Widespread white matter and conduction defects in PSEN1-related spastic paraparesis

Neurobiol Aging. 2016 Nov:47:201-209. doi: 10.1016/j.neurobiolaging.2016.07.030. Epub 2016 Aug 8.


The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition.

Keywords: Diffusion tensor imaging; Electrophysiology; PSEN1; White matter; spastic paraparesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism
  • Amyloidogenic Proteins / metabolism
  • Anisotropy
  • Diffusion Tensor Imaging
  • Electrophysiological Phenomena
  • Female
  • Genetic Association Studies*
  • Humans
  • Male
  • Middle Aged
  • Motor Cortex / physiopathology
  • Mutation*
  • Neural Conduction*
  • Paraparesis, Spastic / diagnostic imaging*
  • Paraparesis, Spastic / genetics*
  • Paraparesis, Spastic / pathology
  • Paraparesis, Spastic / physiopathology
  • Presenilin-1 / genetics*
  • Somatosensory Cortex / physiopathology
  • White Matter / diagnostic imaging*
  • White Matter / metabolism
  • White Matter / pathology*
  • White Matter / physiopathology


  • Amyloid beta-Protein Precursor
  • Amyloidogenic Proteins
  • PSEN1 protein, human
  • Presenilin-1