Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia

Author:

Malpetti Maura1ORCID,Cope Thomas E12,Street Duncan1,Jones P Simon1,Hezemans Frank H12,Mak Elijah3ORCID,Tsvetanov Kamen A1,Rittman Timothy1ORCID,Bevan-Jones W Richard3,Patterson Karalyn12ORCID,Passamonti Luca1,Fryer Tim D14,Hong Young T14,Aigbirhio Franklin I14,O’Brien John T3ORCID,Rowe James B12

Affiliation:

1. Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK

2. Medical Research Council Cognition and Brain Sciences Unit , Cambridge CB2 7EF , UK

3. Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ , UK

4. Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 0QQ , UK

Abstract

Abstract Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (−0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Funder

Wellcome trust

Race Against Dementia Alzheimer’s Research

Cambridge University Centre

National Institute for Health Research

Cambridge Biomedical Research Centre

Medical Research Council

Alzheimer’s Society

Evelyn Trust

Guarantors of Brain

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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