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    • br Methods br Results br

    2022-12-12


    Methods
    Results
    Discussion By following a large cohort of older persons for up to 11 years, we found that subjects with more degraded FR in motor activity (i.e., weaker temporal activity correlations at time scales < 1.5 hours as characterized by lower α values) had a higher risk for the subsequent development of AD dementia and MCI. Consistently, lower α was also associated with a faster decline of global cognitive function over time. Those associations did not change across demographic lines (such as age, sex, and education) and were independent from other risk factors including physical activity, sleep, and daily activity rhythm. The concept of FR has been applied in many fields of physiology to evaluate the health status of physiological systems and to predict the clinical outcomes in patients with diseases such as stroke and myocardial infarction [1], [7], [29]. This is the first large, community-based study to our knowledge, however, demonstrating the potential of this novel concept for predicting the risk for AD and MCI. In the cohort of the present study, the average time lag between baseline assessments and clinical AD diagnosis is 4.6 years, suggesting that the perturbation of FR is already detectable 4.6 years before the clinical AD onset. Moreover, our results also show that the ability of FR to predict incident AD dementia and MCI risk is independent of many other AD risk factors including age, physical activity, sleep fragmentation, and stability of daily activity rhythms. After adjusting for the effects of α, none of these traditional measures was significantly associated with AD risk or MCI risk, except that (1) age was still associated with incident AD dementia and incident MCI, and (2) physical activity level was still associated with incident AD dementia. Our results indicate that FR may be another risk factor for AD, and its degradation may be integral to AD pathology. Previous studies showed that AD and other BRD 7552 sale pathologies affect diverse clinical phenotypes and are related to level of diverse motor constructs [30], [31], [32], [33], [34] and that poorer motor function (e.g., lower physical activity level, loss of muscle strength and bulk, and physical frailty) predicts MCI, AD, and cognitive decline [20], [34]. These findings raise the hypothesis that motor dysfunction and cognitive impairment may share certain common pathophysiology (i.e., brain pathology). Supporting this hypothesis, the present study showed a strong association between degraded FR of motor activity and cognitive decline. Regarding the specific neuronal circuitries linking motor regulation and cognition, the neural network of the circadian control system may be one of the candidates because disrupting the circadian control acutely causes cognitive impairment [35], [36], and long-term circadian disruption, as occurred to chronic shift work, is associated with accelerated brain aging [37]. Indeed, it is proposed that circadian dysfunction is one early sign of AD, preceding the onset of cognitive symptoms [38] and that it may exacerbate the progression of this disease [18], [19], [21], [39]. More relevant to FR, our animal and human studies showed the circadian control system impacts fractal activity regulation [2]. In rats, lesioning of the suprachiasmatic nucleus—the well-established central circadian clock in mammals [40]—causes a breakdown of fractal activity patterns with different temporal structures at time scales < 2 hours and >4 hours [41]. In a human postmortem study, perturbed FR was associated with reductions in the amounts of two major circadian neurotransmitters in the suprachiasmatic nucleus (i.e., the vasopressinergic and neurotensinergic neurons) [42]. In addition, fractal activity patterns are perturbed in chronic shift workers during night shifts [43]; and certain interventions such as light treatments that are normally used to treat sleep and circadian disorders turn out to be beneficial for cognition and fractal activity regulation in patients with dementia [11]. Thus, circadian dysfunction may explain degraded fractal activity regulation and its prediction for AD risk.