1205 - Martin Turner - 0
1205 - Martin Turner - 0
1205 - Martin Turner - 0
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:
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:
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
• 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.
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:
“run to death”
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%
‘Flail arm’
Survival 5-10 years
vs. Bulbar-onset
Survival 1-2 years
Brain 1925; 48: 492-534
Nucleus Cytoplasm
Incomplete penetrance
De novo mutations
Non-paternity
ALS with BI
TDP-43
FUS
C9orf72
Hereditary ALS is clinically indistinguishable
from apparently sporadic ALS
• 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
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
Rakesh Malcolm
Sharma Proudfoot
MND patient
Total duration: 135 s
Total no. of fixations: 393
Neurofilament light chain:
the leading neurochemical biomarker
Liz Gray
7. The pre-symptomatic landscape
Symptom onset
Diagnosis
Number of motor neurons
100%
Cumulative
survival
?
RNA
mishandling? Protein
inclusions
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