intrinsic disease and true quantitative assessment is possible (Barthel et al., 2015). progression has developed for a long time; patients rapidly Thirdly, molecular imaging can be applied to measure the dose- decline and develop irrevocable brain damage (Masters et al., related occupancy of specific targets caused by drugs under test, 2006; Romano and Buratti, 2013). Therefore, there is a great which allows the characterization of the optimal therapeutic need for efficient treatment that should be initiated in a very window and thus a more effective design of subsequent clinical early phase of the disease. Strict definite diagnosis can still drug trials (Broich et al., 1998; Passchier et al., 2002). Although only be made post-mortem, on the basis of two pathological PET is able to provide a much higher spatial resolution and hallmarks: SP and NFTs (Hyman et al., 2012), although use of dynamic scanning with higher temporal resolution and better biomarkers is strongly advocated in research guidelines (Dubois quantification than SPECT, SPECT cameras are more widely et al., 2014). More than 90% of clinical trials aiming to intervene available and cheaper than PET cameras. Both the availability at the causative pathological elements have failed to produce and the economical aspect are important to consider when disease altering effects. A major concern hereby is the lack of performing large multi-center clinical trials (Rahmim and Zaidi, objective biomarkers assisting in the evaluation of inclusion- and 2008). outcome criteria of participating patients, as many participants The most frequently used PET radiopharmaceutical is turned out to be misdiagnosed, particularly in the early AD 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, Figure 1), a disease stages (Jack et al., 2010; Barthel et al., 2015; James et al., glucose derivative which allows measurement of brain glucose 2015). Currently five biomarkers for AD have been used for metabolism directly related with viability of brain tissue in AD evaluation of disease and monitoring of disease progression (Barthel et al., 2015). This commercially available compound, (Jack et al., 2010): CSF levels of Ab42, CSF levels of total tau with various clinical applications, has been well established and p-tau181 and p-tau231, structural imaging (CT and MRI) in routine clinical practice, but also in the recruitment and and functional imaging (PET with [18F]FDG). Elevated levels of follow-up of the majority of AD clinical trials which use PET CSF tau and reduced levels of CSF Ab allow the prediction of, as biomarker technique (Barthel et al., 2015). Indeed, several respectively, the NFT load and the SP deposits (Ahmed et al., AD clinical trials are currently recruiting and following up 2014; de Souza et al., 2014; Wurtman, 2015). Therefore, these patients with [18F]FDG (CTI: NCT02593318, NCT01561053, CSF levels appear to be useful biomarkers in the diagnosis of and NCT02560753). Although FDG-PET is able to provide AD (Wallin et al., 2006; Weiner et al., 2015). Nonetheless, CSF information about regional glucose metabolism, which sampling requires an invasive lumbar puncture, quantification of can aid in the detection and prognosis of MCI for further CSF levels is hampered by interlaboratory variability and CSF progression to AD, there is a great need for PET- and SPECT values do not provide regional information on tau- and Ab radiopharmaceuticals which deliver more target-specific deposits. The regional concentration of tau- and Ab deposits is information of a variety of (patho)physiological processes that however essential for a differential diagnosis of AD, especially are happening in AD. In this review we will therefore focus on among the different tauopathies (Hampel and Teipel, 2004; Gozes some of the major molecular pathophysiological changes known et al., 2009; Hampel et al., 2010). Structural volume measurement to occur in AD, along with emerging pharmacological treatment can be used to measure regional cerebral atrophy. Although approaches. Furthermore, specific attention will be attributed not highly specific for AD due to overlap with ‘normal’ aging, to the role that PET- and SPECT biomarkers (can) play during the degree of atrophy follows neuropathological progression in these clinical trials. AD and severity of volume loss correlates well with disease progression (Masters et al., 2006; Jack et al., 2010). Regarding the biomarkers that can be visualized and quantified by the molecular imaging techniques PET and SPECT, there are three important
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