The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer’s disease: a longitudinal PET study

Abstract

Background: 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. Methods: Forty-three subjects with mild cognitive impairment (MCI) had serial 11 C-PK11195 PET over 2 years to measure inflammation changes, and 11 C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18 F-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. Results: Those MCI subjects with high 11 C-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 11 C-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 11 C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11 C-PiB and 18 F-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. Conclusions: Our 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.

The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease

“…Using transgenic PS1-APP mice, an established model of AD, Hickman et al demonstrated that the continuous production of proinflammatory cytokines reduces the expression of the phagocytosis receptors expressed in microglia and alters their functions ( 109 ). The sustained activation of microglia cells has been shown to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of AD ( 110 , 111 ). Indeed, the prolonged activation results in an impaired clearance of Aβ and increased accumulation in the CNS ( 112 ).…”

Alteration of Payload in Extracellular Vesicles by Crosstalk With Mesenchymal Stem Cells From Different Origin

“…It has been reported that APBA2 is involved in the MAPK signaling pathway and it alters cell viability, migration, and invasion [52]. However, the relationship between amyloid activity and neuroin ammation has been reported [54]; the role of in ammation in auditory hearing loss relief should be explored in further studies.…”

Imaging Biomarkers for Monitoring the Inflammatory Redox Landscape in the Brain

“…R -[ 11 C]PK11195, combined with tracers for Aβ and tau protein, revealed a biphasic neuroinflammation pattern in AD patients: initially, the R -[ 11 C]PK11195 signal was high in subjects bearing low Aβ levels and mild cognitive impairment (MCI) but, eventually, R -[ 11 C]PK11195 levels decreased as Aβ loads rose to pathological levels. At this later phase, the tau protein levels increased, and prompted the second wave of microglial activation, reaching the pathological phenotype of concomitant high levels of Aβ and tau protein and cognitive deterioration [ 193 ]. Similarly, the signal of the second-generation TSPO tracer [ 11 C]PBR28 was elevated in more than 50 MCI patients, potentially indicating a protective microglial activation at early AD [ 194 ].…”