Abstract
BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.
Highlights
The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease
The follow-up cohort comprised of thirty-eight of the mild cognitive impairment (MCI) cases which had longitudinal PET with 11C-Pittsburgh compound B (PiB) and PK11195, and 22 of these cases had additional longitudinal PET with flortaucipir
In summary, we have investigated at baseline and at a 2year follow-up the relationship between inflammation levels and the loads of Aβ and tau across a group of MCI cases, the majority of whom had prodromal Alzheimer’s disease
Summary
The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. The pathological hallmarks of AD are the presence of extracellular beta-amyloid (Aβ) fibrillar plaques and intraneuronal neurofibrillary tau tangles (NFT). Brain slices of AD cases show that both extracellular Aβ plaques and neurons containing NFTs are surrounded by activated microglia, the intrinsic cellular immune inflammatory response to brain injury [1, 2]. Activated microglia can exhibit a protective or neurotoxic phenotype depending on their environment. The neurotoxic phenotype releases cytokines such as TNFα and IL1β which can cause or contribute to tissue damage and disease pathology so driving disease progression [4]
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