The leading etiological hypothesis of Alzheimer's disease (AD) points to excessive brain β-amyloid (Aβ) that aggregates to form extracellular plaques and vascular wall deposits . With increasing prevalence and associated cost of care and the likelihood of greater benefit if therapies are applied early, earlier and more accurate identification of AD has become a research priority.
Dementia is usually preceded by a transition period of cognitive decline commonly referred to as mild cognitive impairment (MCI). Characterized by an objective impairment of memory and/or other cognitive domains, MCI is not severe enough to significantly interfere with activities of daily living . The prevalence of MCI in people aged 65 is believed to be 10 to 20%, with over 10% who have been classified as MCI converting to dementia per year . Histopathologic studies on brains of MCI subjects have shown characteristic AD pathology including Aβ plaques and neurofibillary tangles in the majority of cases . MCI has been further classified based on whether memory has been affected (amnestic MCI) or spared (nonamnestic MCI), and whether the cognitive deficit affected is mainly in one cognitive domain (single-domain MCI) or more than one domain (multidomain MCI). Hence, MCI can be classified into four clinical subtypes: nonamnestic single-domain, nonamnestic multiple domains, amnestic single-domain (asMCI), and amnestic multiple domains (amMCI). These subtypes probably differ in etiology and outcome. Impaired episodic memory, which characterizes asMCI and amMCI, is thought to be a prodromal condition for AD [3, 4].
The new research diagnostic criteria for AD and MCI allow for Aβ imaging in the workup of individuals with cognitive impairment [5, 6]. Non-invasive Aβ imaging to confirm the presence of AD neuropathology could aid in early differential diagnosis, identify at-risk individuals, help predict or monitor disease progression, and potentially evaluate the response to disease-specific therapy. 11C-Pittsburgh Compound B (PiB) has been the most widely used agent in dementia research to assess Aβ burden in vivo . The major disadvantage of PiB is that it is radiolabeled with carbon-11, which has a short decay half-life (20 minutes) that limits its use to centers with an onsite cyclotron and 11C-radiochemistry expertise.
To overcome these limitations, a number of novel fluorine-18 Aβ imaging tracers such as 18F-florbetaben (BAY 94-9172) [8–10], 18F-florbetapir (AV45) [11, 12] and 18F-flutemetamol (GE067) [13, 14] have been developed. The 110-minute radioactive decay half-life of fluorine-18 allows centralized synthesis and regional distribution of these tracers as currently practiced worldwide in the supply of 18F-fluorodeoxyglucose for routine clinical positron emission tomography (PET) imaging.
18F-florbetaben (FBB; trans-4-(N-methyl-amino)-4"(2-(2-(2-[18F] fluoro-ethoxy)ethoxy)-ethoxy)stilbene), developed by Avid Radiopharmaceuticals (Philadelphia, USA) and Bayer-Schering Pharma (Berlin, Germany), has been shown to bind with high affinity to Aβ in brain homogenates and selectively labeled Aβ plaques and cerebral amyloid angiopathy (CAA) in AD tissue sections . After injection into Tg2576 transgenic mice, ex vivo brain sections showed localization of FBB in regions with Aβ plaques as confirmed by thioflavin binding . At the tracer concentrations achieved during human PET studies, FBB did not show binding to α-synuclein in Lewy bodies or to tau lesions in postmortem cortices from dementia with Lewy bodies, AD or frontotemporal lobar degeneration patients . In human studies, cortical retention of FBB was significantly higher in AD patients compared with age-matched controls and frontotemporal lobar degeneration patients, with binding matching the reported postmortem distribution of Aβ plaques . Phase II clinical studies further confirmed these results . FBB is highly correlated with 11C-PiB (r = 0.97 with a slope of 0.71) , and was used to detect the presence or absence of AD pathology in the brain in participants with a wide spectrum of neurodegenerative diseases including a few MCI participants . Phase III studies for FBB have reached completion .
Human postmortem studies have shown that while soluble Aβ oligomers and the density of neurofibrillary tangles strongly correlate with neurodegeneration and cognitive deficits, the density of Aβ insoluble plaques does not [20–24] and Αβ burden as assessed by PET does not strongly correlate with cognitive impairment in AD patients [25, 26]. The severity of tau pathology in AD patients is closely related to neuronal loss , hippocampal atrophy [28, 29] and memory impairment [30, 31]. Amyloid imaging studies in MCI have shown an association between Aβ burden and memory , an association that is believed to be mediated by hippocampal atrophy . Vascular pathology, as reflected in white matter hyperintensities (WMH), has been shown to be associated with cognitive impairment, particularly affecting working memory and executive function, as well as visuospatial abilities among people with MCI .
The purpose of this study was to characterize FBB binding in a well-characterized MCI cohort, and to explore the relationships of Aβ burden cognitive performance, hippocampal volume (HV), and WMH.