Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis.
BACKGROUND
Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described.


OBJECTIVE
To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS.


METHODS
Performance of an immunohistochemical whole-central nervous system scan for evidence of pathological TDP-43 in ALS patients.


METHODS
An academic medical center.


METHODS
We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants.


METHODS
Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology.


RESULTS
In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls.


CONCLUSIONS
These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.
Geser
Felix
F
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging, Philadelphia, USA.
Brandmeir
Nicholas J
NJ
Kwong
Linda K
LK
Martinez-Lage
Maria
M
Elman
Lauren
L
McCluskey
Leo
L
Xie
Sharon X
SX
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D004268:DNA-Binding Proteins