 |
|
Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies
Felix Geser, MD, PhD;
Maria Martinez-Lage, MD;
John Robinson, BS;
Kunihiro Uryu, PhD;
Manuela Neumann, MD;
Nicholas J. Brandmeir, MS;
Sharon X. Xie, PhD;
Linda K. Kwong, PhD;
Lauren Elman, MD;
Leo McCluskey, MD;
Chris M. Clark, MD;
Joe Malunda;
Bruce L. Miller, MD;
Earl A. Zimmerman, MD;
Jiang Qian, MD;
Vivianna Van Deerlin, MD, PhD;
Murray Grossman, MD, EdD;
Virginia M.-Y. Lee, PhD, MBA;
John Q. Trojanowski, MD, PhD
Arch Neurol. 2009;66(2):180-189.
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.
Design Performance of immunohistochemical whole–central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.
Setting An academic medical center.
Participants 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.
Main Outcome Measure 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.
Conclusion 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.
Author Affiliations: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging (Drs Geser, Martinez-Lage, Uryu, Kwong, Van Deerlin, Lee, and Trojanowski and Messrs Robinson, Brandmeir, and Malunda), and Departments of Biostatistics and Epidemiology (Dr Xie) and Neurology (Drs Elman, McCluskey, Clark, and Grossman), University of Pennsylvania School of Medicine, Philadelphia; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain (Dr Martinez-Lage); Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany (Dr Neumann); Alzheimer's Disease Center, Albany Medical Center (Dr Zimmerman and Mr Brandmeir), and Department of Pathology and Laboratory Medicine, Albany Medical College (Dr Qian), Albany, New York; and Department of Neurology, University of California at San Francisco (Dr Miller).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
This Month in Archives of Neurology
Arch Neurol. 2009;66(2):151-152.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
The heritability and genetics of frontotemporal lobar degeneration
Rohrer et al.
Neurology 2009;73:1451-1456.
ABSTRACT
| FULL TEXT
Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis
Pesiridis et al.
Hum Mol Genet 2009;18:R156-R162.
ABSTRACT
| FULL TEXT
|
