378th Goulstonian Lecture

Motor Neurone Disease: FTD

Biomarker development
for an expanding cerebral syndrome
 The 1st Goulstonian Lecture 1639
Dr William Rant
De morbis partium quibus optime doctissimeque se gessit
On those areas of disease he studied most

With assistance from Goulstonian neurologists past who have contributed to the MND story

1860 1937
 Overview
• The essential clinical syndrome
• A little about risk factors
• Clinical heterogeneity
• Molecular heterogeneity
• The emergence of the wider brain
• The biomarker quest (imaging, eye-tracking, CSF)
• Pre-symptomatic studies
1. An unmistakable clinical
syndrome
The first written description of classical MND:

A. Jacob Augustus Lockhart Clarke

B. Lou Gehrig
C. Jean-Martin Charcot
D. Jean Cruveilhier
E. Charles Bell
 The British and Foreign Medico-Chirurgical Review 1862; 30: 215-225.

Charles Bland Radcliffe (1822-1889)

222nd RCP Goulstonian Lecturer 1860
John Hughlings Jackson (1835-1911)
Med Chir Trans 1867; 50: 489-498
231st Goulstonian Lecturer 1869
 Jean-Martin Charcot (1825-1893)
“The diagnosis as well as the anatomy and physiology of the condition amyotrophic lateral sclerosis is
one of the most completely understood conditions in the realm of clinical neurology.”
 Pre-ALS:
“Progressive Muscular Atrophy”

Sir Charles Bell

Jean Cruveilhier
 La sclérose amyotrophique

LMN + UMN
corticospinal tract ‘sclerosis’

wasting &
fasciculation
anterior horn cell loss (amyotrophy)

spasticity
UMN LMN
 The sine qua non of MND:

A. Pure motor symptoms

B. Sparing of cognition
C. Fasciculations
D. Combined upper and lower motor neuron signs
E. Progressive symptoms
 The 3 Ps of MND

•Progressive Sine qua non: No progression, not MND

•Painless Occasional symptoms, but no signs

•Paralysis May report fluctuation, but relentless

secretions cognition
nutrition behaviour
communication
emotionality

disability

loss of
respiratory
independence
insufficiency
 The median survival in months from
symptom onset is:

A. 30
B. 60
C. 20
D. 75
E. 90
The neurological examination as we know it today

Sir Gordon Morgan Holmes (1876-1965)

277th Goulstonian Lecturer 1915
The role of neurophysiology

• To demonstrate
denervation not
visible at the bedside
– Only 60% sensitive Derek Earnest Denny-Brown
(1901-1981)
• To exclude significant 299th Goulstonian Lecturer 1937

nerve conduction or
myopathy (with
strong clinical
suspicion)
• No role in monitoring
progression
2. Risk factors
It is much more
important to know
what sort of a patient
has a disease than what
sort of a disease a
patient has.

Sir William Osler (1849-1919)

247th Goulstonian Lecturer 1885
On heredity in progressive muscular atrophy as illustrated in Regius Professor of Medicine, Oxford
the Farr family of Vermont. Arch Med 1880
 Lifetime risk of MND
(slide courtesy of Ammar Al-Chalabi)
0.50.5
0.45
0.45

Males
0.40.4
0.35
0.35
1 in 300
0.30.3
Percent

Females
0.25
0.25

0.20.2
0.15
0.15

0.10.1
0.05
0.05

00 0 10 20 30 40 50 60 70 80 90 100
0 10 20 30 40 50 60 70 80 90 100
Age
Johnston CA et al, ALS in an Urban Setting. J Neurol 2006
 An old chestnut
• No “nicer” than others pre-morbidly
• Perhaps more accepting or passive
• Low incidence of depression and suicide

• Serotonin changes
– 11C-WAY100635 PET shows marked 5-HT1A
binding reduction in frontotemporal regions:

Turner MR et al. Brain 2005

Turner’s “elastic band sign”

MND Not MND

Athleticism: Cause versus association
“born to run”

“run to death”

Sir Edward Farquhar Buzzard (1871-1945)

269th Goulstonian Lecturer 1907
Regius Professor of Medicine, Oxford
The controversial issue of head trauma
(chronic traumatic encephalopathy shares some of the molecular signature of MND)
 Physical
Cardiovascular injury
(Turner MR et al. Neurology 2015)

fitness Physical
(Turner MR et al. JNNP 2011 )
activity

Metabolism:
Lower higher cholesterol
less gout
BMI
3. A heterogeneous clinical
syndrome
 8%
30%
2%
30%

30% Focality of
symptom onset
(and relative sparing)
Clinicopathological correlation
John Ravits
 Heterogeneity in survival
100%

50%

5 years 10 years 15 years

Decline in function
 Rate of decline
(past performance does reflect future performance)

Sir William Gowers (1845-1915)

242nd Goulstonian Lecturer 1880
 Regional
heterogeneity

‘Flail arm’
Survival 5-10 years
vs. Bulbar-onset
Survival 1-2 years
 Brain 1925; 48: 492-534

Brain 1891; 14: 473-495

Howard Henry Tooth (1856-1925) Macdonald Critchley (1900-1997)

251st Goulstonian Lecturer 1889 293rd Goulstonian Lecturer 1931
• 50% of bulbar-onset sent to TIA or ENT
• 25% tested for myasthenia
• Caution in dysphagia without dysarthria

• “Progressive bulbar palsy”

• Often elderly females
• EMG often normal
• Rapid anarthria
• Turner
Remain MR et al. Brain
ambulant for 2012
many months, even years
4. A heterogeneous molecular
syndrome
1994 – MND is solved!
• Toxic gain of function
• “Oxidative stress”
• Mouse model
• (only 2% cases, no
cognitive impairment)
 TDP-43 pathology underpins
98% of MND and 50% of FTD

