P Simon Jones

University of Cambridge

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

James B. Rowe

MRC Cognition and Brain Sciences Unit

John T. O’Brien

Bedford Institute of Oceanography

Franklin I. Aigbirhio

University of Cambridge

Maura Malpetti

University of Cambridge

Tim D. Fryer

University of Cambridge

Timothy Rittman

University of Cambridge

Luca Passamonti

University of Cambridge

Young T. Hong

University of Cambridge

W Richard Bevan‐Jones

University of Cambridge

Kamen A. Tsvetanov

University of Cambridge

Cooperative Institutions

University of Cambridge

University College London

Cambridge University Hospitals NHS Foundation Trust

MRC Cognition and Brain Sciences Unit

National Hospital for Neurology and Neurosurgery

Medical Research Council

Ludwig-Maximilians-Universität München

Addenbrooke's Hospital

Munich Cluster for Systems Neurology

Universitat de Barcelona

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Asymmetrical atrophy of thalamic subnuclei in Alzheimer's disease and amyloid‐positive mild cognitive impairment is associated with key clinical features

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring (2019)

Audrey Low Elijah Mak Maura Malpetti Leonidas Chouliaras Nicolas Nicastro

Although widespread cortical asymmetries have been identified in Alzheimer's disease (AD), thalamic asymmetries and their relevance to clinical severity in AD remain unclear.Lateralization indices were computed for individual thalamic subnuclei of 65 participants (33 healthy controls, 14 amyloid-positive patients with mild cognitive impairment, and 18 patients with AD dementia). We compared lateralization indices across diagnostic groups and correlated them with clinical measures.Although overall asymmetry of the thalamus did not differ between groups, greater leftward lateralization of atrophy in the ventral nuclei was demonstrated in AD, compared with controls and amyloid-positive mild cognitive impairment. Increased posterior ventrolateral and ventromedial nuclei asymmetry were associated with worse cognitive dysfunction, informant-reported neuropsychiatric symptoms, and functional ability.Leftward ventral thalamic atrophy was associated with disease severity in AD. Our findings suggest the clinically relevant involvement of thalamic nuclei in the pathophysiology of AD.

10.1016/j.dadm.2019.08.001

Cite

Citations (36)

Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Luca Passamonti Kamen A. Tsvetanov P Simon Jones W Richard Bevan‐Jones Robert M. Arnold

Abstract Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer’s disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [ 11 C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (13 females/15 males) with clinical diagnosis of probable Alzheimer’s disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 females/6 males). Source-based ‘inflammetry’ was used to extract principal components of [ 11 C]PK11195 PET signal variance across all participants. rs-fMRI data were pre-processed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal co-variance between neuroinflammation and brain connectivity profiles, in relation to group and cognitive status. Patients showed significantly higher [ 11 C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [ 11 C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits. Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer’s disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia. Significance Statement Neuroinflammation is an important aspect of Alzheimer’s disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses; and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

Cognitive Decline

10.1101/532291

Cite

Citations (10)

The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

Psychophysiology (2020)

Kamen A. Tsvetanov Richard N. Henson P Simon Jones Henk J. M. M. Mutsaerts Delia Fuhrmann

Abstract Accurate identification of brain function is necessary to understand neurocognitive aging, and thereby promote health and well‐being. Many studies of neurocognitive aging have investigated brain function with the blood‐oxygen level‐dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is, therefore, essential to distinguish the age effects on vascular versus neural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable, and robust means to calibrate vascular responsivity, as an alternative to breath‐holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age‐related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health (CVH) and cerebrovascular function, are insufficient when used alone to fully explain age‐related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population‐based, lifespan Cam‐CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age differences in RSFA, after controlling for CVH. The results were consistent between voxel‐level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterize neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging.

