PET imaging of β-amyloid
Amyloid β (Aβ) is a peptide fragment (usually 39-42 amino acids) of the amyloid precursor protein (APP), which is a type-1 transmembrane protein. Aβ is cleaved from APP by β and γ-secretases, first at the NH2 terminus of Aβ by β-secretase, and then at the carboxylic acid terminus by γ-secretase, releasing Aβ from the rest of the APP into the extracellular space. Amyloid β is soluble and does not seem to possess a unique tertiary fold, but when abundant, can aggregate into fibrillar β-pleated sheet structure. Aβ42 is especially prone to self-aggregation. Amyloidosis is characterized by extracellular deposits of insoluble amyloid fibrils, leading to progressive dysfunction of the affected organ(s).
The extracellular Aβ aggregates are the main component of senile plaques in the brains of Alzheimer’s disease (AD) patients. Amyloid plaques are also found in other neurological disorders, including Parkinson’s disease, dementia with Lewy bodies, cerebral amyloid angiopathy (CAA), and traumatic brain injury (TBI). The other characteristic protein depots in AD, intracellular neurofibrillary tangles, are composed of filaments of hyperphosphorylated tau protein.
APP and its two homologs amyloid-like proteins 1 and 2 (APLP1 and APLP2) have important functions in growth of neuron dendrites and axons, and synaptogenesis.
The CSF concentrations of Aβ42 and intermediate APP proteolysis products α-APP and β-APP are reduced in RR and PR forms of multiple sclerosis. Proteolytic processing of APP is upregulated in damaged axons, leading to accumulation of β-APP. Aβ can trigger microglial activation, and its levels are higher than normal in MS lesions. A component of myelin, MBP, inhibits Aβ fibril assembly.
Cardiac amyloidosis is caused by deposition of “amyloid” proteins (not Aβ) in the heart, leading to hypertrophy, diastolic dysfunction, and heart failure. Despite the different origins and contents of the protein deposits, cardiac amyloidosis is also being investigated as a potential target for β-amyloid PET (Antoni et al., 2013; Kero et al., 2016).
Several PET tracers have been developed for imaging amyloid-β plaques, including [11C]PIB, [18F]flutemetamol, [18F]florbetapir ([18F]AV-45), [18F]florbetaben ([18F]BAY94-9172), [18F]NAV4694 (AZD4694), and [18F]FACT. [18F]FDDNP is a tracer that mainly binds Aβ but also to the neurofibrillary tangles.
Thioflavin T derivatives, such as [11C]PIB, [18F]florbetaben, [18F]florbetabir, and [18F]NAV4694, are not specific to fibrillar amyloid-β but have affinity to all molecular structures containing β-pleated sheets, including myelin. [11C]PIB binding is reduced also in areas of white matter hyperintensities (WMH) (Goodheart et al., 2015; Glodzik et al., 2015).
Clinical brain studies with different Aβ tracers can be converted to the same quantitative scale using centiloid scale method (Klunk et al., 2015; Rowe et al., 2016): The same young healthy subjects and typical AD subjects must be scanned twice with the two tracers, usually [11C]PIB as the standard. PET images are transformed into reference brain atlas space based on anatomical MR or CT scans. From each a subject a ratio between cerebral neocortex and whole cerebellum is calculated. A linear transformation is then used to scale the mean of the young healthy subjects to a centiloid value of 0, and the mean of AD subjects to centiloid value of 100.
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Updated at: 2019-02-20
Created at: 2015-08-17
Written by: Vesa Oikonen