Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia

Sleep disruption and other circadian rhythm disturbances are frequently see n in dementia patients. In this study, we examined the suprachiasmatic nucl eus (SCN), the putative site of the hypothalamic circadian pacemaker, to de termine the nature and degree of pathologic changes caused by severe dement ia. Neuropathologic examination indicated that among 30 patients with a cli nical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheim er disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick dise ase and 2 had severe hippocampal sclerosis. Comparisons were made with a co ntrol group composed of 13 age-matched patients with no clinical or patholo gical evidence of dementia or other CNS disorders. To determine the patholo gic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intest inal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neuro fibrillary tangle formation. Only rare diffuse plaques were noted. The path ologic changes within the SCN were less severe than in the other brain regi ons. Morphometric analysis was accomplished using a stereological, approach to sample the average total number of positively stained neurons and astro cytes in 10 different 0.1mm(2) microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrea se in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These stud ies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable in dicator of disease-related pathology within the SCN. Taken collectively, ou r data support the hypothesis that damage to the SCN may be an underlying a natomical substrate for the clinically observed changes in circadian rhythm icity that have been observed in Alzheimer patients.