32 Sleep in neurodegeneration ISMC 2021 · The clinical presentation can be different and masked by other medical comorbidities. Certain sleep ... • “Take me through a typical

Biography  

Dr Kirstie Anderson 

Consultant Neurologist and Honorary Senior Lecturer 

Dr Anderson,  Consultant Neurologist  and Honorary  Senior  Lecturer, works within  one of  the UK’s 

largest  sleep  services  in  Newcastle  and  explores  the  links  between  sleep,  mental  health  and 

neurodegeneration within her research in Newcastle University. She was the clinical lead developing 

the online  insomnia programme Sleepstation, now available within the NHS. As one of the few UK 

neurologists  to  specialise  in  sleep,  she  sees  and  treats  paediatric  and  adult  sleep  disorders,  has 

published widely on sleep disorders and lectures regionally and nationally. She is current president 

of the Sleep Medicine section of the Royal Society of Medicine and runs annual sleep training days in 

Newcastle. 

Abstract 

The  lecture  will  provide  an  understanding  of  the  role  of  sleep  and  sleep  disorders  in 

neurodegeneration.  Firstly  it  is  necessary  to understand  the normal  changes  in  sleep with  ageing. 

Next the talk will cover the primary sleep disorders which are common in those over the age of 65. 

The clinical presentation can be different and masked by other medical comorbidities. Certain sleep 

disorders and in particular REM sleep behaviour disorder can predict subsequent neurodegenerative 

disorders  and  finally  an  approach  to  the  management  of  poor  sleep  in  the  neurodegenerative 

disorders will be covered including common clinical scenarios. 

Learning objectives 

1, To understand sleep physiology during normal ageing 

2.  To  understand  the  common  primary  sleep  disorder  and  approach  to  diagnosis  in  those  with 

neurodegenerative conditions 

3. To understand the pattern of sleep disturbance in neurodegeneration and parkinson’s disease in 

particular and an approach to treatment alongside common clinical scenarios 

References 

Li J, Vitiello MV, Gooneratne NS. Sleep in Normal Aging. Sleep Med Clin. 2018 Mar;13(1):1‐11. doi: 

10.1016/j.jsmc.2017.09.001. 

Wilson  S,  Anderson  K,  Baldwin  D,  et  al.  British  Association  for  Psychopharmacology  consensus 

statement on evidence‐based treatment of  insomnia, parasomnias and circadian rhythm disorders: 

An update. J Psychopharmacol. 2019 Aug;33(8):923‐947. doi: 10.1177/0269881119855343.  

Postuma RB,  Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in  idiopathic 

REM  sleep  behaviour  disorder:  a  multicentre  study.  Brain.  2019  Mar  1;142(3):744‐759.  doi: 

10.1093/brain/awz030 

Louter M, Aarden WC, Lion J, Bloem BR, Overeem S. Recognition and diagnosis of sleep disorders in 

Parkinson's disease.  J Neurol. 2012 Oct;259(10):2031‐40. doi: 10.1007/s00415‐012‐6505‐7. 

Leng  Y,  Musiek  ES,  Hu  K,  Cappuccio  FP,  Yaffe  K.  Association  between  circadian  rhythms  and 

neurodegenerative  diseases.  Lancet  Neurol.  2019  Mar;18(3):307‐318.  doi:  10.1016/S1474‐

4422(18)30461‐7. 

32 Anderson Sleep and neurodegeneration

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Sleep and neurodegeneration“the past is a foreign country, they do things differently there”

1. Sleep and circadian rhythm in ageing

2. Primary sleep disorders in the elderly

3. Sleep disturbance within neurodegeneration

..

Van Cauter et al. JAMA 2000

SWS

32 Anderson Sleep and neurodegeneration

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The Ageing HoursAge 35

Age 75

The Ageing Clocks

Decreased circadian amplitude

Phase advance by 30 minutes a decade

Decreased ability to tolerate phase shift declines eg shift work, jet lag

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Ageing Glymphatics – is bad sleep neurotoxic

The glymphatic system – waste clearance system for the mammalian central nervous system – clearance of the interstitial fluid and extracellular fluids. Facilitated by aquaporin water channels

“Sleep drives metabolic clearance from the adult brain” Science 2013 Xie et al. with a 60% increase in the interstitial fluid space during sleep

Increased rate of B amyloid clearance –therefore sleep to remove potentially neurotoxic waste products.

