Michelle Naessens

University of Cambridge

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James B. Rowe

MRC Cognition and Brain Sciences Unit

Matthew A Rouse

MRC Cognition and Brain Sciences Unit

Negin Holland

Cambridge University Hospitals NHS Foundation Trust

Alexander G. Murley

University of Cambridge

Duncan Street

Cambridge University Hospitals NHS Foundation Trust

Thomas Cope

Cambridge University Hospitals NHS Foundation Trust

David J. Whiteside

Cambridge University Hospitals NHS Foundation Trust

Laura E. Hughes

University of Cambridge

Natalie Adams

University of Cambridge

Maura Malpetti

University of Cambridge

Cooperative Institutions

University of Cambridge

Cambridge University Hospitals NHS Foundation Trust

MRC Cognition and Brain Sciences Unit

University College London

Medical Research Council

National Hospital for Neurology and Neurosurgery

UK Dementia Research Institute

Ludwig-Maximilians-Universität München

Munich Cluster for Systems Neurology

Universitat de Barcelona

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The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

Research Square (Research Square) (2022)

Alistair Perry Laura Hughes Natalie Adams Michelle Naessens Alexander G. Murley

Abstract There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioral variant frontotemporal dementia, 10 progressive supranuclear palsy) and 20 healthy age- and gender- matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10mg memantine, an uncompetitive NMDA-receptor antagonist. Ultrahigh-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. There was no overall effect of memantine on the magnitude of the mismatch negativity response in right frontotemporal cortex in patients, or controls. However, the change in right auditory cortex response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration, or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline-dependency in pharmacological restoration of neurotransmitter deficits, to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

Frontotemporal lobar degeneration

Neurochemical

Memantine

10.21203/rs.3.rs-1609477/v1

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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

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Synaptic density affects clinical severity via network dysfunction in syndromes associated with Frontotemporal Lobar Degeneration

Figshare (2023)

David J. Whiteside Timothy Rittman James B. Rowe Negin Holland Elijah Mak

Data used to derive figures and results in the primary manuscript and in the supplementary materials for Synaptic density affects clinical severity via network dysfunction in syndromes associated with Frontotemporal Lobar Degeneration. We have also uploaded the Zip folder for the Maybrain software.

Frontotemporal lobar degeneration

Degeneration (medical)

10.6084/m9.figshare.24188580

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GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration

Alzheimer s & Dementia (2025)

Laura E. Hughes Natalie Adams Matthew A Rouse Michelle Naessens Alexander D. Shaw

Abstract INTRODUCTION We examined how abnormal prefrontal neurophysiology and changes in gamma‐aminobutyric acid‐ergic (GABAergic) neurotransmission contribute to behavioral impairments in disorders associated with frontotemporal lobar degeneration (FTLD). METHODS We recorded magnetoencephalography during an adaptive visuomotor task from 11 people with behavioral‐variant frontotemporal dementia, 11 with progressive supranuclear palsy, and 20 age‐matched controls. We used tiagabine, a gamma‐aminobutyric acid (GABA) re‐uptake inhibitor, as a pharmacological probe to assess the role of GABA during motor‐related beta power changes. RESULTS Task impairments were associated with diminished movement‐related beta power. Tiagabine facilitated partial recovery of behavioral impairments and neurophysiology, moderated by executive function, such that the greatest improvements were seen in those with higher cognitive scores. The right prefrontal cortex was revealed as a key site of drug interaction. DISCUSSION Behavioral and neurophysiological deficits can be mitigated by enhancement of GABAergic neurotransmission. Clinical trials are warranted to test for enduring clinical benefits from this restorative‐psychopharmacology strategy. Highlights Event‐related beta power changes during movement can be altered by the GABA reuptake inhibitor, tiagabine. In people with behavioral‐variant frontotemporal dementia and progressive supranuclear palsy, tiagabine enhanced beta modulation and concurrently improved task performance, dependent on baseline cognition, and diagnosis. The effects of the drug suggest a GABA‐dependent beta‐related mechanism that underlies adaptive motor control. Restoring selective deficits in neurotransmission is a potential means to improve behavioral symptoms in patients with dementia.

Frontotemporal lobar degeneration

Tiagabine

10.1002/alz.14531

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Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration

Nature Communications (2023)

David J. Whiteside Negin Holland Kamen A. Tsvetanov Elijah Mak Maura Malpetti

Abstract There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [ 11 C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Frontotemporal lobar degeneration

Degeneration (medical)

Loss function

10.1038/s41467-023-44307-7

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Frontotemporal lobar degeneration changes neuronal beta-frequency dynamics during the mismatch negativity response

NeuroImage Clinical (2024)

Alistair Perry Laura E. Hughes Natalie Adams Michelle Naessens Niels A. Kloosterman

Frontotemporal lobar degeneration

Magnetoencephalography

10.1016/j.nicl.2024.103671

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045 Survival in frontotemporal lobar degeneration: identifying blood, brain and behavioural predictors of survival

Journal of Neurology Neurosurgery & Psychiatry (2022)

