Abstract Background Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4‐repeat (4R) tauopathies and its role in accelerating disease progression. Objective We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. Methods We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F‐PI‐2620 PET and 18F‐GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3‐T resting‐state functional magnetic resonance imaging template derived from age‐matched healthy elderly controls. Results In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO‐PET across brain regions that are functionally connected to each other ( β = 0.414, P &lt; 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient‐specific tau epicenters ( β = −0.594, P &lt; 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F‐PI‐2620 PET. Conclusions Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease‐modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroinflammation Parallels 18F‐PI‐2620 Positron Emission Tomography Patterns in Primary 4‐Repeat Tauopathies