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. 2020 May 6;17(1):151.
doi: 10.1186/s12974-020-01820-6.

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

Rola Ismail  1 , Peter Parbo  2 , Lasse Stensvig Madsen  3 , Allan K Hansen  2 , Kim V Hansen  2 , Jeppe L Schaldemose  3 , Pernille L Kjeldsen  3 , Morten G Stokholm  2 , Hanne Gottrup  4 , Simon F Eskildsen  5 , David J Brooks  3   6   7
Affiliations

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

Rola Ismail et al. J Neuroinflammation. .

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 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.

Results: Those 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.

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.

Keywords: Alzheimer; Flortaucipir; MCI; Microglia; Neuroinflammation; PET; PK11195; PiB; Tau; β-amyloid.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Cortical surface maps of mean tracer uptake and changes. a Cortical surface maps of mean PiB (upper), PK (middle) and flortaucipir (lower row) uptake for the high PiB MCI subjects at baseline and after 2 years follow-up. On the right, results of a paired t test between baseline and follow-up show increased amyloid in all cortical association areas, increased tau in frontal and occipital cortical areas, and reduced inflammation in fronto-temporal cortical regions after 2 years. b Mean PiB (upper) and PK (lower) uptake for the low PiB subjects at baseline and after 2 years follow-up. The results of a paired t test show small areas of increased amyloid, but no changes in inflammation levels over 2 years (P < 0.05; cluster FWE rate, P < 0.05)
Fig. 2
Fig. 2
Amyloid and inflammation correlations in the low PiB group. Regions where uptake of PiB and PK are positively correlated in the low PiB group at baseline and after 2 years. a Across the 15 low PiB MCI subjects. b Baseline and follow-up correlation for the 7 low PiB subjects who showed increasing PiB signal over 2 years—three crossing the 1.5 threshold. c Baseline and follow-up correlation for 8 cases in the low PiB subgroup who showed no increase in PiB uptake over 2 years (P < 0.05; cluster FWE rate, P < 0.05)
Fig. 3
Fig. 3
Amyloid and inflammation level correlation maps. Regions where levels of PiB and PK uptake were positively correlated a across high PiB MCI subject at baseline and after 2 years of follow-up. b Baseline and follow-up correlations after correction for tau influence across 22 subjects who had all three tracers. P < 0.05; cluster FWE rate, P < 0.05. Tau load influences the correlation between amyloid and inflammation levels
Fig. 4
Fig. 4
Tau and inflammation correlation maps in 13 high PiB MCIs. Positive correlation between flortaucipir and PK uptake. a Baseline and follow-up correlation in 13 high PiB MCI subjects. b baseline and follow-up correlation after correction for amyloid influence (P < 0.05; cluster FWE rate, P < 0.05). Amyloid load did not influence the correlation between tau and inflammation levels
Fig. 5
Fig. 5
Tau and amyloid correlation maps in 13 high PiB subjects. a Positive correlation between PiB and flortaucipir levels in 13 high PiB subjects at baseline and after 2 years of follow-up. b The above correlation after correction for inflammation (P < 0.05; cluster FWE rate, P < 0.05). Inflammation did not influence the correlation between tau and amyloid levels
See this image and copyright information in PMC

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