Nucleus Cytoplasm

Images courtesy of Olaf Ansorge, John Radcliffe Hospital, Oxford

 What is the proportion of MND currently
attributable to a single genetic mutation?
A. 20%
B. 50%
C. 60%
D. 10%
E. 95%
 Family history 5% Apparently sporadic 95%
MUST CONSIDER FTD

Incomplete penetrance

Death before symptoms

De novo mutations

Non-paternity

Hidden illness, especially

FTD

Turner MR et al. Lancet Neurology 2013

Proc R Soc Med. 1912; 5: 144–148

Sir Henry Head (1861-1940)

263rd Goulstonian Lecturer 1901
SOD1 I113T Common
endpoint

ALS with BI

TDP-43

FUS

C9orf72
Hereditary ALS is clinically indistinguishable
from apparently sporadic ALS

A final common pathway

 Genetic trials on the horizon

• SOD1:
– Anti-sense
• C9orf72:
– Expansion excision
– Peptide silencing
5. MND as a cerebral disease
 Nigel Leigh

MND pre-1987
 MND overlaps most commonly with:

A. Corticobasal degeneration
B. Diffuse Lewy body dementia
C. Posterior cortical atrophy variant of
Alzheimer’s
D. Behavioural variant frontotemporal dementia
E. Progressive supranuclear palsy
 Bernard Hart (1879-1966)
288th RCP Goulstonian Lecturer 1926
 SPECT

Ludolph A et al. Eur Neurol 1989

The Third Space: Extra-motor involvement

ALScu ALSmci ALS-FTD

 Frontotemporal involvement in MND
(a clinical continuum)
• Frank dementia 10%
– Precedes the onset of motor problems
– Faster progression of motor disease
• Clinical features:
– Apathy or disinhibition (personal neglect)
– Poor insight
– Altered food preference, narrowed and
favouring sweet foods
– Food cramming (can precipitate choking)
• Involve extended family
– Minimize risk-taking behaviour
• Ask about subtle behavioural change
– Source of carer morbidity
– Loss of Theory of Mind
6. The biomarker challenge
 Role of biomarkers in
therapeutic trials
• Enrollment:
– EARLIER diagnosis:
• Average delay from symptom onset 1 year
• Start drugs prior to disability
– MORE INCLUSIVE:
• Sub-clinical UMN involvement
• Stratification:
– FAST and SLOW progressors
– PREDICTION of regional spread:
• Bulbar problems (PEG)
• Respiratory involvement (NIV)
• Cognitive involvement
• Efficacy:
– ALSFRS slope is the benchmark
– Faster ‘NO-GO’ decisions too
 BioMOx
The Oxford Study for Biomarkers in
Motor Neuron Disease

www.biomox.net
 A multimodal, longitudinal approach
• Every 3-6 months:
• Clinical assessment
• MRI (3T):
• T1
• DTI
• R-fMRI
• Eye-tracking
• Serum
• CSF
• Single study from healthy controls and disease mimics
 More than the picture:
The era of advanced neuroimaging
PET
Cerebral microglial activation in vivo
Faulty brakes
A failure of cortical
inhibition in MND
Preserved motor GABA-ergic influence in
those with slower disease progression

sALS homD90A
40% sensitive, 70% specific
 Voxel-based
Grey Matter
morphometry and
cortical thickness analysis:
automated grey matter quantification
Cross-sectional cortical thickness analysis
(Ratti et al. unpublished)
 Reduced FA Diffusion
tensor imaging:
white matter
tract pathology

Reduced FA

Higher FA

Higher FA

 Dxx Dxy Dxz 

 
D =  Dxy Dyy Dyz 
 Dxz Dyz Dzz 

Longitudinal studies:
An essential challenge
 Functional MRI: The BOLD effect
• Oxy-Hb DIAMAGNETIC
– paradoxical increase with neuronal activity
• Deoxy-Hb PARAMAGNETIC
The brain as a series of functional networks
(detecting task-free patterns in BOLD fluctuation)

Smith et al. PNAS 2009

The ALS-specific cortical network shows
increased functional connectivity Multimodal analysis improves classification
Mathematical modeling and machine learning
 Machine-learning classification based on
resting-state BOLD fluctuations within the
ALS motor network
(Fekete et al. 2013 PLoS ONE)
The eyes have it
Fixations & saccades
during Trail B
Healthy control
Total duration: 27.6 s
Total no. of fixations: 78

Rakesh Malcolm
Sharma Proudfoot

MND patient
Total duration: 135 s
Total no. of fixations: 393
 Neurofilament light chain:
the leading neurochemical biomarker

Petzold A. J Neurol Sci 2005

Ching-Hua
Lu Andrea
Malaspin
a

Liz Gray
7. The pre-symptomatic landscape
 Symptom onset
Diagnosis
Number of motor neurons
100%

Cumulative
survival
?
RNA
mishandling? Protein
inclusions

Potential therapeutic window 3 years 10 years 15 years

Studying asymptomatic carriers of high-risk MND gene

mutations as a window on the earliest events
 Where does MND begin then?

A. Dying back from B. Dying back and C. Dying forward

NMJ forward from the from cortex
spinal anterior horn (corticofugal)
 UMN (PLS)
LMN
(PMA)

FTD
Oxford MND Centre BioMOx team

Kevin Talbot Rachael Marsden Jenny Rolfe Lynn Ossher Ricarda Menke Malcolm Proudfoot Liz Gray Alex Thompson
Neurologist Specialist Nurse OT Post-doc Post-doc Neurologist-in- Post-doc Neurologist-in-
Clinic Coordinator Research Coordinator MRI training Neurochemistry training