Neuroimaging Biomarkers for Alzheimer's Disease
About Alzheimer's Disease
With an aging population and a prevalence of about 10% in the population older than 65 years old (Alzheimer’s Association, 2013), Alzheimer's disease is a severe public health issue and the most common cause of dementia. Difficulties remembering names and recent events, apathy, and depression are often early clinical symptoms. Later on, the symptoms include impaired judgment, disorientation, confusion, behavior changes, and difficulty speaking, swallowing, and walking (Alzheimer’s Association, 2013).
Amyloid and Tau Imaging
The disease is a neurodegenerative one, characterized by the accumulation of insoluble protein aggregates such as amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau in the brain, resulting in brain atrophy and progressive loss of cognitive function (Nordberg, 2015). However, the origin and mechanisms of the disease are not totally understood. The amyloid hypothesis posits that an abnormal accumulation of the beta-amyloid protein in the brain is the primary influence in Alzheimer's disease pathogenesis, the rest of the process, including tangle deposition and neurodegeneration, being considered as downstream effects of an imbalance between Aβ production and clearance.
Positron emission tomography (PET) radioligand 11C-Pittsburgh compound B (PiB) has been developed more than a decade ago. It binds to fibrillar amyloid, the form of amyloid that is found in plaques, making it possible to image, in vivo, the accumulation of the amyloid protein in the brain (Klunk et al., 2004). The advent of new 18F-labeled ligands (Florbetapir, Flutemetamol, and Florbetaben), with a longer half-life, have made clinical amyloid imaging possible (Petrella, 2013). The accumulation of amyloid in the brain has been identified as an early biomarker of Alzheimer’s disease (Bateman et al., 2012). However, the interpretation of the examination, and especially of the cut-off points, is still debated (Murray et al., 2015). At this stage, its use in clinical practice is still limited because of practical, medical, and ethical considerations (Johnson et al., 2013).
In addition, the amyloid hypothesis is debated, and several recent clinical trials of anti-amyloid drugs have failed (Grainger, 2014; Nordberg, 2015), casting doubt on the usefulness of clearing amyloid at the late stage of the disease, when the brain is already severely damaged (Nordberg, 2015). A recent study identified the accumulation of the tau protein as the main driver of cognitive decline and memory loss (Murray et al., 2015), suggesting that amyloid may not be the main culprit.
As for beta-amyloid, PET tracers have been developed that specifically bind to the tau protein. However, because of Idiosyncrasies of the tau aggregation and because of a more complex tracer design, in vivo tau imaging is still limited to research purposes (Villemagne et al., 2015).
Structural Magnetic Resonance Imaging
Neuroimaging biomarkers use brain imaging techniques in order to image the morphology (e.g., MRI), the function (e.g. fMRI), the microenvironment (e.g., perfusion MRI), the metabolism (e.g., PET-FDG), or the molecular content (e.g., MR spectroscopy) of the brain and its lesions (Boland. 2014).
Neuroimaging biomarkers of Alzheimer's Disease include measurement of beta-amyloid deposition with amyloid PET, of brain metabolism with FDG-PET, of brain and hippocampal atrophy with MRI (Bateman et al. 2012). Read more about neuroimaging biomarkers for Alzheimer's disease.
Fluorodeoxyglucose-Positron Emission Tomography
A progressive reduction in glucose metabolism, as measured by 18F-FDG PET, has been reported to occur years in advance of clinical symptoms in patients with Alzheimer’s disease. This decrease is especially apparent in the parieto-temporal, frontal and posterior cingulate cortices, and is correlated with the severity of dementia. It is, therefore, a good biomarker to monitor the clinical progression of Alzheimer’s disease (Nordberg et al., 2010).
Functional Magnetic Resonance Imaging
Functional MRI and, especially, resting-state fMRI, in which the cooperation of the patient is not necessary, are promising tools in the diagnosis and the follow-up of patients with Alzheimer's disease (Hampel et al., 2011). However, their use is still limited to research studies. Other MRI-based techniques, such as perfusion imaging or arterial spin labeling (ASL) also show promise as diagnostic markers, but have not yet been validated as clinical biomarkers (Frisoni et al., 2010).
Time Course
The curves of the disease’s progression show that amyloid deposition in the brain, decreased concentration of Aβ in the cerebrospinal fluid (CSF), tau-mediated neuronal injury, increased concentration of the tau protein in the CSF, brain atrophy, and decreased glucose metabolism can be observed at least one decade before the onset of the symptoms (Jack et al., 2010; Bateman et al., 2012; Petrella, 2013).
The diagnosis of Alzheimer’s disease, and especially of the progression from its pre-symptomatic phase, to its prodromal phase (mild cognitive impairment - MCI) to its clinical phase (dementia) is challenging. An international working group (IWG-2) has recently updated the diagnosis criteria for the disease (Dubois et al., 2014). In addition to specific clinical phenotype (i.e. MCI or dementia), decreased Aβ in the CSF, increased tau in the CSF and/or increased tracer retention on amyloid PET are defined as diagnostic biomarkers. Volumetric MRI and FDG-PET can serve as biomarkers of the disease’s progression (Dubois et al., 2014).
These early biomarkers pave the way for early detection of the disease and, potentially, for better prevention strategies (Nordberg, 2015). The development of new treatments targeting the pre-symptomatic stage of the disease is one of the most promising avenues in order to manage this disease, as well as avoid a pandemic in the aging population.
Differential Diagnosis with Non-Alzheimer's Causes of Dementia
Alzheimer’s disease is not the only cause of dementia. Distinctive features, such as strategic infarct or extensive white matter changes (in vascular dementia), focal frontal or temporal atrophy (in frontotemporal degeneration), dementia with preserved medial temporal lobes (in dementia with Lewy bodies), atrophy of putamen, middle cerebellar peduncle, pons and cerebellum (in multiple system atrophy), or high signal in the basal ganglia or in the pulvinar thalamic nuclei on FLAIR images, as well as changes in the striatum or cortical ribbon on diffusion images (in Creutzfeldt–Jakob disease) can help to discriminate Alzheimer’s disease from other causes of dementia (Frisoni et al., 2010).
References
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