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K Ray Chaudhuri MD FRCP (Lond, Edin) DSc (Lond)Consultant Neurologist and Professor of Neurology and Movement Disorders
The impact of Covid-19 on the PD community
Parkinson’s Foundation Centre of Excellence
King’s College Hospital, King’s College London, London, UK
FATIGUE IN PARKINSON’S DISEASE: HIDDEN FACE REVEALED
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• Advisory board: AbbVie, UCB , GKC, Bial, Cynapsus, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Therevance, Scion, Britannia, Acadia, 4D
• Honoraria for lectures: AbbVie, Britannia, UCB, Zambon, Novartis, BoeringerIngelheim, Bial
• Grants (Investigator Initiated): Britania Pharmaceuticals, AbbVie, UCB, GKC, Bial
• Aacdemic grants: EU, IMI EU, Horizon 2020, Parkinson's UK, NIHR, PDNMG, EU (Horizon 2020), Kirby Laing Foundation, NPF, MRC, Wellcome Trust
Disclosures
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FATIGUE
Friedman et al. NPJ Parkinsons Dis 2016;2:15025.
“A sense of exhaustion for a defined period that is unexplained by drug effects, medical,
or psychiatric disorders.”
“Significantly diminished energy level or an increased perception of effort disproportionate
to attempted activities”Kluger et al. Neurology 2013;80:409-416
Often associated with:
• Difficulty in initiating or sustaining voluntary activity / reduced motivation
• Nonrestorative rest
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Patients report fatigue as a problem that affects their lives
• European Parkinson’s Disease Association survey (1999), N>8,000: 92% thought ‘tiredness’ had significant impact on daily function
• Brown et al (1995): N=711, fatigue ‘problematic’ in 67%
• Brown et al (2011): N=513, 45% report doing less because of fatigue (or to avoid fatigue)
• Friedman et al (1993): >50% reported fatigue as ‘one of 3 most disabling symptoms’, 33% the most disabling
• Gallagher et al (2010): Fatigue strongest predictor, with depression, of QoL (PDQ-39, r=0.74)
Clinical significance of fatigue
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REM sleep behaviour disorder
(RBD)
80% progression to alpha synucleinopathy in
approximately 10-12 years
REM sleep behaviour events Polysomnographic evidence of developing RBD
Late onset hyposmia/anosmia Progression to motor PD
Episodic major depression Prodromal PD feature
Constipation Higher risk of developing PD
Excessive daytime somnolence Higher risk of developing PD
Fatigue Higher risk of developing PD
Abnormal colour vision/visual
perception
Higher risk of developing PD
Erectile dysfunction Higher risk of developing PD
Pain (often unilateral) Pain often evident on side first affected at
motor PD diagnosis
Cognitive impairment Recent evidence of prodromal feature from
PPMI cohort studies
Prodromal non-motor Parkinson’s disease
Postuma RB et al. Neurology 2015;84:1104-13
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Early (‘pre-diagnostic’) but persistent symptom
“I realised that nobody had my after match routine. Usually the adrenaline is still pumpingand most of the lads would be talking about what happened on the pitch, grabbing a coke orchicken leg. They were always doing something-all except me. I used to slump hunched in myseat too tired to talk or move.”[Ray Kennedy, former Arsenal and Liverpool – in Lees AJ, Mov Disord 1992]
Fatigue
Schifitto et al., Neurology 2008Schrag et al., Lancet Neurol 2015
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Movement Disorders 2016
SMN and DMN connectivity changes. (A) ROI analysis within the SMA cluster and whole-brain significant connectivity differences within LPFC and PCC-PrC clusters between f-PD and nf-PD patients (P < 0.05 corrected) overlaid on the standard “Colin-27” brain T1 template. (B) Bar graphs of the ROI-averaged ICA z-scores (6SD) for HCs, f-PD, and nf-PD patients (SMA: HCs, 1.4 6 0.2; nf-PD, 1.3 6 0.2; f-PD, 0.8 6 0.2; #P 5 0.7; §*P < 0.001; LPFC: HCs, 1.6 6 0.4; f-PD, 1.5 6 0.4; nf-PD, 0.5 6 0.3; §P 5 0.8; #*P < 0.001; PCC-PrC: HCs, 2.8 6 0.3; f-PD, 2.6 6 0.5; nf-PD, 1.1 6 0.6; §P 5 0.6; #*P < 0.001). (C) Positive and negative correlations between PFS-16 scores and SMA and DMN average ICA z-scores in f-PD. #HCs vs. nf-PD; §HCs vs. f-PD; *f-PD vs. nf-PD. R, right.
