Pathologic Evaluation of the Human Suprachiasmatic Nucleus in Severe Dementia
Abstract
Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic 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 intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease 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 studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.
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AD brains show marked loss of neurons in the SCN, and SCN neuronal loss correlates with reductions in the amplitude of motor activity rhythms in the same individuals before death.
“AD brains show marked loss of neurons in the SCN243,244,262, and SCN neuronal loss correlates with reductions in the amplitude of motor activity rhythms in the same individuals before death240.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [262]
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Berra, B., & Rizzo, A. M. (2009) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2008.04.003 · Cited by 54 · see citing works
Current management of sleep disturbances in dementia
Boeve, B. F., Silber, M. H., & Ferman, T. J. (2002) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-002-0027-0 · Cited by 50 · see citing works
Petrásek, T., Vojtěchová, I., Lobellová, V., Popelíková, A., Janikova, M., Brožka, H., Houdek, P., Sládek, M., Sumová, A., Krištofiková, Z., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00250 · Cited by 51 · see citing works
- Authors
- Stopa, E. G., Volicer, L., Kuo-Leblanc, V., Harper, D., Lathi, D., Tate, B., & Satlin, A.
- Affiliations
- Harvard University (US)
- Brown University (US)
- Edith Nourse Rogers Memorial Veterans Hospital (US)
- Corresponding author
- Stopa, Edward G.
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-01
- Volume
- 58
- Issue
- 1
- Pages
- 29-39
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W1965668843
- Cited by
- 265
- References
- 0
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 11 · 2022: 7 · 2021: 19 · 2020: 20 · 2019: 10 · 2018: 13 · 2017: 11 · 2016: 16 · 2015: 9 · 2014: 11 · 2013: 10 · 2012: 14
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag009301-08, 5r01ag010682-06)
- National Institute on Aging (AG10682, AG-09301)
- National Institute of Mental Health (MH.NS 31862)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- suprachiasmatic nucleus, advanced dementia, Alzheimer's disease, circadian rhythm disruption, sleep disruption, vasopressin neurons, neurofibrillary tangles, neurodegeneration, hypothalamus, Pick's disease, hippocampal sclerosis, Parkinson's disease
- MeSH terms
- Circadian Rhythm, Dementia, Evaluation Studies as Topic, Humans, Immunohistochemistry, Male, Middle Aged, Neuroglia, Neurons, Suprachiasmatic Nucleus, Case-Control Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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