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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: Cambridge Trust Vice-Chancellor's Award Award for Medical Sciences, Funder: Fitzwilliam College scholarship, Funder: Association of British Neurologists, Patrick Berthoud Charitable Trust, Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson's disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson's disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity. More broadly, these results reconcile emerging predictive processing accounts of the role of noradrenaline in goal-directed behaviour with the clinical symptom of apathy and its potential pharmacological treatment.

Funder: Cambridge Commonwealth, European and International Trust; Id: http://dx.doi.org/10.13039/501100003343, Funder: China Scholarship Council; Id: http://dx.doi.org/10.13039/501100004543, Brain aging is a complex process that requires a multimodal approach. Neuroimaging can provide insights into brain morphology, functional organization, and vascular dynamics. However, most neuroimaging studies of aging have focused on each imaging modality separately, limiting the understanding of interrelations between processes identified by different modalities and their relevance to cognitive decline in aging. Here, we used a data-driven multimodal approach, linked independent component analysis (ICA), to jointly analyze magnetic resonance imaging (MRI) of grey matter volume, cerebrovascular, and functional network topographies in relation to measures of fluid intelligence. Neuroimaging and cognitive data from the Cambridge Centre for Ageing and Neuroscience study were used, with healthy participants aged 18-88 years (main dataset n = 215 and secondary dataset n = 433). Using linked ICA, functional network activities were characterized in independent components but not captured in the same component as structural and cerebrovascular patterns. Split-sample (n = 108/107) and out-of-sample (n = 433) validation analyses using linked ICA were also performed. Global grey matter volume with regional cerebrovascular changes and the right frontoparietal network activity were correlated with age-related and individual differences in fluid intelligence. This study presents the insights from linked ICA to bring together measurements from multiple imaging modalities, with independent and additive information. We propose that integrating multiple neuroimaging modalities allows better characterization of brain pattern variability and changes associated with healthy aging.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods: N=42 patients with probable PSP and N=39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N=9 patients who also had post-mortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: N=10 patients were classified in stage I/II, N=26 in stage III/IV, N=5 in stage V/VI, while N=1 was not classifiable. An explorative sub-staging identified N=2 patients in stage I, N=8 in stage II, N=9 in stage III, N=17 in stage IV and N=5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion: 18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18–88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging.

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n=708, age 18-88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging.

Cross-sectional population-based observational study (Cam-CAN cohort) investigating the impact of locus coeruleus integrity on response inhibition in older healthy adults.

