ReviewNeuroimaging biomarkers in Alzheimer’s disease and other dementias
Introduction
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by memory loss and cognitive decline that severely affect the activities of daily living (Masters et al., 2006). AD is the leading cause of dementia in the elderly, leading invariably to death, usually within 7–10 years after diagnosis (Khachaturian, 1985). The progressive nature of the neurodegeneration suggests an age-dependent process that ultimately leads to synaptic failure and neuronal damage in cortical areas of the brain essential for memory and other cognitive domains (Isacson et al., 2002). AD not only has devastating effects on the sufferers and their caregivers, but it also has a tremendous socioeconomic impact on families and the health system; a burden which will only increase in the upcoming years as the population of most countries ages (Johnson et al., 2000). In the absence of reliable biomarkers, direct pathologic examination of brain tissue derived from either biopsy or autopsy remains the only definitive method for establishing a diagnosis of AD (O’Brien et al., 2000). The typical macroscopic picture is gross cortical atrophy, whilst microscopically, there is widespread cellular degeneration and diffuse synaptic and neuronal loss, accompanied by reactive gliosis and the presence of the pathological hallmarks of the disease: intracellular neurofibrillary tangles (NFT) and extracellular β-amyloid (Aβ) plaques (Jellinger, 1990, Masters, 2005, Masters and Beyreuther, 2005). Whilst NFT are intraneuronal bundles of paired helical filaments mainly composed of the aggregates of an abnormally phosphorylated form of tau protein, (Jellinger and Bancher, 1998, Michaelis et al., 2002) neuritic plaques consist of dense extracellular aggregates of Aβ, (Masters et al., 1985) surrounded by reactive gliosis and dystrophic neurites. Aβ is a 4 kDa 39–43 amino acid metalloprotein derived from the proteolytic cleavage of the amyloid precursor protein (APP), by β and γ-secretases (Cappai and White, 1999). To date, all available genetic, pathological, biochemical and cellular evidence strongly supports the notion that an imbalance between the production and removal of Aβ leading to its progressive accumulation is central to the pathogenesis of AD (Villemagne et al., 2006). The “Aβcentric theory” (Masters et al., 2006) postulates that Aβ plaque deposition is the primary event in a cascade of effects that lead to neurofibrillary degeneration and dementia (Hardy, 1997), while other hypotheses postulate that Aβ deposition occurs in parallel with other interacting pathological events, as a necessary, but not sufficient, cause of the pathological processes leading to AD dementia (Chetelat, 2013, Pimplikar et al., 2010, Small and Duff, 2008).
While biomarkers play a crucial role in the new diagnostic criteria for AD (McKhann et al., 2011), the clinical diagnosis of AD is still largely based on progressive impairment of memory and decline in at least one other cognitive domain, as well as excluding other conditions that might also present with dementia such as frontotemporal lobar degeneration (FTLD), dementia with Lewy-bodies (DLB), stroke, brain tumour, normal pressure hydrocephalus or depression (Cummings et al., 1998, Larson et al., 1996). A variable period of up to five years of prodromal decline in cognition characterized by a relatively isolated impairment in recent episodic memory that may also be accompanied by impairments of working memory, known as amnestic Mild Cognitive Impairment (MCI), usually precedes the formal diagnosis of AD (Petersen, 2000, Petersen et al., 1999). At this point there is no cure for AD nor proven way to slow the rate of neurodegeneration. Symptomatic treatment with an acetylcholinesterase inhibitor or a glutamatergic moderator provides modest benefit in some patients usually by temporary stabilization rather than a noticeable improvement in memory function (Masters and Beyreuther, 2006).
Section snippets
Aβ imaging in Alzheimer’s disease
The development of PET tracers for Aβ deposition has allowed in vivo assessment of Aβ pathology. Since the first study published more than 10 years ago (Klunk et al., 2004), several hundreds of Aβ PET studies have been performed, improving our knowledge on the topography, timing, propagation, rates of accumulation and covariates of Aβ accumulation in the living Human brain.
On visual inspection, cortical 11C-PiB retention is usually higher in AD than in cognitively intact controls. Quantitative
Aβ deposition in non demented individuals and its relation with cognition
About 25–35% of elderly subjects performing within normal limits on cognitive tests present with high cortical 11C-PiB retention, predominantly in the prefrontal and posterior cingulate/precuneus regions (Aizenstein et al., 2008, Mintun et al., 2006, Mormino et al., 2009, Reiman et al., 2009, Rowe et al., 2010, Rowe et al., 2007, Villemagne et al., 2008b). These findings are in perfect agreement with post mortem reports that ∼25% of non-demented older individuals over the age of 75 have Aβ
Relation of Aβ imaging with other biomarkers
Another rapidly growing area is the exploration of the potential association between Aβ burden as measured by PET, and CSF biomarkers of Aβ deposition or neuroimaging biomarkers of neurodegeneration (Albert et al., 2011, Blennow et al., 2007, Clark et al., 2008, de Leon et al., 2006, McKhann et al., 2011, Morris et al., 2005, Shaw et al., 2007, Storandt et al., 2012, Sunderland et al., 2005, Thal et al., 2006, Wahlund and Blennow, 2003, Jack et al., 2010, Jack et al., 2008a).
Aβ imaging in other neurodegenerative conditions
Aβ imaging in a wide spectrum of neurodegenerative conditions has allowed the assessment of the presence or absence in these different conditions. Although slightly lower than in AD, similar patterns of 11C-PiB retention are usually observed in DLB (Gomperts et al., 2008, Maetzler et al., 2009, Rowe et al., 2007). Cortical 11C-PiB retention, specifically in occipital areas, is also higher in subjects diagnosed with CAA (Johnson et al., 2007), while there is usually no cortical 11C-PiB retention
Aβ imaging in the development of disease-specific therapeutics
Aβ imaging with PET is also contributing to the development of more effective therapies by allowing better selection of patients for anti-Aβ therapy trials and providing a means to measure their impact on Aβ burden (Ostrowitzki et al., 2011, Rinne et al., 2010). While these studies represent one of the principal applications of Aβ imaging, they have brought forward an issue that needs to be addressed, namely that the advent of novel Aβ tracers with differing pharmacological and pharmacokinetics
CODA
The clinical diagnosis of AD is typically based on progressive cognitive impairments whilst excluding other diseases. Clinical diagnosis of sporadic disease is challenging, however, often presenting mild and non-specific symptoms attributable to diverse and overlapping pathology presenting similar phenotypes. Overall, the accuracy of clinical diagnosis of AD compared to neuropathological examination ranges between 70 and 90% (Beach et al., 2012). While clinical criteria, together with current
Acknowledgements
This work was supported in part by grant 1071430 of the National Health and Medical Research Council (NHMRC) of Australia. VLV is supported by the NHMRC through a Senior Research Fellowship. The Institut National de la Santé et de la Recherche Médicale (Inserm), the Fondation Plan Alzheimer (Alzheimer Plan 2008-2012), Programme Hospitalier de Recherche Clinique (PHRC National 2011, complément PHRC 2012), Agence Nationale de la Recherche (ANR LONGVIE 2007), and Région Basse Normandie also
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