Neurocognitive

Blood-oxygen-level dependent

10.1111/psyp.13714

Cite

Citations (69)

O4-04-05: MICROGLIAL ACTIVATION AND TAU BURDEN PREDICT COGNITIVE DECLINE IN ALZHEIMER'S DISEASE

Alzheimer s & Dementia (2019)

Maura Malpetti Luca Passamonti Rogier Kievit P Simon Jones Kamen A. Tsvetanov

Neurodegeneration, tau pathology, and neuroinflammation are key etiopathogenic processes of Alzheimer's disease (AD). Understanding whether these features predict cognitive decline in AD is crucial to developing prognostic measures. We studied the independent prognostic value of atrophy (structural MRI), tau burden ([18F]AV-1451 PET), and neuroinflammation ([11C]PK-11195 PET) in predicting longitudinal cognitive decline in patients with AD dementia, and amyloid positive Mild Cognitive Impairment (MCI+). 29 healthy controls (HC) and 26 patients with AD pathology (12 AD and 14 MCI+) underwent a cross-sectional assessment with structural MRI, dynamic [11C]PK-11195, and [18F]AV-1451 PET imaging as part of the NIMROD study (NeuroImaging of MemoRy and Other related Disorders). An annual cognitive follow-up (using the Revised Addenbrooke's Cognitive Examination (ACE-R)) was performed for two years. Regional grey matter volumes were derived from structural MRI in AD-specific regions, while [18F]AV-1451 and [11C]PK-11195 non-displaceable specific binding were calculated for these volumes to quantify tau pathology and neuroinflammation. To reduce dimensionality of the data, we used a Principal Component Analysis (PCA) on each imaging method. A Latent Growth Curve model (LGCM) was used to test for the independent predictive value of the PCA-derived neuroimaging measures on longitudinal cognitive decline (Figure 1). PCA identified a global component for grey matter volumes, and two components for each PET ligand: one in anterior temporal regions, and another in posterior temporo-parietal regions (Figure 2). The LGCM using MRI (χ2(4)=2.82, p=0.59, RMSEA=0.00, CFI=1.00) showed a positive association between grey-matter volumes and longitudinal ACE-R scores (Std all=0.56, p<0.001). LGCM with [11C]PK-11195 (χ2(6)=1.50, p=0.96, RMSEA=0.00, CFI=1.00) indicated a positive association with 2-year cognitive decline in both anterior (Std all=−0.42, p<0.001) and posterior (Std all=−0.35, p=0.016) components. Furthermore, in LGCM with [18F]AV-1451 (χ2(6)=10.63, p=0.10, RMSEA=0.12, CFI=0.98), longitudinal cognitive performance correlated negatively with values in the posterior (Std all=−0.61, p=0.01) and anterior (Std all=−0.43, p<0.001) components.

Cognitive Decline

Grey matter

Pittsburgh compound B

10.1016/j.jalz.2019.06.4762

Cite

Citations (0)

Frontoparietal network integrity supports cognitive function despite atrophy and hypoperfusion in pre-symptomatic frontotemporal dementia: multimodal analysis of brain function, structure and perfusion

medRxiv (Cold Spring Harbor Laboratory) (2024)

Xulin Liu P Simon Jones Maurice Pasternak Mario Masellis Arabella Bouzigues

ABSTRACT INTRODUCTION Genetic mutation carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion and functional patterns in pre-symptomatic stage could inform accurate staging and potential mechanisms. METHODS We included 207 pre-symptomatic genetic mutation carriers and 188 relatives without mutations. The grey matter volume, cerebral perfusion, and resting-state functional network maps were co-analyzed using linked independent component analysis (LICA). Multiple regression analysis was used to investigate the relationship of LICA components to genetic status and cognition. RESULTS Pre-symptomatic mutation carriers showed an age-related decrease in the left frontoparietal network integrity while non-carriers did not. Executive functions of mutation carriers became dependent on the left frontoparietal network integrity in older age. DISCUSSION The frontoparietal network integrity of pre-symptomatic mutation carriers showed a distinctive relationship to age and cognition compared to non-carriers, suggesting a contribution of the network integrity to brain resilience, despite atrophy and hypoperfusion.