Distressing fatigue in drug-
naïve patients with early
PD is associated with
decreased connectivity
within the SMA and an
increased connectivity
within the prefrontal and
posterior cingulate hubs of
the DMN.
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35.742.9
55.7
0
10
20
30
40
50
60
Baseline Year 5 Year 8
% Fatigue
Progression of fatigue in PD
Alves et al (2004)
8 year prospective
longitudinal study,
community sample
‘lack of energy’
The prevalence of fatigue increases with disease duration
TALK TITLEdateProgression of fatigue in PD
The prevalence of fatigue increases with disease stage
% Fatigue
Barone et al (2009)
PRIAMO Study
N=1072
Barone et al. Mov Disord. 2009 Aug 15;24(11):1641-9
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7 subtypes of PD Brainstem:
Limbic:
Neocortical/Cognitive:
Sauerbier et al. Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S41-6.
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Non-motor subtypes
Sauerbier et al. Clin Med (Lond). 2016;16(4):365-70Marras and Chaudhuri. Mov Disord. 2016 ;31(8):1095-102.
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PET scanning
•18F-dopa is a marker of monoaminergicsystems
•11C-DASB is a marker of serotonin transporter (SERT) binding`
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Fatigue: biomarkers and imaging - 11C-DASB binding in PD
PD with fatigue
PFS-16 = 15
PD without fatigue
PFS-16 = 2
Subtype specific treatment with serotonergic agents?
Healthy volunteer
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Motor UPDRS not fluctuationsAnxiety and DepressionNMS burdenSleep DysfunctionFrontal assessment battery
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• Patients with fatigue describe ‘tiredness’, not ‘sleepiness’
• Sleepiness not perceived as aversive, not provoked by stress
• Severity of EDS and fatigue only weakly related (Havlikova et al, 2008). Can occur independently.
• Fatigue and daytime sleepiness both common; high levels of co-morbidity
• Distinct clinical phenotypes
Fatigue and day-time sleepiness
0 2 4 6 8 100
4
8
12
16
20
24
Fatigue intensity
Epw
orth
Sle
epin
ess
Sca
le
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Measuring fatigue
Brown et al. Parkinsonism Relat Disord. 2005 Jan;11(1):49-55.
Validation in PD: Herlofson et al. Eur J Neurol. 2002 Nov;9(6):595-600
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Clinical measures
• Modified Fatigue Impact Scale: validated in 100 PD patients; involves evaluation of cognitive as well as physical and social functioning (Schiehser et al Parkinsonism Relat Disord 2013).
