ALTERATIONS IN NITROGEN MONOXIDE-SYNTHESIZING CORTICAL-NEURONS IN AMYOTROPHIC-LATERAL-SCLEROSIS WITH DEMENTIA

Cognitive impairment in the absence of lesions indicative of Alzheimer 's disease and other dementing conditions has long been recognized in a subgroup of patients with motor neuron disease (MND), including amyo trophic lateral sclerosis. However, the mechanisms underlying this cog nitive deterioration and its relationship with the relatively selectiv e involvement of motor neurons remains elusive. We used histo- and imm unocytochemical labeling methods to study the nitrogen monoxide (NO; a .k.a. nitric oxide) synthase (NOS)-/NADPH diaphorase-containing neuron s (NOSN) in three patients with MND and dementia (MND + D), two patien ts with MND without dementia, and 19 controls that included patients w ith Alzheimer and non-Alzheimer dementias. Patients with MND + D, but not those with MND without dementia, exhibit numerous dystrophic perik arya and neurites throughout all sensory, motor, association, and limb ic neocortices examined. Interestingly, affected NOSN appear to corres pond to some subtypes (smooth stellate and spiny neurons), while other neurons containing the same molecular phenotype (such as layer I loca l circuit neurons and layer II granule cells) are either spared or sig nificantly less affected. These observations indicate that cognitive i mpairment and dementia in MND may be due, at least in part, to a panco rtical involvement of certain types of NOSN. Consequently, the elucida tion of the factors that make NOSN vulnerable in MND, and the preventi on or pharmacological palliation of their loss, may eventually help to prevent or ameliorate cognitive impairment in MND and may also shed s ome light on the nature of the insult that targets motor neurons.