Several observations suggest that neuronal shrinkage rather than cell death is the major phenomenon in neurodegenerative diseases. In order to make this distinction, smaller cells should also be included in cell counts. Also, morphometric determination of total cell numbers of brain structures is required. Morphometry was performed on the locus coeruleus using a newly developed method to delineate this nucleus from five patients who had died with Alzheimer's disease, five with Parkinson's disease, five with amyotrophic lateral sclerosis and from five control subjects who had died from causes that would not have affected the locus coeruleus. The length and volume of the locus coeruleus and its total number of large pigmented neurons, small unpigmented neurons and glial cells were determined. Since reliable delineation of the boundaries of the locus coeruleus is a requirement for the determination of total cell numbers, an image analyser-assisted procedure was developed. In Alzheimer's disease we found an 82% decrease in the number of large pigmented neurons and a 39% decrease of small unpigmented neurons. In Parkinson's disease, we found a 39% decrease of large pigmented neurons but also a 44% (though not significant) increase of small unpigmented neurons, which is indicative of a shift from large pigmented neurons to small unpigmented neurons in Parkinson's disease. The large pigmented/small unpigmented neuron number ratio was greatly and significantly reduced in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. These findings support the hypothesis that the decrease of large pigmented neurons of the locus coeruleus in some neurodegenerative diseases is not entirely due to cell death, but rather to cell shrinkage and a loss of phenotype. This hypothesis may have consequences for the development of therapeutic strategies since atrophied cells can be activated. On the other hand our data confirm that, at least in Alzheimer's disease, large pigmented neurons do also undergo cell death.