Widespread white matter and conduction defects in PSEN1-related spastic paraparesis.
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.
University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA.
Steffan K
SK
Soosman
Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Nelly
N
Joseph-Mathurin
Department of Neurology, Keck School of Medicine of USC Center for the Health Professionals, Los Angeles, CA, USA.
Meredith N
MN
Braskie
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Yvette M
YM
Bordelon
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Mary S. Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
David
D
Wharton
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Mary S. Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Maria
M
Casado
Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Neurology, David Geffen School of Medicine, #3506C Gonda Neuroscience and Genetics Research Center, UCLA, Los Angeles, CA, USA.
Giovanni
G
Coppola
Department of Neurology, Keck School of Medicine of USC Center for the Health Professionals, Los Angeles, CA, USA.
Holly
H
McCallum
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Marc
M
Nuwer
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Pedro
P
Coutin-Churchman
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Mary S. Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Departments of Neurology, Radiology, Medical and Molecular Genetics, Indiana University School of Medicine, Indiana Alzheimer's Disease Center, Indianapolis, IN, USA.
Liana G
LG
Apostolova
Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Tammie
T
Benzinger
Department of Neurology, Keck School of Medicine of USC Center for the Health Professionals, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Mary S. Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: john.ringman@med.usc.edu.
John M
JM
Ringman
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism; D016880:Anisotropy; D056324:Diffusion Tensor Imaging; D055724:Electrophysiological Phenomena; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology; D009154:Mutation; D009431:Neural Conduction; D020336:Paraparesis, Spastic / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics*; D013003:Somatosensory Cortex / Q000503:physiopathology; D066127:White Matter / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1
Diffusion tensor imaging; Electrophysiology; PSEN1; White matter; spastic paraparesis