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Molecular Imaging in Alzheimer's Disease CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central Nordberg Alzheimer’s Research & Therapy 2011, 3:34 http://alzres.com/content/3/6/34 REVIEW Molecular imaging in Alzheimer’s disease: new perspectives on biomarkers for early diagnosis and drug development Agneta Nordberg* Introduction Abstract Alzheimer’s disease (AD) is characterized by a slow Recent progress in molecular imaging has provided continued deterioration of cognitive processes. Th e fi rst new important knowledge for further understanding symptoms of episodic memory disturbances might be the time course of early pathological disease processes quite subtle. When the patient is assessed for memory in Alzheimer’s disease (AD). Positron emission problems the disease has most probably been ongoing in tomography (PET) amyloid beta (Aβ) tracers such as the brain for several years and has most probably induced Pittsburgh Compound B detect increasing deposition nonrepairable disturbances of important functional of fi brillar Aβ in the brain at the prodromal stages of neuronal networks and loops of the brain. It is a challenge AD, while the levels of fi brillar Aβ appear more stable to test whether some of these changes could be reversed at high levels in clinical AD. There is a need for PET or slowed down with early drug treatment. ligands to visualize smaller forms of Aβ, oligomeric Th e recent progress in AD research has provided new forms, in the brain and to understand how they knowledge for further understanding the pathology interact with synaptic activity and neurodegeneration. processes of AD that precede the onset of clinical disease The infl ammatory markers presently under by many years. It is still an open question why some development might provide further insight into the people can cope with AD brain pathology better than disease mechanism as well as imaging tracers for tau. others. Do they have greater capacity of neuronal com- Biomarkers measuring functional changes in the brain pen sation? Is there ongoing neurogenesis in the brain? such as regional cerebral glucose metabolism and Th e resistance toward increased pathological burden neurotransmitter activity seem to strongly correlate especially observed in highly educated subjects might be with clinical symptoms of cognitive decline. Molecular a sign of increased brain plasticity as well as greater imaging biomarkers will have a clinical implication in cognitive reserve [1]. AD not only for early detection of AD but for selecting Since Dr Alois Alzheimer fi rst described the AD patients for certain drug therapies and to test disease- disease, amyloid beta (Aβ) has played a central role in AD modifying drugs. PET fi brillar Aβ imaging together pathology. It has not yet been proven that Aβ is the with cerebrospinal fl uid biomarkers are promising as primary causative factor of AD. A puzzling observation biomarkers for early recognition of subjects at risk for from autopsy AD brain studies has been the weak AD, for identifying patients for certain therapy and for correlation between fi brillar Aβ load in the brain and quantifying anti-amyloid eff ects. Functional biomarkers cognition while the amount of neurofi brillary tangles such as regional cerebral glucose metabolism together signifi cantly correlates with the cognitive status and with measurement of the brain volumes provide duration of dementia [2-4]. Th e eff ects of Aβ in the valuable information about disease progression and clinical stages of AD are most probably mediated by the outcome of drug treatment. presence of neurofi brillary tangles in the brain [5]. In addition, a sequential cascade of events including oxidative stress reactions, infl ammatory processes and neurotransmitter and receptor dysfunction most *Correspondence: [email protected] probably contributes to the impairment of cognitive Karolinska Institutet, Alzheimer Neurobiology Center, Karolinska University, function [6]. Hospital Huddinge, Novum 5th fl oor, 141 86 Stockholm, Sweden Molecular imaging techniques have rapidly developed during recent years. Th is development not only allows © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd one to measure brain structural changes in patients Nordberg Alzheimer’s Research & Therapy 2011, 3:34 Page 2 of 9 http://alzres.com/content/3/6/34 (atrophy, volume changes and cortical thickness) by Table 1. Pathological and functional biomarkers in magnetic resonance imaging, but also to visualize and Alzheimer’s disease quantify brain pathology (fi brillar Aβ, tau, activated Pathological Alzheimer’s disease biomarkers microglia and astrocytosis) as well as functional changes Positron emission tomography (cerebral glucose metabolism, neurotransmitter and Fibrillar amyloid beta (11C-Pittsburgh Compound B, 18F-fl utemetamol, neuroreceptor activity) by positron emission tomography 18F-fl orbetapir, and18 F-fl orbetaben) (PET) (Table 1). Molecular imaging