Circadian rhythms and functioning in neurodegenerative disease

Transcription

1 Circadian rhythms and functioning in neurodegenerative disease Eus Van Someren Netherlands Institute for Neuroscience & Leiden University Medical Center Amsterdam, The Netherlands Acknowledgement S&C team members, for the presented work mostly Rixt Riemersma; Dick Swaab (NIN); Erik Scherder & Joukje Oosterman (VU).

2 The clinical problem Inability to sleep increases with aging? Or not?... Fragmentation and amplitude loss Human A Non-human primate Huang et al, (2) Physiol Behav 76: Cayetanot et al. (5) J Biol Rhythms 2:

3 The clinical problem: relevance In demented elderly, nocturnal restlessness is a primary cause for institutionalisation The biological problem: clues. Suprachiasmatic Nucleus (SCN): Decrease of (rhythmic) expression of SCN-output signal vasopressin and mrna at high age and even more so in dementia Swaab et al. Brain Res (1985) 342: Hofman MA and Swaab DF (1994) Brain Res 651: Liu et al. J Neuropathol Exp Neurol () 59:

4 The biological problem: clues. Hypothalamic Suprachiasmatic Nucleus (SCN): Ante-mortem sleep-wake fragmentation correlates with post-mortem vasopressin expression in dementia C A 1 5 Harper et al. (8) Brain, 131:169- ; Hu, Van Someren et al. (9) PNAS, 16:249- The biological problem: hypotheses Maintenance of function of the circadian timing system in demented elderly is promoted by regular input. Light Van Someren et al. 2 Progr. Brain Res. 138: 25-31

5 The biological problem: hypotheses Maintenance of function of the circadian timing system in (demented) elderly is promoted by regular input. Light 2:19 PM, 27 lux Lack of light exposure, the primary input to the SCN predicts severity of sleep-wake rhythm disturbance in dementia (picture: courtesy of Sonia Ancoli-Israel) AVP cell number low light intensity high light intensity young (3 mo) middle aged (2 yr) old (3 yr) Age Additional light restores SCN-Vasopressin and sleep-wake rhythm amplitude in old rats Van Someren EJW et al. 1996) Biol Psychiatry 4: Van Someren EJW et al. (2) Prog Brain Res 138: Lucassen PJ et al. (1995) Brain Res 693: Witting W et al. (1993) Brain Res Bull 3: Approach Manipulate SCN-input in dementia: (light) (picture: courtesy of Masako Okawa) Okawa et al. (1989) Jap J Psychiatry Neurol 43: 293-5

6 Approach Manipulate SCN-input in dementia: (light) Satlin et al. (1992) Am J Psychiatry 149: Approach Van Someren et al. (1997) Biol Psychiatry 41:955-63

7 Results (Short Term) : 18: 23: 4: 9: 19: 5: : 18: 23: 4: 9: 19: 5: : 18: 23: 4: 9: 19: 5: Van Someren et al. (1997) Biol Psychiatry 41: A better approach is required... Cochrane review Forbes 4:... no adequate evidence of the effectiveness of BLT in managing sleep, behaviour, and mood disturbances associated with dementia

8 A better approach is required... Approach (Long Term) Manipulate SCN-input: (light) LTMCDBPCRCT, n=189 max 3.5 yrs: light<>placebo

9 Approach Manipulate input: 14 1 light >> placebo mainly 1:-17: hr caregivers experience equal (p=.62) Light intensity (lux) Pre Light Placebo 3: 6: 9: 15: 18: 21: Time of day Results Sleep-wake rhythm: Activity rhythm amplitude Light: Amplitude increase (8%) Riemersma-van der Lek et al. (8) JAMA 299:2642-

10 Results Depressive symptoms Light effects: Improved CSDD (-19%) depressive symptoms Riemersma-van der Lek et al. (8) JAMA 299:2642- Functional Limitations (ADL) Results Light effects: Improved NI-ADL (-53%, rate of worsening) Functional limitations Riemersma-van der Lek et al. (8) JAMA 299:2642-

11 Results Cognitive decline Results Cognitive decline MMSE Light:.88±.43 Riemersma-van der Lek et al. (8) JAMA 299:2642-

12 Results compared to Cholinesterase-inhibitors Cognitive decline MMSE: Light:.88±.43 Riemersma-van der Lek et al. (8) JAMA 299:2642- Brain areas sensitive to fragmented sleep What are the neuronal networks that mediate the link between sleep & cognition in elderly? Riemersma-van der Lek et al. (8) JAMA 299:2642-

13 Conclusion Hippocampal/MTL sensitivity to fragmentation and a loss of amplitude of the circadian rhythm in activity. Light can be applied to enhance the sleep-wake rhythm, cognition and mood. Reason to continue * 2 yrs * at home * early dementia * skeleton photoperiod

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