In-vivo two photon imaging using small fluorescent tracers

Illiff and Needergard2012

Measuring sleep in ageing

Actigraphy 65yr olds

Objective versus subjective sleep complaintsMrOS recruited from 2003-2005, Home PSG 2,601 at baseline. Wrist actigraphy , AMT6s and self report. Average follow up 3.5 yearsMultiple analyses but…fragmented sleep and objectively reduced TST predicts cognitive decline, depression but does not correlate with self report EDS or PSQI. Lower nocturnal melatonin predicts worse EDS and poorer night sleep

1. Blackwell T et al. Sleep 20142. Song Y et al. Sleep 20153. Smagula SF et al. Am J Psychiatry 2015

The Newcastle 85+ cohort study (421 patients)Anderson KN et al. Age and Ageing 2014PSQI ESS useless

32 Anderson Sleep and neurodegeneration

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Summary

Objective evidence of impaired sleep homeostat and circadian rhythm (the hours and the clocks) with greatest changes from early 30s to 60s

Decrease in TST by approx. 30 minutes a decade from middle age with marked decline in percentage of slow wave sleep

In elderly subjective complaints highly variable and daytime naps not clearly correlated with objective sleepiness

Other medical comorbidities correlate with worse sleep. Sleep disruption for any reason is associated with increased mortality and morbidity and impaired cognition.

Bad sleep is neurotoxic – whatever the reason

Primary sleep disorders in ageing

Up to 50% of older adults complain of significant chronic sleep disturbance (Foley et al. 1995)

• Obstructive sleep apnoea 10% of men over 40, 5% of women• Restless legs syndrome 5%• Parasomnia 2-3 %• Insomnia 5%• Circadian Rhythm Disorder

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Take A Sleep History• Snoring +/- witnessed apnoeas, neck circ > 17, increased BP (STOPbang)• Restless legs ? – duvet off, hot feet, PLMS (15-30 secs for most)• “Take me through a typical 24 hours”• “Are you out of the house every day?”• Daytime napping versus fatigue – partner history where possible• For insomnia – typically a low Epworth Sleepiness Score (beware the three R’s –

RLS, reflux, rhythm)• Epworth Sleepiness Score (added value when also from spouse)

• The rest of the prescription• Uppers -nasal decongestants, OTC painkillers, betahistine, inhalers• Downers – opioids, pregabilin, gabapentin, amitriptyline• Caffeine – count the cups, nicotine and alcohol

Obstructive sleep apnoea in older adults

10-20% prevalence in >65

May present atypically (lower BMI, “insomnia”, falls, cognitive impairment)Evidence for CPAP improving attention, cognition, decreasing falls and cardiovascular outcomeCPAP effective at all ages when symptomatic including those over 75Therefore screen if symptomatic sleepiness in all with treatment resistant hypertension, AF, diabetes, vascular events (STOPbang)Treatment - Effect on cognition in the well elderly not proven to date with RCTDriving safety – the past predicts the future – ask about crashes/near misses. 5-7X increased risk of serious crash with untreated OSA

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Restless Legs SyndromeAt least 10% of sleep disturbed PD, 30% of diabetics, co-existent sleep apnoea. Increased age a risk factor. Typically variable but progressive over the years when severe.The best diagnostic test – ask the patient!

Lifestyle first –nicotine/caffeine/alcohol/ferritin replacement if below 75, ?aggravating medications

Dopamine agonists, Ropinirole, Pramipexole, Rotigotine patch – all licensed but. 5-11% ICD at least and augmentation over time in 50-70%

•Pregabilin/Gabapentin but evening only•Not melatonin/amitriptyline/mirtazepine•(IV iron – RCT mixed results – helpful for some who can’t tolerate other treatments)

Insomnia Disorder in neurodegeneration

“How do people go to sleep? I'm afraid I've lost the knack.” ― Dorothy Parker

If no trouble falling asleep – consider OSA

Difficulty falling asleep but not staying asleep, consider RLS

First line treatment CBTi – greater evidence for exercise in older adults

Increased risk of falls with hypnotics in the elderly (Xu and Anderson ACNR, 2018).

