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

Acta Neuropathol. 2018 Feb;135(2):213-226. doi: 10.1007/s00401-017-1797-4. Epub 2017 Dec 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / psychology*
  • Atrophy
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology*
  • Cohort Studies
  • DNA-Binding Proteins / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phosphorylation
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology*
  • Prefrontal Cortex / ultrastructure
  • Synapses / metabolism
  • Synapses / pathology*
  • Synapses / ultrastructure

Substances

  • DNA-Binding Proteins
  • TDP-43 protein, human