Katherine Stockton Michelle Naessens Alexander G. Murley Ian Coyle‐Gilchrist Claire J. Lansdall

My ABN fellowship focusses on the syndromes caused by frontotemporal lobar degeneration. Despite distinctive pathological causes, these highly heterogeneous syndromes overlap in clinical manifesta- tions and pathophysiology. This is both a challenge and an opportunity for future trials aimed at slowing the diseases or treating their symptoms. By modelling phenotypic data and long-term outcomes, I will determine the features of blood, brain and behaviour that predict survival. The “PIck’s disease and Pro- gressive supranuclear palsy Prevalence and INcidence” study (PiPPIN), has 440 participants from previous recruitment phases, of whom 318 have died. I have recruited 91 from an expected 220-250 patients in this 3rd phase. My initial analysis of existing samples will test the hypothesis that metabolic signatures dif- ferentiate disorders (PSP, FTD, controls). Preliminary results from N=269 samples confirm multiple metabolic differences between patients and controls, focussing within the lipid pathways. This will be analysed in relation to clinical severity, phenotype, and survival outcomes. Subsequent analysis will integrate cognitive/behavioural profiles, magnetic resonance imaging and spectroscopy, and blood biomarkers (including metabolites) in multivariate models of survival. Prediction of survival does not indicate causation but will generate hypotheses of promising targets for intervention and tools for risk-based stratification.

Frontotemporal lobar degeneration

10.1136/jnnp-2022-abn2.89

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Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Amirhossein Jafarian Laura E. Hughes Natalie Adams Juliette H Lanskey Michelle Naessens

Abstract We present a hierarchical and empirical Bayesian framework for testing hypotheses about synaptic neurotransmission, based on the integration of ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals’ neurophysiological observations. At the second level, individuals’ 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare models of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. We perform cross-validation using split-sampling of the MEG dataset. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

Magnetoencephalography

10.1101/2022.06.17.493881

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Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

NeuroImage (2023)

Amirhossein Jafarian Laura E. Hughes Natalie Adams Juliette H Lanskey Michelle Naessens

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters' concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals' neurophysiological observations. At the second level, individuals' 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare alternative model evidence of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by individual differences in neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. Using within-subject split-sampling of the MEG dataset (i.e., validation by means of a held-out dataset), we show that model comparison for hypothesis testing can be highly reliable. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

Magnetoencephalography

10.1016/j.neuroimage.2023.120193

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The effect of memantine on cortical network function in frontotemporal lobar degeneration is conditional on baseline GABA physiology

Alzheimer s & Dementia (2021)

Alistair Perry Natalie Adams Laura E. Hughes Ece Kocagöncü Matthew A Rouse

Abstract Background Frontotemporal lobar degeneration (FTLD) is associated with deficits to GABA and glutamatergic neurotransmitters, particularly in the frontal cortex. While targeting GABAergic systems has shown to restore frontotemporal deficits in FTLD, little is known whether pharmacological probes of glutamatergic functioning have similar effects in these circuits. Method Twenty participants with a FTLD‐associated syndrome (11 with PSP, 9 with bvFTD) and 20 healthy‐controls undertook two magnetoencephalography (MEG) sessions with a roving auditory oddball paradigm assessing frontotemporal change detection: (1) session on placebo and (2) after 10mg of oral memantine, which aims to blocks glutamatergic ecotoxicity. The mean amplitude of MEG “mismatch negativity” responses (MMN; standard‐deviants, 125‐175ms) was calculated across gradiometer sensors and for bilateral frontotemporal sources. Glutamate and GABA levels were measured using 7T proton magnetic resonance spectroscopy of the right inferior frontal gyrus (IFG). Frequentist and Bayesian ANOVAs assessed the differential mean MMN responses between controls and patients across placebo and drug conditions. Evoked difference waveforms (standard‐deviants) across the peristimulus time‐window were analysed using random field theory (RFT) (crit p =0.05, FWER) for the interaction effects of interest (i.e. drug session x group and drug x MRS levels). Result Patients and controls did not demonstrate differential mean MMN amplitudes on placebo at the average‐sensor ( p =0.95) or source‐level ( p >0.27) (BF 10 =0.3‐0.5). Across sensors, only controls exhibited a differential drug‐dependent MMN, reflected by a steeper rebound of difference waveforms between 206‐288ms on memantine (Fig 1A; p FWER =0.026, cluster‐level). However, no interaction was found for mean MMNs ( p >0.053). Notably, RFT (Fig 1B) and linear mixed models (Fig 1C) identified that greater GABA levels in patients are significantly associated with stronger MMN responses in right‐hemisphere areas under memantine. Glutamate levels did not moderate the mean MMN response to memantine ( p >0.065). Conclusion Overall, we show that targeting glutamatergic systems may not lead to a restoration of frontotemporal physiology across patients. However, the effects of memantine are conditional on patient's baseline GABA, suggesting a critical balance between glutamatergic and GABA physiology that may underlie the large‐scale neural deficits in FTLD.

Frontotemporal lobar degeneration

Magnetoencephalography

Memantine

10.1002/alz.051049

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Citations (1)