Clinical and pathological continuum of multisystem TDP-43 proteinopathies.
OBJECTIVE
To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.


METHODS
Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.


METHODS
An academic medical center.


METHODS
We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.


METHODS
Neuronal and glial TDP-43 pathology.


RESULTS
We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.


CONCLUSIONS
These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.
Geser
Felix
F
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
Martinez-Lage
Maria
M
Robinson
John
J
Uryu
Kunihiro
K
Neumann
Manuela
M
Brandmeir
Nicholas J
NJ
Xie
Sharon X
SX
Kwong
Linda K
LK
Elman
Lauren
L
McCluskey
Leo
L
Clark
Chris M
CM
Malunda
Joe
J
Miller
Bruce L
BL
Zimmerman
Earl A
EA
Qian
Jiang
J
Van Deerlin
Vivianna
V
Grossman
Murray
M
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D003704:Dementia / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000473:pathology / Q000503:physiopathology; D009069:Movement Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism; D054875:Ubiquitination
D004268:DNA-Binding Proteins; D025801:Ubiquitin