Cognitive impairment in sporadic ALS - A pathologic continuum underlying amultisystem disorder

Background: Traditionally considered a motor neuron-selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Alth ough the pathologic substrate of cognitive impairment remains to be defined , the presence of ubiquitin-immunoreactive (Ub--) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. Methods: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact pa tients with ALS, and four neurologically normal patients. The extent and lo ad of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial lin ear spongiosis (SLS) was determined among a number of cortical, hippocampal , and subcortical regions. Results: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively imp aired and cognitively intact patients with ALS, their density and extent wa s greater among the former, with the difference greatest in the cingulate g yrus. Ub+ neurites were observed in a similar distribution. Only the presen ce of SLS, affecting the first and second cortical layers, reliably disting uished between the cognitively impaired and cognitively intact ALS subpopul ations. In three of four cognitively impaired patients with ALS, SLS was as sociated with transcortical microglial activation, in the absence of detect able differences in astrocytosis, density of calbindin or parvalbumin neuro ns, or optical density of synaptophysin and SNAP-25. Conclusions: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both A LS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesti ng a disease continuum. Moreover, cognitive impairment was uniformly associ ated with superficial linear spongiosis, a pathologic feature common to sev eral forms of frontotemporal dementia.