thus provides impor- Tau (18F-FDDNP) tant insight into the ongoing pathological processes in Microglia (11C-PK11195, 11C-DA1106) AD in relation to clinical symptoms and disease progres- sion. An important step forward has been in vivo imaging Astrocytes (11C-D-deprenyl) of Aβ pathology in AD patients. Although the histo- Magnetic resonance imaging (atrophy, hippocampal volume, cortical thickness) patho logical confi rma tion of diagnosis at autopsy is Cerebrospinal fl uid (amyloid beta 1–42, tau, p-tau) impor tant, it refl ects the end stage of a disease that may Functional Alzheimer’s disease biomarkers have been ongoing for decades. Positron emission tomography Th e new molecular imaging techniques provide possi- Cerebral glucose metabolism (18F-FDG) bilities to develop early diagnostic biomarkers for early detection of AD at preclinical stages, as well as for Neurotransmitter activity (for example, 11C-CFT, 11C-PMP) monitor ing eff ects of drug therapy. Recent research has Neuroreceptors (for example, 11C-raclopride, 18F-alanserine, 11C-nicotine) thus also changed the view on incorporating biomarkers Functional magnetic resonance imaging, spectroscopy into the standardized clinical diagnosis of AD as suggested Single-photon emission computed tomography (cerebral blood fl ow) by Dubois and colleagues [7,8] and the recommendations from the National Institute on Aging–Alzheimer Association workgroups on diagnostic guidelines for AD there is no information on how the smaller soluble Aβ [9,10]. oligomers, which are known for triggering synaptic dys- function [28-30], can be visualized in vivo in man with Amyloid imaging in Alzheimer’s disease patients the presently available Aβ tracers. It is therefore a Among the fi rst Aβ PET tracers was Pittsburgh Com- challenge to try to develop PET tracers that can visualize pound B (11C-PIB) when 16 AD patients were initially these smaller forms of Aβ in the brain, although the scanned in Sweden [11]. Th e high 11C-PIB retention ob- probably lower content of oligomers in AD brains served in cortical and subcortical brain regions of mild compared with fi brillar Aβ might be a limiting factor. Th e AD patients compared with age-matched healthy sub- soluble Aβ oligomers are important since they probably jects has consistently been confi rmed with 11C-PIB in can induce and interfere with the neurotransmission in several other studies (for a review see [12-14]). Several the brain [30,31]. other Aβ PET tracers have also been tested in AD and control patients [12,15] although so far 11C-PIB is the Longitudinal PET amyloid studies in Alzheimer’s most explored. 18F-labeled tracers will probably be more disease patients suitable for use in the clinic, with their longer half-life. Th ere are still few longitudinal studies of Aβ PET imaging 18F-FDDNP was the fi rst 18F-PET tracer used for in AD patients. Th ese studies are important to under- visualizing Aβ plaque in AD patients [16], showing lower stand the rate of accumulation of amyloid in the brain binding affi nity to Aβ plaques than 11C-PIB but also and are important for evaluation of intervention in anti- suggested to bind to neurofi brillary tangles [16,17]. Th e amyloid drugs. A 2-year follow-up study with 11C-PIB in 18F-labeled Aβ PET tracers 18F-fl utemetamol, 18F-fl orbetapir AD patients revealed at group level consistent stable and 18F-fl orbetaben have shown promising results in AD fi brillar Aβ levels in the brain [32]. Two additional 1-year patients [18-20]. and 2-year follow-up studies confi rmed these observa- Th e PET Aβ tracers quantify fi brillar Aβ in the brain by tions [33,34] as well as a recent 5-year follow-up PET binding in the nanomolar range to the Aβ peptide [21]. study of the fi rst imaged PIB PET cohort [35]. In the Th e in vivo 11C-PIB retention correlates with 3H-PIB latter study it was evident at the individual level that binding as well as levels of Aβ measured in autopsy AD increased, stable and decreased PIB retention were brain tissue [22-25]. 18F-fl orbetapir PET imaging has also observed and the disease progression was refl ected in been shown to correlate with the presence of Aβ amyloid signifi cant decline in cerebral regional cerebral glucose at autopsy [26], as well as 18F-fl utemetamol PET imaging metabolism (rCMRglc) and cognition [35]. In a recent to amyloid measured in cortical biopsies [27]. 20-month follow-up study, Villemagne and colleagues A still unknown factor is the relationship between reported a 5.7% increase in fi brillar Aβ in AD patients fi brillar Aβ (plaques) and soluble Aβ oligomers. Presently [36]. Th e longitudinal imaging studies mainly support the Nordberg Alzheimer’s Research & Therapy 2011, 3:34 Page 3 of 9 http://alzres.com/content/3/6/34 assumption that the Aβ levels in the AD brain reach a maximal level at the early clinical stage of the disease, although both increase and decline in later stages of the disease cannot be excluded [12,37,38].
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