CIRCADIAN RHYTHM DYSFUNCTION IN ALZHEIMER’S DISEASE: HOW TO DETERMINE CIRCADIAN PHASE AND THE ROLE OF TAYLORED LIGHT THERAPY ON SLEEP AND COGNITION

In this thesis circadian rhythm alterations in Alzheimer’s disease (AD) are taken into account, in particular concerning the early stage of disease. In the first part of this 3-year work the research was focused on determining the circadian phase in early AD patients using subjective and objective measures: clinical scales, sleep-wake diaries, salivary melatonin determination (DLMO), phase angles between sleep and melatonin onset. To achieved this goal we performed a case-control observational study comparing the circadian phase of early AD patients elderly healthy controls (Hc). The main results of this first step were that Initial evening secretion of melatonin proves to be delayed and mildly impaired in patients with mild/moderate form of Alzheimer disease while patient’s subjective sleep parameters and chronotype are reported similar to those of HC. This data indicate that, subclinical altered patterns of melatonin secretion occur in subjects with AD at an early stage of the disease. The second part of the study aimed at comparing circadian phase of early AD patients to the one of another neurodegenerative dementia (OD), determining melatonin secretion in different biological fluids at different daytime. This case-control observational study was performed enrolling patients affected by probable Frontotemporal lobar degeneration (FTLD) and cortico-basal syndrome (CBS) at the early stage of the disease. The main results of this second step were that evening melatonin secretion was confirmed to be delayed and impaired in both AD and OD groups than Hc, but with some important differences between groups: in AD patients melatonin secretion was more delayed and less decreased than OD patients, at this fact was not affected by other factors than disease diagnosis. Furthermore, OD and AD patients showed an higher rate of phase angle alterations and circadian phase misperceptions than Hc. Melatonin secretion proved to correlate in the different biological fluids at a certain time among patients, an this finding support the use of DLMO determination in saliva as a sensitive marker of circadian phase. The third part of the work was focused on the use of a circadian phase modulator in order to interact with the circadian phase of AD patients and evaluate the effect on sleep and cognition. After a systematic review of the literature on this topic, light therapy showed some, albeit limited evidence supporting its use as circadian rhythm modulator in sleep disturbances and agitation in persons with cognitive impairment, with most studies examining light exposure reporting positive effects on at least one sleep measure. However, light therapy, including BLT, did not show any significant effect in 4 recent systematic reviews and meta-analysis including a Cochrane review specifically examining the results of RCTs. This suggests that the evidence supporting light therapy is at best equivocal due to the heterogeneity in sample size, degree and subtype of dementia, study design, type of light therapy and devices used. The future studies might include randomized controlled trials on specific subtypes of dementia, using preferentially blue-enriched light therapy carefully controlled, which effect must be verified with objective measures. Taking into account this evidences, we performed a single blind randomised control trial to investigate the effects of a tailored light therapy protocol on sleep and cognition parameters in patients with Alzheimer Disease (AD) of mild /moderate severity. The preliminary findings of this study showed that light therapy protocol tailored on the circadian phase proved to be feasible and associated to an objective phase shift in accordance to the melatonin phase response curve, a trend to an increased subjective sleep quality, 24-hour TST and cognitive performance.