Response inhibition is an important function underpinning the appropriate control of everyday behavior. The inability to prevent or stop inappropriate responses is a symptom in many neurological and psychiatric disorders (Passamonti et al., 2018). There is converging evidence from animal models (Eagle and Baunez, 2010; Bari et al., 2011; Bari and Robbins, 2013) to human psychopharmacology (Chamberlain, 2006; Robinson et al., 2008; Chamberlain et al., 2009), showing that the noradrenergic system facilitates the inhibitory processes underpinning rapid action cancellation. Specific cortical areas are also implicated in response inhibition, including the inferior frontal gyrus (rIFG) and pre-supplementary motor area (pSMA; Chambers et al., 2006; Frank et al., 2007; Duann et al., 2009; Forstmann et al., 2012; Aron et al., 2014; Rae et al., 2015). Cerebral noradrenergic innervation arises from the locus coeruleus, in the brainstem. By exploiting the accumulation of iron-rich neuromelanin, magnetization-transfer sensitive magnetic resonance imaging sequences can be used to image the locus coeruleus (Betts et al 2019; Ye et al 2020). Such studies have associated locus coeruleus signal intensity with diverse cognitive function in health (Liu et al., 2020) and disease (O’Callaghan et al., 2020). We hypothesize that variations in the locus coeruleus integrity (as quantified by changes in signal intensity using a magnetization transfer weighted MRI sequence) reflect variation in changes in noradrenergic-dependent processes of inhibitory control. We focus on healthy adults over the age of 50 years, because of the robustness of locus coeruleus imaging signals in older adults (Zecca et al., 2004). Variation in performance might also be expressed relative to the degree to which a participant has “successfully aged” cognitively and maintained cognitive ability on par with early adult life - in contrast to “unsuccessfully aged” cognitively with decline in cognitive ability. To estimate this change in cognitive ability, one can compare current fluid intelligence to crystallized intelligence. This difference approximates the degree to which a participant has sustained or changed their cognitive ability (McDonough et al., 2016). We predict that “unsuccessful ageing” (with lower fluid than crystallised intelligence) is accompanied by reduced locus coeruleus signal and poor inhibitory control. There is inconsistent evidence for an association between cognitive functions and locus coeruleus subregions. In Parkinson’s disease, where the integrity of locus coeruleus predicts the improvement of response inhibition following noradrenergic treatment, the caudal subregion of the locus coeruleus is more impaired compared to central and rostral subregions (O’Callaghan et al., 2020). In healthy ageing, however, age-related neural loss predominates in the rostral locus coeruleus (Betts et al., 2017) and has been associated with decline in cognitive functions (Dahl et al., 2019). Here, we will estimate the association between the integrity of rostral, central, and caudal locus coeruleus subregions with response inhibition performance. In this cross-sectional study we will use neuromelanin-sensitive MRI to investigate the relationship between locus coeruleus integrity and inhibitory control in cognitively normal healthy adults from the Cambridge Centre for Ageing and Neuroscience cohort (Cam-CAN; Shafto et al., 2014), an open-access, population-based dataset. We will focus on a subset of the cohort where inhibitory control was assessed with a Stop-Signal Task (SST), in which participants perform a reaction time task but must occasionally cancel an action after it has been initiated. Our study has five main differences with respect to an earlier analysis of the Cam-CAN cohort (Liu et al., 2019): (i) we will extract the locus coeruleus signal in an atlas-based segmentation pipeline using a probabilistic atlas generated with high-resolution 7T images, which provides unbiased estimation, with superior accuracy and reliability compared to manual and semi-automatic segmentation approaches (Ye et al., 2020). This is especially important with the low resolution of the Cam-CAN MRI MT-weighted images, that limits the precision of manual segmentation approaches. (ii) we will focus on healthy adults aged above 50 years. Neuromelanin accumulates with age (Zecca et al., 2004). Below 50 years the locus coeruleus neurons may not yet be sufficiently pigmented to allow reliable inference on structural integrity by neuromelanin-sensitive MRI. (iii) We will adopt recent consensus recommendations (Verbruggen et al.,2019) to estimate individual efficiency of response inhibition in terms of the stop-signal reaction times (SSRT), and use a hierarchical Bayesian estimation of an ex-Gaussian race model (Matzke et al., 2013). (iv) To assess the specificity of the predicted relationship between locus coeruleus integrity and response inhibition, we will examine whether changes in inhibitory control are related to changes in cortical functional connectivity as well as to regional variations in grey matter volume. For this purpose, we will extract fMRI functional connectivity and voxel-based morphometry measures from functional masks of the preSMA and rIFG regions defined in a previous fMRI study employing a stop-signal task (Tsvetanov et al. 2018). (v) We will adopt age-related changes in participants’ fluid intelligence relative to fluid intelligence in their early adult life (as reflected by crystallized intelligence) as a measure of successful versus unsuccessful aging (McDonough et al., 2016).

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

There is an urgent need for a better understanding of the pathophysiology of cognitive impairment in syndromes associated with frontotemporal lobar degeneration. Here, we used magnetic resonance spectroscopy to quantify metabolite deficits in sixty patients with a clinical syndrome associated with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia n = 11, progressive supranuclear palsy n = 26, corticobasal syndrome n = 11, primary progressive aphasias n = 12), and 38 age- and sex-matched healthy controls. We measured nine metabolites in the right inferior frontal gyrus, superior temporal gyrus and right primary visual cortex. Metabolite concentrations were corrected for age, sex, and partial volume then compared with cognitive and behavioral measures using canonical correlation analysis. Metabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64) = 1.73, p < 0.001, corrected for age, sex, and atrophy within the voxel). N-acetyl aspartate and glutamate concentrations were reduced in the right prefrontal cortex in behavioral variant frontotemporal dementia and progressive supranuclear palsy, even after partial volume correction. The reduction of these metabolites was associated with executive dysfunction and behavioral impairment (canonical correlation analysis R = 0.85, p < 0.001).