Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia

Abstract

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain-behaviour relationships in the human.

Melanopsin retinal ganglion cell loss in Alzheimer disease

“…Neuronal loss and classical AD neuropathology have been shown in the SCN 2, 5, 6, 7. A recent longitudinal study also demonstrated a significant loss of neurons in the hypothalamic ventrolateral preoptic nucleus correlated with sleep fragmentation, as documented by actigraphic recordings 72.…”

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…Harper et al (44) also provide evidence that neuropathological progression (as measured by Braak stage) in postmortem AD brains is associated with the severity of circadian abnormalities, suggesting that the circadian rhythm disturbances in AD are directly linked to the central neuropathology of the disease. There is also evidence for neurodegeneration in the SCN in both AD and frontotemporal dementia, as determined by the neuron/glia ratio, and this degeneration correlates to the magnitude of circadian rhythm impairment in core body temperature and activity parameters (45). Loss of SCN neurotensin cells was also associated with dampened activity rhythm amplitude but not with increased fragmentation of the rhythm, although loss of AVP neurons in the dorsomedial SCN was associated with rhythm fragmentation but not dampened amplitude (45).…”

“…There is also evidence for neurodegeneration in the SCN in both AD and frontotemporal dementia, as determined by the neuron/glia ratio, and this degeneration correlates to the magnitude of circadian rhythm impairment in core body temperature and activity parameters (45). Loss of SCN neurotensin cells was also associated with dampened activity rhythm amplitude but not with increased fragmentation of the rhythm, although loss of AVP neurons in the dorsomedial SCN was associated with rhythm fragmentation but not dampened amplitude (45). Expression of the MT1 melatonin receptor in the SCN is also markedly decreased in late stage AD (40).…”

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…However, the correlation between the neuron-glia ratio and nucleoside levels in the human brain is weak (Kovács et al 2010a ) . Importantly, the neuron-glia ratio is changed in some brain areas implicated in the development of major depressive and bipolar disorders, schizophrenia, Huntington's and Alzheimer's disease, and frontotemporal dementia (Bowley et al 2002 ;Brauch et al 2006 ;Harper et al 2008 ;Öngür et al 1998 ;Roos et al 1985 ) . Table 29.1 shows that altered nucleoside metabolic enzyme activity may result in an uneven distribution of nucleosides and their metabolites in the human brain (Kovács et al 2010a (Table 29.1 ).…”