TALK TITLEdate

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

TALK TITLEdate

• 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

TALK TITLEdate

Fatigue Fatigability Induced by activityPresent at rest

TALK TITLEdate

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

TALK TITLEdate

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

TALK TITLEdate

Titova & Chaudhuri. Med J Aust 2018;208(9):404-9

When does fatigue start?

FATIGUE

TALK TITLEdate

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

TALK TITLEdate

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

TALK TITLEdate

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.

TALK TITLEdate

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

TALK TITLEdate

title

Siciliano et al. Mov Disord. 2018 Nov;33(11):1712-1723.

TALK TITLEdate

title

Siciliano et al. Mov Disord. 2018 Nov;33(11):1712-1723.

50%

TALK TITLEdate

WHY FATIGUE IN PD ?????

2020

TALK TITLEdate

7 subtypes of PD Brainstem:

Limbic:

Neocortical/Cognitive:

Sauerbier et al. Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S41-6.

TALK TITLEdate

Non-motor subtypes

Sauerbier et al. Clin Med (Lond). 2016;16(4):365-70Marras and Chaudhuri. Mov Disord. 2016 ;31(8):1095-102.

TALK TITLEdate

PET scanning

•18F-dopa is a marker of monoaminergicsystems

•11C-DASB is a marker of serotonin transporter (SERT) binding`

TALK TITLEdate

18F-Dopa PETResults

TALK TITLEdate

12C-DASB PETResults

TALK TITLEdate

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

TALK TITLEdate

11C-DASB binding in PD

= 9

= 8

= 7

*Normal vs PD

§PD-NF vs PD-F

TALK TITLEdate

TALK TITLEdate

Motor UPDRS not fluctuationsAnxiety and DepressionNMS burdenSleep DysfunctionFrontal assessment battery

TALK TITLEdate

• 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

TALK TITLEdate

TALK TITLEdate

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

TALK TITLEdate

Lazcano-Ocampo et al 2020

TALK TITLEdate

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

TALK TITLEdate

TALK TITLEdate

Lazcano-Ocampo et al , 2020

TALK TITLEdate

From Lazcano-Ocampo et al 2020

TALK TITLEdate

WHO Coronavirus Disease (COVID-19) Dashboard. https://Covid19.who.int. Accessed 1 February 2021

TALK TITLEdate

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

TALK TITLEdate

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

TALK TITLEdate

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

TALK TITLEdate

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

TALK TITLEdate

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