TDP-43 Pathology Progression Along the Olfactory Pathway as a Possible Substrate for Olfactory Impairment in Amyotrophic Lateral Sclerosis.
Odor impairment and its relationship with TAR DNA-binding protein 43 (TDP-43) pathology in patients with amyotrophic lateral sclerosis (ALS) have not been fully elucidated. We performed the odor stick identification test for Japanese (OSIT-J) in 18 ALS patients and in 18 controls. The score was significantly decreased (6.6 ± 2.7) in the patients versus the controls (9.2 ± 2.4) (U = 77.0, p = 0.007). This decrement of the OSIT-J score paralleled the cognitive decline. We then studied samples from a series of 42 postmortem ALS cases. Quantitative analyses demonstrated that TDP-43-positive inclusions were most frequent in the hippocampus and least abundant in the olfactory bulb and were of intermediate density in the primary olfactory cortex. This centrifugal gradient suggests that TDP-43 pathology starts in the hippocampus, spreads into the primary olfactory center, and finally reaches the olfactory bulb. TDP-43, tau, and α-synuclein accumulations appeared to be independent. These observations suggest that impaired odor discrimination in ALS patients may be related to TDP-43-positive lesions affecting predominantly secondary olfactory centers (especially the hippocampus) in contrast to decreased odor sensitivity in Parkinson disease in which α-synuclein pathology mainly involves the peripheral region (i.e., olfactory bulb). We suggest that detectable odor impairments in ALS patients are useful for predicting the presence of TDP-43 pathology in the extramotor system.
From the Department of Neurology, Tokyo Women's Medical University (TT, MI, SU); Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science (TT, TU); Department of Neurology, Tokyo Women's Medical University Yachiyo Medical Center, Tokyo, Japan (TO); and Raymond Escourolle Laboratory of Neuropathology, Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, La Salpêtrière Hospital, Paris, France (TT, DS, CD).
Takahiro
T
Takeda
Mutsumi
M
Iijima
Toshiki
T
Uchihara
Takashi
T
Ohashi
Danielle
D
Seilhean
Charles
C
Duyckaerts
Shinichiro
S
Uchiyama
D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications*; D000704:Analysis of Variance; D003072:Cognition Disorders / Q000209:etiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000857:Olfaction Disorders / Q000209:etiology* / Q000473:pathology*; D066194:Olfactory Cortex / Q000378:metabolism*; D018709:Statistics, Nonparametric
D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human