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“The sleep becomes much disturbed”

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Sleep disturbance in Parkinsonian disorders

• Common, early non-motor symptom. 90-100% in advanced.

• Daytime sleepiness, distinct from sleep attacks (which are uncommon)

• Insomnia – often with night pain and bradykinesia

• RBD and vivid dreams (severe and early in multiple system atrophy)

• Nocturia

• Restless legs

• Sialorrhoea

Sleep and Parkinson’s Disease

ICICLE-PD 159 PD patients at diagnosis assessed every 18monthsSleep sub study – 110 patients and 97 controls.

No correlation between PSQI/ESS/Oximetry. Increased PLMS but not symptomatic RLSPD had more daytime naps but didn’t rate themselves sleepier

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RBD and Parkinson’s disease• The most robust non-motor prodromal

symptom to date. A predictor of early cognitive impairment and visual hallucinations

• 50% of those within a PD clinic, 50% of those with RBD will develop a neurodegenerative problem within 5 years. 91% at 15 years, 70% will have injury

• Normal velocity movements retained in even advanced PD but loss of dream recall common with cognitive impairment

• 10% get better and not all need treatment

Is RBD ever really idiopathic ?

•Postmortem studies suggest lewy body pathology

•50% of patients with confirmed idiopathic RBD have mild cognitive impairment

•DAT scans do progress and predict neurodegeneration (for review of brain imaging findings. Heller et al. Sleep Med Rev. 2016)

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Approach to poor sleep in Parkinson’s disease

Snoring apnoeas (stridor – MSA) drugs (timing, dose), typical 24 hours with sleep diaries if possible, ESS, STOPbang

RBD +/- self injury at night, or partner injury

Nocturia,

Restless legs or restless head (insomnia) ?

Depression – 20% have hypersomnia not EMW, limited evidence for tricyclics, SNRI over SSRI

Sialorrhoea – anticholinergics, clonidine, botox

Modafinil – mixed results from RCTs, headache common, dose range 100-400mg

Cholinesterase inhibitors alerting, may improve RBD

Sialorrhoea – anticholinergics, clonidine, botox

For a flow chart – Louter et al. Journal of Neurology 2012

Can sleep predict which neurodegeneration?

•With questionnaires alone ?

•Primary sleep disorders common in all groups

•RBD the strongest marker for PDD/DLB

•Daytime / fluctuating more common in PDD/DLB

•Sleep apnoea in vascular dementia (VaD)

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Common clinical questions• Q. Sleepy - Do I stop the dopamine agonist? Or switch to an even more expensive

drug?• A. sleepiness commonest at initiation and often wears off, long acting agonists some

benefit improving sleep• Q. Do they need a full sleep study? And will it change the diagnosis• A. Often not, except possibly young onset PD or possible MSA, or research trials but

screen for sleep apnoea more than you are doing• Q. Driving?• A.near misses, claims, accidents at the wheel in the last 12 months? ESS > 17• symptomatic sleepiness due to obstructive sleep apnoea is notifiable to DVLA and

most car insurers, PD notifiable and daytime sleepiness specifically mentioned. • Dementia and driving – history from spouse, issues are multifactorial and need

regular review but “are you still happy for grandad (or grandma) to drive the grandchildren?” my most useful question. ESS from relative as well as patient. Self report sleepiness less useful in those with cognitive impairment.

• Consider driving assessment at your local rehab centre (UK - typically free or low cost)

Summary• Sleep and circadian rhythm disturbance are a biomarker for a badly ageing

brain?• Primary sleep disorders are common and treatable – take a sleep history in all

those with cognitive impairment. Do you go outside every day? Sleep apnoea10%.

• REM sleep behaviour disorder – the most robust predictor of a neurodegeneration. With careful screening 50% have MCI at diagnosis. RCTs still awaited but melatonin has the best safety profile of the current therapies. Ongoing functional imaging research to predict those at high risk of conversion

• Sleep disturbance in PD is multifactorial, nocturia, night bradykinesia, daytime sleepiness, depression (RBD and sleep attacks). So take a history.

• Bright light, physical activity, regular schedules for all