The heterogeneity of MND:Patterns, within the puzzle.

Dr Thanuja Dharmadasa

Neurologist (MBBS, FRACP)

Brain and Mind Centre, University of Sydney

Diagnosis? Prognosis?

Treatment?

“many diseases?”“one disease?”

Overview clinical

genetic

mechanistic

Clinical heterogeneity:

Dharmadasa et al, Med J Aust 2017; 206 (8):357-362 Kiernan MC et al, The Lancet 2011; 377 (9769): 942-955

Upper Motor Neurones

Lower Motor Neurones

Clinical heterogeneity:

Dharmadasa et al, Med J Aust 2017; 206 (8):357-362 Kiernan MC et al, The Lancet 2011; 377 (9769): 942-955

Clinical heterogeneity:

phenotype

/ˈfiːnə(ʊ)tʌɪp/

noun

the set of observable characteristics of an individual (e.g. appearance,

behaviour etc)

Clinical heterogeneity:

LMN UMN

(i) Site-of-onset

(ii) Mix of UMN and LMN involvement

Clinical heterogeneity:

(i) Site-of-onset

(ii) Mix of UMN and LMN involvement

(iii)Rate of disease progression

Swinnen, B. & Robberecht, W. Nat. Rev. Neurol. 10, 661–670 (2014); published online 14 October 2014;

1) ALS- 70% of cases, - classically limb-onset (~80%)- ~20% of patients bulbar onset- combination of UMN&LMN signs

LMN UMN

Contributors to disease heterogeneity:

1. Clinical variability→motor phenotypes

2) Progressive bulbar palsy- 4-8% of cases- Localised to bulbar >6 months- Limb strength ~preserved

LMN UMN

Contributors to disease heterogeneity:

1. Clinical variability→motor phenotypes

3) Progressive muscular atrophy (PMA)- 5% of cases- Pure LMN signs >12 mths- “Flail limb”- either the arm or leg

LMN UMN

Contributors to disease heterogeneity:

1. Clinical variability→motor phenotypes

4) Primary Lateral Sclerosis- 1-3% of cases- Pure UMN signs for >3-5 years- Lower-limb onset (typical)

LMN UMN

Contributors to disease heterogeneity:

1. Clinical variability→motor phenotypes

• Balance, coordination• C9orf72 and ATXN mutations• Basal ganglia involvement• Rigidity, slowness, instability

Dharmadasa et al, Handbook in Clinical Neurology; Elsevier 2017

• Heart rate, BP regulation (50%)• Urinary, gastrointestinal• UMN predominant phenotypes

Contributors to disease heterogeneity:

1. Clinical variability- non-motor systems

• ~20% of patients (inc. pain)

Impact of heterogeneity:

Diagnosis delayed

LMN UMN

No diagnostic test for MNDDiagnostic delay is ~14-20 months on average

Vucic S. ACNR 2014;14(5):27-29

Impact of heterogeneity:

Prognosis affected

LMN UMN

Impact of heterogeneity:

Prognosis affected

LMN UMN

2. Motor systems interaction? - Dying forward?- Dying backwards?- Independently?

Impact of heterogeneity:

How does the disease progress?

Neurophysiology

Transcranial Magnetic Stimulation (TMS)

Looking for UMN changes

Novel techniquesCortical hyperexcitability in the brain

Novel techniquesCortical hyperexcitability in the brain

1. An early pathogenic mechanism (Vucic and Kiernan, 2006)

2. Differentiates ALS from mimics (Vucic et al, 2011; Menon et al 2015)

1. Cortical hyperexcitabiltiy is a global phenomonen

2. Changes correspond to the clinically affected side

Clinical change Central dysfunction

**

Novel techniquesCortical excitability

Cortical hyperexcitability is a common finding

1. Disease implications:- Applicable clinical biomarkers- Earlier diagnosis- Prognostic clarification- Prediction of likely trajectory

2. Cortical ‘hot spots’ to target- The “critical trigger” points

3. Trials• Essential to think about clinical

heterogeneity

4. PRECISION MEDICINE

• Supervisors

• Collaborators and colleagues

• Forefront Neurology Clinic,

Brain and Mind Centre, University of Sydney

• Funding • University of Sydney

• MNDRIA

• Yugilbar Foundation

• Rotary Health Australia