Neurophysiological consequences of synapse loss in progressive supranuclear palsy
Neurophysiological consequences of synapse loss in progressive supranuclear palsy
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 clinical to preclinical models of pathology, and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations like electro- and magneto-encephalography (MEG). Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by [11C]UCB-J positron emission tomography, 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 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 MEG 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.
Cope Thomas E.、Passamonti Luca、Street Duncan、Friston Karl J、Murley Alexander G.、Rouse Matthew A.、Nesbitt David、Perry Alistair、Rowe James B.、Bevan-Jones W. Richard、Holland Negin、Shaw Alexander D.、Jafarian Amirhossein、Hughes Laura E.、Adams Natalie E.
Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeWellcome Centre for Human Neuroimaging, University College LondonDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeWashington Singer Laboratories, University of ExeterDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of CambridgeDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge||MRC Cognition and Brain Sciences Unit, University of Cambridge
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
PSPMEGmodellingPETSV2A
Cope Thomas E.,Passamonti Luca,Street Duncan,Friston Karl J,Murley Alexander G.,Rouse Matthew A.,Nesbitt David,Perry Alistair,Rowe James B.,Bevan-Jones W. Richard,Holland Negin,Shaw Alexander D.,Jafarian Amirhossein,Hughes Laura E.,Adams Natalie E..Neurophysiological consequences of synapse loss in progressive supranuclear palsy[EB/OL].(2025-03-28)[2025-04-28].https://www.medrxiv.org/content/10.1101/2022.06.22.22276697.点此复制
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