ALS May Involve Broader Spectrum of Neurodegeneration
By Charles Bankhead, Staff Writer, MedPage Today
Published: June 20, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Earn CME/CE credit
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PHILADELPHIA, June 20 -- Amyotrophic lateral sclerosis may evolve from a more complex and widespread neurodegenerative disorder than previously recognized, brain scans of ALS patients show.

Evidence of the pathologic effects of the TDP-43 DNA-binding protein appeared in multiple areas of the central nervous system of ALS patients, John Q. Trojanowski, M.D., Ph.D., of the University of Pennsylvania, and colleagues reported in the May issue of Archives of Neurology.

Historically, ALS has been regarded as a neurodegenerative disorder limited to upper and lower motor neurons. Action Points
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Explain to interested patients that a study of the brains of patients with ALS suggests the disease may involve more widespread nerve damage than previously believed.


Note that the findings were based on brain scans of a small number of patients and require confirmation in more patients.


Note, too, that the clinical implications of the study remain to be determined.
"These findings suggest that ALS does not selectively affect the pyramidal motor system, but rather is a multisystem neurodenerative TDP-43 proteinopathy," the authors concluded.
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Pathologic TDP-43 has been identified as the principal disease protein in ALS, although its functions remain poorly understood. The protein is ubiquitous and highly conserved and appears to be involved in transcriptional repression and alternative splicing, the authors said.


Evidence of upper and lower motor neuron degeneration and the absence of other disease processes have been considered diagnostic for ALS. However, whole-brain distribution of degeneration and pathology in the disease had not been well described.


To better define the scope of neurodegeneration, the researchers did immunohistochemical whole-brain scans of 31 patients with sporadic ALS and eight control participants without overt neurologic or cognitive dysfunction.


As expected, involvement of upper and lower motor neurons was observed in the ALS patients.


Unexpectedly, however, the authors identified pathologic TDP-43 in multiple brain areas well outside the pyramidal motor system, including the nigrostriatal system, neocortical and allocortical areas, and the cerebellum.


"Cerebellar inclusions of all types were encountered throughout the CNS of ALS patients," the authors said. "None were observed in the control participants."


"Control participants were virtually devoid of pathological TDP-43," they added.


The pathology appeared to be worse in ALS patients with dementia than in those who did not have any cognitive dysfunction, but the study involved too few patients to confirm that observation.


The findings suggest a possible link between ALS and other neurodegerative disorders, the authors said.


If that's true, they said, then therapy that blocks or reverses TDP-43 pathology in ALS might lead to disease-modifying therapies for a number of associated disorders.

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The study was funded by grants from the National Institutes of Health. The authors reported no disclosures.
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Primary source: Archives of Neurology
Source reference:
Geser F, et al "Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis" Arch Neurol 2008; 65: 636-641.