circadian rhythms and functioning …scn-output signal vasopressin and mrna at high age and even...
TRANSCRIPT
Circadian rhythms and functioning
in neurodegenerative disease
Eus Van SomerenNetherlands Institute for Neuroscience
&
Leiden University Medical Center
Amsterdam, The Netherlands
AcknowledgementAcknowledgement
S&C team members, for the presented work mostly RixtRiemersma; Dick Swaab (NIN); Erik Scherder & JoukjeOosterman (VU).
The clinical problemThe clinical problem
Inability to sleep increases
with aging?
Or not ? ....
Fragmentation and amplitude lossFragmentation and amplitude loss
Huang et al, (2002) Physiol Behav 76: 597-603
Cayetanot et al. (2005) J Biol Rhythms 20: 461-69
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A
Human
Non-human primate
The clinical problem: relevanceThe clinical problem: relevance
In demented elderly, nocturnal
restlessness is a primary cause for
institutionalisation
The biological problem: clues.The biological problem: clues.
Suprachiasmatic Nucleus (SCN):
Decrease of (rhythmic)expression ofSCN-output signalvasopressin and mRNAat high age and evenmore so in dementia
Swaab et al. Brain Res (1985) 342: 37-44
Hofman MA and Swaab DF (1994) Brain Res 651:134-142
Liu et al. J Neuropathol Exp Neurol (2000) 59: 314-22
The biological problem: clues.The biological problem: clues.
Hypothalamic Suprachiasmatic Nucleus (SCN):
Ante-mortem sleep-wake fragmentation correlates withpost-mortem vasopressin expression in dementia
Harper et al. (2008) Brain, 131:1609- ; Hu, Van Someren et al. (2009) PNAS, 106:2490-
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C
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A
Maintenance of function of
the circadian timing system in
demented elderly is promoted
by regular input.
The biological problem: hypothesesThe biological problem: hypotheses
Light
Van Someren et al. 2002 Progr. Brain Res. 138: 250-31
The biological problem: hypothesesThe biological problem: hypotheses
Van Someren EJW et al. 1996) Biol Psychiatry 40:259-270
Van Someren EJW et al. (2002) Prog Brain Res 138:205-231
Lucassen PJ et al. (1995) Brain Res 693:261-266
Witting W et al. (1993) Brain Res Bull 30:157-162
Maintenance of function of
the circadian timing system
in (demented) elderly is
promoted by regular input.
2:19 PM, 27 lux0
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young (3 mo) middle aged (2 yr) old (3 yr)
Age
AV
P cell num
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low light intensity
high light intensity
Lack of light exposure, the primary input to the
SCN predicts severity of sleep-wake rhythm
disturbance in dementia
Additional light restores SCN-Vasopressin and
sleep-wake rhythm amplitude in old rats
(picture: courtesy of Sonia Ancoli-Israel)
Light
ApproachApproach
Manipulate SCN-input in dementia: (light)
Okawa et al. (1989) Jap J Psychiatry Neurol 43: 293-5(picture: courtesy of Masako Okawa)
ApproachApproach
Manipulate SCN-input in dementia: (light)
Satlin et al. (1992) Am J Psychiatry 149:1028-32
ApproachApproach
Van Someren et al. (1997) Biol Psychiatry 41:955-63
Results (Short Term)Results (Short Term)
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Van Someren et al. (1997) Biol Psychiatry 41:955-63
A better approach is required...A better approach is required...
Cochrane review Forbes 2004: “.... no adequate evidence of
the effectiveness of BLT in managing sleep, behaviour, and
mood disturbances associated with dementia”
A better approach is required...A better approach is required...
Approach (Long Term)Approach (Long Term)
Manipulate SCN-input: (light)
LTMCDBPCRCT, n=189
max 3.5 yrs:
light<>placebo0
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ApproachApproach
Manipulate input:
light >> placebo
mainly 10:00-17:00 hr
caregivers experience
equal (p=0.62)
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Time of day
Lig
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Pre
Light
Placebo
ResultsResults
Sleep-wake rhythm:
Light:
Amplitude increase (8%)
Riemersma-van der Lek et al. (2008) JAMA 299:2642-
Activity rhythm amplitude
ResultsResults
Depressive symptoms
depressive symptomsLight effects:
Improved CSDD (-19%)
Riemersma-van der Lek et al. (2008) JAMA 299:2642-
ResultsResults
Functional Limitations (ADL)
Light effects:
Improved NI-ADL
(-53%, rate of worsening)
Riemersma-van der Lek et al. (2008) JAMA 299:2642-
Functional limitations
ResultsResults
Cognitive decline
ResultsResults
Cognitive decline
MMSE
Light: 0.88±0.43
Riemersma-van der Lek et al. (2008) JAMA 299:2642-
Results compared to Cholinesterase-inhibitorsResults compared to Cholinesterase-inhibitors
Cognitive decline
MMSE:
Light: 0.88±0.43
Riemersma-van der Lek et al. (2008) JAMA 299:2642-
Brain areas sensitive to fragmented sleep 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. (2008) JAMA 299:2642-
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.
ConclusionConclusion
Reason to continueReason to continue
* 2 yrs
* at home
* early dementia
* skeleton photoperiod
