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  • 1
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    Neurophysiological consequences of synapse loss in progressive supranuclear palsy
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 6 ( 2023-06-01), p. 2584-2594
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 6 ( 2023-06-01), p. 2584-2594
    Abstract: Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson’s syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density—as a subject-specific prior on laminar-specific neuronal populations—markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac471
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
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    Magnetoencephalography insights to dementia and drug intervention
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Magnetoencephalography (MEG) is a promising tool for experimental medicine in dementia, and a core technology for the Dementias Platform UK. It quantifies in vivo human network and synaptic physiology, with high‐dimensional data at a millisecond time‐scale. Its proven sensitivity to neurodegenerative disease has applications in diagnostics and early detection, mechanistic studies of pathogenesis, and biomarkers to accelerate clinical trials and evidence target engagement. Here, we build on recent work with Serotonin and GABA‐ergic modulation, to illustrate MEG insights into the neurophysiological effects of the NMDA receptor antagonist Memantine. We use Frontotemporal dementia and Progressive supranuclear palsy (bvFTD, PSP) as demonstrator conditions in view of their focal glutamatergic deficits. Method 24 Patients with bvFTD and PSP, and 20 healthy controls underwent magnetoencephalography, 7T MRI spectroscopy and a battery of cognitive tests in a double‐blind placebo‐controlled crossover design, using Memantine 10mg/Placebo. We test the relationship between cortical oscillations, baseline glutamate concentration and response to pharmacological intervention. Result Neurophysiological activity was impaired in patients, with diminished low frequency oscillations and disrupted cortical connectivity. These abnormalities correlated with reduced baseline glutamate concentration. Memantine enhanced the neuronal response, particularly in prefrontal regions. Conclusion MEG provides insights into targetable pathophysiological effects of neurodegeneration and markers for treatment studies. It is sensitive to disease and individual differences in pathophysiology, reliable, safe, well‐tolerated and sufficiently scalable for early phase trials. MEG evidence of selective neuronal dysfunction and network reorganisation can couple with microcircuit models for synaptic assays, or be used directly as a readout for interventional studies. MEG is ideally suited to support both academic and pharma initiatives, with quantitative tools for early phase clinical trials, illustrated here with Memantine, but applicable to other compounds.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.052536
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 3
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    GABAergic cortical network physiology in frontotemporal lobar degeneration
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 7 ( 2021-08-17), p. 2135-2145
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 7 ( 2021-08-17), p. 2135-2145
    Abstract: The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab097
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 4
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    Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome
    Wiley ; 2023
    In:  Human Brain Mapping Vol. 44, No. 11 ( 2023-08), p. 4239-4255
    Details
    In: Human Brain Mapping, Wiley, Vol. 44, No. 11 ( 2023-08), p. 4239-4255
    Abstract: There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson‐plus and the UK National PSP Research Network (PROSPECT‐MR). Resting‐state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large‐scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between‐network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five‐fold cross‐validation. In PSP and CBS, between‐network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between‐network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    URL: Article
    DOI: 10.1002/hbm.v44.11
    DOI: 10.1002/hbm.26342
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1492703-2
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  • 5
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    GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography
    Society for Neuroscience ; 2020
    In:  The Journal of Neuroscience Vol. 40, No. 8 ( 2020-02-19), p. 1640-1649
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 40, No. 8 ( 2020-02-19), p. 1640-1649
    Abstract: To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions. SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1689-19.2019
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2020
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 6
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    Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes
    Public Library of Science (PLoS) ; 2022
    In:  PLOS Computational Biology Vol. 18, No. 5 ( 2022-5-9), p. e1010079-
    Details
    In: PLOS Computational Biology, Public Library of Science (PLoS), Vol. 18, No. 5 ( 2022-5-9), p. e1010079-
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1553-7358
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    DOI: 10.1371/journal.pcbi.1010079
    DOI: 10.1371/journal.pcbi.1010079.g001
    DOI: 10.1371/journal.pcbi.1010079.g002
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    DOI: 10.1371/journal.pcbi.1010079.t001
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    DOI: 10.1371/journal.pcbi.1010079.r003
    DOI: 10.1371/journal.pcbi.1010079.r004
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2022
    detail.hit.zdb_id: 2193340-6
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  • 7
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    Online Resource
    The effect of memantine on cortical network function in frontotemporal lobar degeneration is conditional on baseline GABA physiology
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.051049
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 8
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    Locus coeruleus integrity is linked to response inhibition deficits in Parkinson’s disease and progressive supranuclear palsy
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience
    Details
    In: The Journal of Neuroscience, Society for Neuroscience
    Abstract: Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetisation-transfer-weighted imaging of the LC. Parameters of ‘race models’ of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioural modelling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to LC integrity. Significance Statement Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson’s disease and progressive supranuclear palsy. We used cognitive modelling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson’s disease and progressive supranuclear palsy.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0289-22.2023
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2023
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 9
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    Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants
    Oxford University Press (OUP) ; 2021
    In:  Brain Communications Vol. 3, No. 3 ( 2021-07-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 3, No. 3 ( 2021-07-01)
    Abstract: Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk–benefit and cost–benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional UK healthcare service. Longitudinal clinical data from people with Richardson’s syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination and the revised Addenbrooke’s Cognitive Examination. Subgroup analyses considered patients meeting recent Phase II trial entry criteria and patients with neuropathological confirmation. Two hundred and twenty-seven patients [male = 59%, mean age (±standard deviation), 71.8 (±7.0) years] were followed for a mean 21.6 (±15.6) months. One hundred and seventy-four (77%) had Richardson’s syndrome at the outset, 25 had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and 28 had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson’s syndrome was faster than variant phenotypes on the Mini-Mental State Examination (−1.8 versus −0.9/year, P = 0.005) and revised Addenbrooke’s Cognitive Examination (−5.3 versus −3.0/year, P = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 versus 7.1/year, P = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 versus 2.3/year, P = 0.4). However, for those with more than 1 years’ follow-up, a significant difference was observed between Richardson’s syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 versus 6.3/year, P = 0.04). Survival was longer in variant phenotypes than Richardson’s syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02] . Pathologically confirmed cases (n = 49) supported these findings. Patients meeting basic trial-eligibility criteria (n = 129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 versus 6.1/year, P = 0.001). In conclusion, phenotypes other than Richardson’s syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcab206
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3020013-1
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  • 10
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    GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 11 ( 2020-11-01), p. 3449-3462
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 11 ( 2020-11-01), p. 3449-3462
    Abstract: Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson’s syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa305
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
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