Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis

Christopher M Henstridge, Dimitrios I Sideris, Emily Carroll, Sanziana Rotariu, Sally Salomonsson, Makis Tzioras, Chris-Anne McKenzie, Colin Smith, Christine A F von Arnim, Albert C Ludolph, Dorothée Lulé, Danielle Leighton, Jon Warner, Elaine Cleary, Judith Newton, Robert Swingler, Siddharthan Chandran, Thomas H Gillingwater, Sharon Abrahams, Tara L Spires-Jones

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Abstract

In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS.
Original languageEnglish
Pages (from-to)213-226
Number of pages14
JournalActa Neuropathologica
Volume135
Issue number2
DOIs
Publication statusPublished - Feb 2018

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Amyotrophic Lateral Sclerosis
Prefrontal Cortex
Synapses
Nerve Degeneration
Brain
Genetic Testing
Frontal Lobe
Motor Neurons
Cognitive Dysfunction
Neurodegenerative Diseases
Atrophy
Dementia
Electron Microscopy
Alzheimer Disease
Tomography
Pathology
Survival

Keywords

  • Journal Article

Cite this

Henstridge, C. M., Sideris, D. I., Carroll, E., Rotariu, S., Salomonsson, S., Tzioras, M., ... Spires-Jones, T. L. (2018). Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. Acta Neuropathologica, 135(2), 213-226. https://doi.org/10.1007/s00401-017-1797-4
Henstridge, Christopher M ; Sideris, Dimitrios I ; Carroll, Emily ; Rotariu, Sanziana ; Salomonsson, Sally ; Tzioras, Makis ; McKenzie, Chris-Anne ; Smith, Colin ; von Arnim, Christine A F ; Ludolph, Albert C ; Lulé, Dorothée ; Leighton, Danielle ; Warner, Jon ; Cleary, Elaine ; Newton, Judith ; Swingler, Robert ; Chandran, Siddharthan ; Gillingwater, Thomas H ; Abrahams, Sharon ; Spires-Jones, Tara L. / Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. In: Acta Neuropathologica. 2018 ; Vol. 135, No. 2. pp. 213-226.
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abstract = "In addition to motor neurone degeneration, up to 50{\%} of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS.",
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Henstridge, CM, Sideris, DI, Carroll, E, Rotariu, S, Salomonsson, S, Tzioras, M, McKenzie, C-A, Smith, C, von Arnim, CAF, Ludolph, AC, Lulé, D, Leighton, D, Warner, J, Cleary, E, Newton, J, Swingler, R, Chandran, S, Gillingwater, TH, Abrahams, S & Spires-Jones, TL 2018, 'Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis', Acta Neuropathologica, vol. 135, no. 2, pp. 213-226. https://doi.org/10.1007/s00401-017-1797-4

Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. / Henstridge, Christopher M; Sideris, Dimitrios I; Carroll, Emily; Rotariu, Sanziana; Salomonsson, Sally; Tzioras, Makis; McKenzie, Chris-Anne; Smith, Colin; von Arnim, Christine A F; Ludolph, Albert C; Lulé, Dorothée; Leighton, Danielle; Warner, Jon; Cleary, Elaine; Newton, Judith; Swingler, Robert; Chandran, Siddharthan; Gillingwater, Thomas H; Abrahams, Sharon; Spires-Jones, Tara L.

In: Acta Neuropathologica, Vol. 135, No. 2, 02.2018, p. 213-226.

Research output: Contribution to journalArticle

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AU - Henstridge, Christopher M

AU - Sideris, Dimitrios I

AU - Carroll, Emily

AU - Rotariu, Sanziana

AU - Salomonsson, Sally

AU - Tzioras, Makis

AU - McKenzie, Chris-Anne

AU - Smith, Colin

AU - von Arnim, Christine A F

AU - Ludolph, Albert C

AU - Lulé, Dorothée

AU - Leighton, Danielle

AU - Warner, Jon

AU - Cleary, Elaine

AU - Newton, Judith

AU - Swingler, Robert

AU - Chandran, Siddharthan

AU - Gillingwater, Thomas H

AU - Abrahams, Sharon

AU - Spires-Jones, Tara L

PY - 2018/2

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N2 - In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS.

AB - In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS.

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DO - 10.1007/s00401-017-1797-4

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