• Online Features  This Article  • Full text  • PDF  • eTable  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (56)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in this journal  Topic Collections  • Neurology  • Amyotrophic Lateral Sclerosis  • Cognitive Disorders  • Dementias  • Neurogenetics  • Motor Neuron Disease  • Neuromuscular diseases  • Alert me on articles by topic  Social Bookmarking   What's this?

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. doi:10.1001/archneurol.2008.558

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    Delicious    Digg    Facebook    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

Mesial Prefrontal Cortex Degeneration in Amyotrophic Lateral Sclerosis: A High-Field Proton MR Spectroscopy Study
Usman et al.
Am. J. Neuroradiol. 2011;32:1677-1680.
ABSTRACT | FULL TEXT  

Motor Neuron dysfunction in frontotemporal dementia
Burrell et al.
Brain 2011;134:2582-2594.
ABSTRACT | FULL TEXT  

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration
Rohrer et al.
Brain 2011;134:2565-2581.
ABSTRACT | FULL TEXT  

Large Proportion of Amyotrophic Lateral Sclerosis Cases in Sardinia Due to a Single Founder Mutation of the TARDBP Gene
Chio et al.
Arch Neurol 2011;68:594-598.
ABSTRACT | FULL TEXT  

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor
Dewey et al.
Mol. Cell. Biol. 2011;31:1098-1108.
ABSTRACT | FULL TEXT  

TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia
Rohrer et al.
Neurology 2010;75:2204-2211.
ABSTRACT | FULL TEXT  

Pathological 43-kDa Transactivation Response DNA-Binding Protein in Older Adults With and Without Severe Mental Illness
Geser et al.
Arch Neurol 2010;67:1238-1250.
ABSTRACT | FULL TEXT  

Neurotoxic effects of TDP-43 overexpression in C. elegans
Ash et al.
Hum Mol Genet 2010;19:3206-3218.
ABSTRACT | FULL TEXT  

A Drosophila model for TDP-43 proteinopathy
Li et al.
Proc. Natl. Acad. Sci. USA 2010;107:3169-3174.
ABSTRACT | FULL TEXT  

Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome
Lippa et al.
Arch Neurol 2009;66:1483-1488.
ABSTRACT | FULL TEXT  

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