Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Abstract

Abstractβ-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease

“…These findings are in line with in vivo observations that point to associations between microglial activation and tau pathology, and with recent large GWAS studies underscoring the interaction between microglial, Aβ and tau-linked pathways [ 62 , 63 ]. In vivo PET studies also show stronger and more frequent association between microglial activation (measured with TSPO PET) and regional tau (measured with tau PET), than with regional Aβ (measured with amyloid PET) [ 64 ]. Here, they also found a positive correlation between CSF sTREM2 and tau PET in 4-repeat tau patients, but no correlation between CSF sTREM2 and amyloid PET [ 64 ].…”

“…In vivo PET studies also show stronger and more frequent association between microglial activation (measured with TSPO PET) and regional tau (measured with tau PET), than with regional Aβ (measured with amyloid PET) [ 64 ]. Here, they also found a positive correlation between CSF sTREM2 and tau PET in 4-repeat tau patients, but no correlation between CSF sTREM2 and amyloid PET [ 64 ]. Moreover, others have also reported elevated concentrations of CSF glial activation markers in SNAP cases (A−/T+) [ 65 – 67 ].…”

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

“…125 Indeed, neuroinflammation and microglial activation are consistent features across neurodegenerative diseases, including AD, [126][127][128] PD, 86,129 HD, 130,131 FTD, 91,132 and ALS. 89,[133][134][135] Numerous studies have reported that misfolded proteins and protein aggregates, including tau, [136][137][138][139] Aβ, 138,140 α-synuclein, [141][142][143][144] mutant huntingtin, 145 TDP-43, 132,146 superoxide dismutase 1 (SOD1), [147][148][149] and fused in sarcoma (FUS) 150 induce microglial activation and neuroinflammation. Autophagy deficiency induced by protein aggregates has been shown to be a major driver of microglial activation (Fig.…”

The novel imaging methods in diagnosis and assessment of cerebrovascular diseases: an overview

“…It can also be used to assess the viability of brain tissue in regions at risk of infarction before interventional procedures such as carotid endarterectomy. It can also be utilized for the detection and characterization of cerebral amyloid deposition in disorders like Alzheimer’s disease ( 89 , 90 ). The use of specific amyloid-targeting tracers allows for the quantification of amyloid plaques in the brain, aiding in diagnosis and monitoring disease progression ( 91 , 92 ).…”