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From Robarts Research Institute (Drs. Yang, Sopper, and Strong, and C. Leystra-Lantz) and The Department of Clinical Neurological Sciences (Dr. Strong), The University of Western Ontario, London, Canada.
Address correspondence and reprint requests to Dr. Michael J. Strong, Department of Clinical Neurological Sciences, Room 7OF 10, UC, LHSC, 339 Windermere Road, London, Ontario, Canada, N6A 5A5; e-mail: mstrong{at}uwo.ca
Background: The authors compared tau protein deposition in the frontal cortex of patients with cognitive impairment of amyotrophic lateral sclerosis (ALSci) (n = 6), cognitively intact patients with ALS (n = 6), and age-matched controls (n = 6) in order to determine the pathologic substrate of ALSci.
Methods: Archival paraffin-embedded tissue was examined using Gallyas staining and immunostaining for tau-1 (phosphorylation-dependent tau epitope), tau-2 (phosphorylation independent), Alzheimer-specific tau phosphoepitopes (AT 8; ser396 phosphorylation), ß-amyloid, glial fibrillary acid protein, SMI 31 (recognizing phosphorylated NFH), 
-synuclein, or ubiquitin.
Results: Tau immunoreactive astrocytic and dense neuronal inclusions were found in both ALS and ALSci, although to a greater extent in ALSci. Superficial linear spongiosis and Gallyas-positive intraneuronal aggregates, immunoreactive with tau-1 and AT 8 but rarely to ser396 tau, were unique to ALSci. Dense extracellular aggregates were observed by both Gallyas staining and tau-1 immunostaining. Tufted degenerating astrocytes containing tau-1 and AT 8 immunoreactive aggregates and, rarely, dense Gallyas positive neuritic plaques immunoreactive with tau-1 and AT 8, but not with ser396 tau or ß-amyloid, were observed in ALSci. Tau positive glial coiled bodies were observed in the deep cortical layers and adjacent subcortical white matter in ALSci. Although 3R and 4R tau mRNA isoforms were expressed to similar levels in the frontal cortex of all cases, the total amount of tau mRNA was increased in both ALS and ALSci. Both gray and white matter soluble tau protein expression was similar among control, ALS, and ALSci cases.
Conclusions: Cognitive dysfunction in ALS may reflect abnormal tau protein metabolism.
Received April 28, 2003. Accepted in final form June 30, 2003.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 23 issue to find the title link for this article.
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