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Musiek ES, Bhimasani M, Zangrilli MA, Morris JC, Holtzman DM, Ju YS. Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):582-590. PubMed.
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Instituto de Medicina Molecular, Fac Medicine Lisbon
Circadian rhythms—physiological and behavioral cycles with a periodicity of approximately 24 hours—are generated by an endogenous biological clock, mastered by the suprachiasmatic nucleus (SCN) in the hypothalamus. Recent research suggests circadian dysfunction contributes to, and escalates, neurodegenerative pathologies. In clinical studies, dampened or shifted circadian rhythms in aging individuals were predictive of increased risk of mild cognitive impairments and dementia. Similarly, weaker circadian rhythms were also predictive of future cognitive impairments in older individuals without dementia. In many cases, the cognitive disruptions may be secondary to compromised neural circuitry where brain regions regulating output rhythms are disturbed.
Nevertheless, it has been difficult to establish whether circadian system disturbances contribute to age-related memory loss or they are merely symptomatic of the disease process.
One potential candidate as central synchronizer is adenosine, which modulates excitability in several brain areas and is considerably altered upon aging. We found evidence of a glucocorticoid-adenosine link in Alzheimer’s disease (Laurent et al., 2014), following previous work pinpointing circadian disorders, linked to adenosine dysfunction, as a trigger for accelerated cognitive loss (Batalha et al., 2013).
The fact that circadian rhythm abnormalities were now reported in the preclinical phase of Alzheimer’s disease in this paper, prior to occurrence of any sleep disorder, strongly supports the idea that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.
Taken together, the evidence strongly suggests that the circadian dysfunction is a multifactorial condition associated with age-related cognitive loss. In my view, a more objective and systematic approach to test this hypothesis is needed. This is now becoming possible with the novel, minimally invasive, and highly sensitive tools at our disposal. Those in the field must strive to search for an objective definition of human endophenotype for circadian disorders, to clearly identify the circadian players in cognitive dysfunction and finally to validate these mechanisms in cognitive-impaired patients with known circadian disturbances. I believe that the possibility of establishing the pattern of central clock gene expression and hormone oscillations in patients, the use of functional MRI to diagnose hypothalamus-hippocampus feedback control, and the novel and more reliable ways of associating activity/sleep to cognitive performance will definitely push the chronobiology forward.
References:
Laurent C, Burnouf S, Ferry B, Batalha VL, Coelho JE, Baqi Y, Malik E, Mariciniak E, Parrot S, Van der Jeugd A, Faivre E, Flaten V, Ledent C, D'Hooge R, Sergeant N, Hamdane M, Humez S, Müller CE, Lopes LV, Buée L, Blum D. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry. 2014 Dec 2; PubMed.
Batalha VL, Pego JM, Fontinha BM, Costenla AR, Valadas JS, Baqi Y, Radjainia H, Müller CE, Sebastião AM, Lopes LV. Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry. 2013 Mar;18(3):320-31. Epub 2012 Feb 28 PubMed.
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