Frontotemporal lobar degeneration

10.1101/2024.03.06.24303617

Cite

Citations (0)

Synaptic loss in behavioural variant of frontotemporal dementia:an in vivo [¹¹C]UCB‐J PET study

Alzheimer s & Dementia (2022)

Maura Malpetti P Simon Jones Thomas Cope Negin Holland Michelle Naessens

Abstract Background Post‐mortem clinical studies and animal models described severe synaptic loss as an early feature of neurodegenerative disease, including frontotemporal dementia. Recently, PET radiotracers that bind to synaptic vesicle glycoprotein 2A have been developed and proven to enable in vivo quantification of synaptic loss in people with neurodegenerative diseases. This study used [ 11 C]UCB‐J PET to quantify synaptic loss in people with behavioural variant frontotemporal dementia (bvFTD). Method We recruited 10 people with a clinical diagnosis of bvFTD and 24 age‐ and sex‐matched healthy controls. Participants underwent dynamic [ 11 C]UCB‐J PET‐MR, and a neuropsychological assessment, including the Addenbrooke's cognitive examination (ACE‐R) as a global measure of cognitive performance, and the INECO frontal screening. Synaptic density was estimated using [ 11 C]UCB‐J non‐displaceable binding potential (BP ND ) at voxel level and in whole‐brain regions of interest. General linear models were used to compare [ 11 C]UCB‐J binding voxel‐wise between groups, and correlate synaptic density with cognitive performance in bvFTD cohort. These analyses were also performed using regional [ 11 C]UCB‐J binding potentials, with and without partial‐volume correction. Regional correlations were performed with both frequentist and Bayesian approaches. Result People with bvFTD showed severe synaptic loss compared to controls at individual level and as a group. [ 11 C]UCB‐J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insula cortex and medial temporal lobe (5.1 ≤ t ≤ 9.3, p < 0.05 FWE at voxel level, Figure 1A). Results from ROI‐based analyses mirrored the voxel‐wise results, with and without partial‐volume correction. Synaptic loss in the left frontal and cingulate regions significantly correlated with cognitive impairments as assessed with ACE‐R and INECO (r > 0.8, p<0.001 at voxel level, p<0.05 FWE at cluster level, Figure 1B). Correlations were confirmed by regional‐based analyses, with both frequentist and Bayesian approaches (Figure 1C). Conclusion Different analytic approaches converged showing a significant and widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [ 11 C]UCB‐J PET could therefore be a useful supporting tool for translational studies and experimental medicines strategies for new disease‐modifying treatments in this condition.

Frontal lobe

Superior frontal gyrus

Posterior cingulate

Frontotemporal lobar degeneration

10.1002/alz.061706

Cite

Citations (0)

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Alzheimer s & Dementia (2020)

Kamen A. Tsvetanov Stefano Gazzina P Simon Jones John van Swieten Barbara Borroni

Abstract Introduction The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data‐driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure‐function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non‐carriers, and increased with proximity to the expected onset of disease. Discussion Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

10.1002/alz.12209

Cite

Citations (48)

Altered network stability in progressive supranuclear palsy

Neurobiology of Aging (2021)

David J. Whiteside P Simon Jones B Ghosh Ian Coyle‐Gilchrist Alexander Gerhard

The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states.

10.1016/j.neurobiolaging.2021.07.007

Cite

Citations (12)

In vivo evidence for pre‐symptomatic neuroinflammation in a MAPT mutation carrier

Annals of Clinical and Translational Neurology (2019)

W Richard Bevan‐Jones Thomas Cope P Simon Jones Luca Passamonti Young T. Hong

Abstract Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown. Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre‐symptomatic carrier of the 10 + 16 MAPT mutation, we show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas. The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre‐symptomatic disease stage. Our findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association.

Tau protein

10.1002/acn3.683

Cite

Citations (31)

Imaging tau burden in dementia with Lewy bodies using [18F]-AV1451 positron emission tomography

Neurobiology of Aging (2020)

Elijah Mak Nicolas Nicastro Maura Malpetti George Savulich Ajenthan Surendranathan

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB.

Lewy body

Colocalization

Binding potential

10.1016/j.neurobiolaging.2020.11.006

Cite

Citations (21)