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), idiopathic normal pressure hydrocephalus (iNPH), 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. They are also present in platelets, vascular endothelial cells, and in circulation. 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).

Higher concentrations of circulating APP and Aβ are associated with higher cardiovascular risk. Amyloid β is present in atherosclerotic plaques, possibly specifically in vulnerable plaques, providing a target for Aβ-PET (Hellberg et al., 2019).

Muscle inflammation may lead to fibrosis. Some idiopathic inflammatory myopathies can be detected and differentiated using β-amyloid PET.

PET radioligands

Several PET radioligands have been developed for imaging amyloid-β plaques, including [11C]PIB, [18F]flutemetamol, [18F]florbetapir ([18F]AV-45, Amyvid), [18F]florbetaben ([18F]BAY94-9172), [18F]NAV4694 (AZD4694), and [18F]FACT. [18F]FDDNP is a radioligand 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 in areas of white matter hyper-intensities (WMH) (Goodheart et al., 2015; Glodzik et al., 2015). The uptake of amyloid-β PET radioligands represents binding to both fibrillar and non-fibrillar Aβ (Biechele et al., 2022).

Flores et al (2023) reported that high level of skull uptake was seen in ∼16% of [18F]florbetabir PET scans; this was not caused only by defluorination of the radioligand, because increased [11C]PIB uptake in skull was seen in these cases, too. Skull uptake was more common on women, and lower skull density was related to higher [18F]florbetabir uptake. Skull uptake impacted quantitative estimates in temporal regions, and the resulting sex and age difference should be addressed in relevant PET studies (Flores et al., 2023).

Several data-driven methods for measuring Aβ burden, including centiloid scaling, amyloid load, Aβ-PET pathology accumulation index (amyloid index), and Amyloid Pattern Similarity Score (AMPSS) (Bollack et al., 2023):

Centiloid scaling

Clinical brain studies with different Aβ radioligands 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 radioligands, 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.

The improved centiloid scale (CLNMF) uses non-negative matrix factorisation to reduce the effects of tracer-related changes in longitudinal studies (Bourgeat et al., 2021).

rPOP pipeline provides Aβ PET image warping and quantification when anatomical images are not available (Iaccarino et al., 2022).

AβL

Global Aβ burden (amyloid load) in human brain can be quantified from static PET scan as a single parameter AβL, which can be calculated using automated algorithm AmyloidIQ. AβL is calculated by modelling an SUVR image as a linear combination of two canonic images: K and NS. AβL is the scaling factor of the carrying capacity canonic image K (Whittington et al., 2018 and 2019). The method has also been applied to calculation of tau protein load (Whittington et al., 2021).


See also:


Literature

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Updated at: 2023-09-15
Created at: 2015-08-17
Written by: Vesa Oikonen