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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: MRC Cognition and Brain Sciences Unit, Funder: Cambridge Centre for Parkinson-Plus, Funder: National Institute for Health and Care Research Cambridge Clinical Research Facility, Funder: Bill & Melinda Gates Foundation, Verbal fluency is widely used as a clinical test, but its utility in differentiating between neurodegenerative dementias and progressive aphasias, and from healthy controls, remains unclear. We assessed whether various measures of fluency performance could differentiate between Alzheimer's disease, behavioural variant of frontotemporal dementia, non-fluent and semantic variants of primary progressive aphasia, progressive supranuclear palsy, corticobasal syndrome and healthy controls. Category and letter fluency tasks were administered to 33 controls and 139 patients at their baseline clinical visit. We assessed group differences for total number of words produced, psycholinguistic word properties and associations between production order and exemplar psycholinguistic properties. Receiver operating characteristic curves determined which measure could best discriminate patient groups and controls. The total word count distinguished controls from all patient groups, but neither this measure nor the word properties differentiated the patient groups. Receiver operating characteristic curves revealed that, when comparing controls to patients, the strongest discriminators were total word count followed by word frequency. Word frequency was the strongest discriminator for semantic variant of primary progressive aphasia versus other groups. Fluency word counts were associated with global severity as measured by Addenbrooke's Cognitive Examination Revised. Verbal fluency is an efficient test for assessing global brain-cognitive health but has limited utility in differentiating between cognitively and anatomically disparate patient groups. This outcome is consistent with the fact that verbal fluency requires many different aspects of higher cognition and language.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.