Recommended for diagnostic screening
Recommended for severity measurement
• Fatigue Severity Scale (FSS) yes yes
• Multi-dimensional Fatigue Inventory (MFI) yes
• Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F)
yes
• Parkinson Fatigue Scale (PFS or PFS-16) yes
Systematic review by the MDS task force (2010)
Report from a multidisciplinary symposium on fatigue in PDParkinson's Disease Foundation Community Choice Research Program (October 2014)
Friedman et al. NPJ Parkinsons Dis. 2016;2:15025
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From Lazcano-Ocampo et al 2020
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WHO Coronavirus Disease (COVID-19) Dashboard. https://Covid19.who.int. Accessed 1 February 2021
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Potential non-motor
symptoms emerging in PwP
during Covid-19 infection
In Preparation
Virtual NMSQuestTo identify individual NMSs
Cognitive decline
AnxietyOlfaction FatigueAcute
depressive episode
PainSleep
disturbances
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An international web-based survey of respondents (n = 3,762) with suspected and confirmed COVID-19 from 56 countries tallied prevalence of 205 symptoms in 10 organ systems, with 66 symptoms traced over 7 months. The most frequent symptoms reported after 6 months were fatigue (77.7%), post-exertional malaise (72.2%), and cognitive dysfunction (55.4%).
Fatigue 77.7%
Post exertion malaise 72.2%
Cognitive dysfunction 55.4%
doi: https://doi.org/10.1101/2020.12.24.20248802
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Delirium
Fatigue
Abdominal pain
Hoarse voice
Diarrhoea
Chest pain
Skipped meals
Unusual muscle pains
Fever
Sore throat
Persistent cough
Loss of smell
Shortness of breath
Headache
0 20 40 60 80 100Days
Duration shortNumber reports shortDuration LC28Number reports LC28Duration LC56Number reports LC56
Long Covid –
symptoms by duration
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Delirium
Fatigue
Abdominal pain
Hoarse voice
Diarrhoea
Chest pain
Skipped meals
Unusual muscle pains
Fever
Sore throat
Persistent cough
Loss of smell
Shortness of breath
Headache
0 20 40 60 80 100Days
Duration shortNumber reports shortDuration LC28Number reports LC28Duration LC56Number reports LC56
Long Covid –
symptoms by duration
Longer term impact for Parkinson’s who have had Covid 19?
Covid CNS study : NHS England – In Progress
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Fatigue is common, hugely troublesome for patients and understanding of
pathophysiology is still largely unclear
There appears to be a serotonergic dysfunction which may be a biomarker for
the Park Fatigue endophenotype
Routine assessment of fatigue in clinic and clinical trials is important
Fatigue is not Sleepiness or Depression but there may be overlap
Advanced therapies may all benefit fatigue and both apomorphine and
levodopa infusion may be effective for central fatigue
Adjuvant therapies could be considered for fatigue
Fatgue is a key element of covid 19 symptomatology in PD
Fatigue could be part of a “Long Covid” syndrome in PD
Conclusions
TALK TITLEdateClinical and Research Team• Prof K Ray Chaudhuri, Director • Dr D van Wamelen, Post-doc Clinical Research Fellow• Dr V Metta, Consultant Researcher• Dr V Leta, Clinical Research Fellow• Dr K Rukavina Clinical Research Fellow• Dr N Dimitrov, Clinical Fellow• Dr P Reddy, Consultant Liaison • Dr YM Wan, Clinical PhD Fellow• Dr D Urso Clinical Research Fellow• Dr Lucia Batzu Clinical Research Fellow• Dr S Rota Clinical Research Fellow• Dr A Sauerbier, Post Doc Clinical Research Fellow
• Ms Vanessa Raeder Research Assistant
Statistical and Data Support• Prof P Martinez-Martin and team (Madrid)
King’s Stereotactic Surgery Group• Mr K Ashkan• Dr M Samuel• Dr R Saha
Research Management • Ms A Rizos, EUROPAR European Manager• Mr D Trivedi, Research Coordinator• Ms A Podlewska, Research Coordinator and PhD Fellow• Ms Juliet Staunton Research Coordinator
Nurse-led COE Research Programme• Miriam Parry, PD Nurse Specialist • Jenny Natividad PD NS
Virtual Technology Team Lead• Dr Dhaval Trivedi/Daniel van Wamelen
Animal Model Team Lead• Prof Peter Jenner
•King’s PAR-COG Group• Prof Dag Aarsland
King’s Parkinson’s Centre of Excellence Research Team