Chair, John Ravits, MD, FAAN, prepared useful Practice Aids pertaining to amyotrophic lateral sclerosis for this CME activity titled “Hope Is on the Horizon for Patients With ALS: Overcoming Diagnostic Difficulties and Exploring Novel Emerging Therapeutic Approaches.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at http://bit.ly/3AgpcKy. CME credit will be available until March 16, 2024.

1. Diagnostic Assessment of ALS
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZXV40
The diagnosis of the disease is ultimately a clinical diagnosis1-4
Electromyography (EMG)
Nerve conduction study (NCS)
Magnetic resonance imaging (MRI)
Muscle biopsy
Genetic testing
Lumbar puncture
Lab tests to rule out infectious diseases (eg, HIV, HTLV,
polio, West Nile virus), metabolic abnormalities
• An exclusion of other mimicking diseases, such as spinal cord compression,
other neurodegenerative diseases, nerve injury, and root injury
• Systemic neurologic examination to identify UMN and LMN dysfunction and to
rule out other potential causes of symptoms, which may include

2. Diagnostic Assessment of ALS
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZXV40
• Progression of symptoms over time
• LMN signs by region (bulbar, cervical, thoracic, lumbosacral)
– Clinical: weakness, fasciculations, atrophy
– Electromyography
LMN loss: fibrillations and positive sharp waves, fasciculations
Reinnervation: large motor units and reduced recruitment
• UMN signs by region (bulbar, cervical, thoracic, lumbosacral)
– Clinical: spasticity, hyper-reflexia, pathologic reflexes, pseudobulbar affect
Clinical/EMG
evidence of LMN +
UMN in 1 region or
isolated UMN signs
in 2 or more regions
or LMN signs rostral
to LMN signs
Clinical LMN + UMN
in 1 region and LMN
signs in 2 regions
Clinical/EMG
evidence of LMN +
UMN in 2 regions
Some UMN signs
rostral to LMN signs
Clinical/EMG
evidence of
LMN + UMN
in 3 regions
Clinically possible ALS
Clinically probable ALS
(laboratory supported)
Clinically probable ALS
Clinically
definite ALS
Revised El Escorial and Awaji Diagnostic Criteria for ALS5
1. Hardiman O et al. Nat Rev Dis Primers. 2017;3:17071. 2. Brown RH et al. N Engl J Med. 2017;377:162-172. 3. Kiernan MC et al. Lancet. 2011;377:942-955. 4. http://webgw.alsa.org/site/PageServer?pagename=GW_12_AAM16_what_is_als#gsc.tab=0.
5. Quinn C, Elman L. Continuum (Minneap Minn). 2020;26:1323-1347.

3. Mechanisms of Action of Emerging
Therapies in ALS1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/ZXV40
Catalyzes oxidation of NADH to NAD+
CNM-Au8 is an oral suspension of clean-surfaced, catalytically active gold nanocrystals
Driving production of ATP and restoring energy in brain cells
Reduces accumulation of TDP-43 aggregates in the cytoplasm
CNM-Au8 Mechanism of Action
ATP
TDP-43
N
NH2
NH2
O O P P
O O O
O O
O
HO HO HO
OH OH
OH
N N
N
N
NADH
N N
NH2
N
N
N+
NH2
O
O O O
O
P P
O
O
OH
HO
OH OH OH
OH
O
NAD+
Emerging Small-Molecule Therapies

4. Mechanisms of Action of Emerging
Therapies in ALS1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/ZXV40
• RIPK1 regulates a
neuroinflammatory
environment in the CNS that
can lead to cell necroptosis
and neurodegeneration
• SAR443820 is a
CNS-penetrant
small-molecule inhibitor
of RIPK1
Microglial cell
Damaged
mitochondrion
• Demyelination
• Axonal degeneration
Cytokines
DAMPs
Neuron
Damaged
lysosome
Oligodendrocyte
Necroptosis
Homeostatic
suppression
RIPK1
RIPK3
RIPK1
RIPK1
RIPK3
MLKL
Deleterious
inflammation
Necroptosis
SAR443820: RIPK1 Inhibitor
Integrated stress
response
DNL343
eIF2B ON
Reinitiated
translation
Reversible
stress granules
Stress response
proteins and genes
(eg, ATF4, CHAC1)
DNL343 Treatment
• DNL343 is currently being investigated in a phase 1b trial to evaluate
safety, PK, and PD in patients with ALS
• In ALS, chronic activation of the integrated stress response (ISR) occurs
because of inactivation of eIF2B and formation of “stress granules,”
precursors to TDP-43 aggregation
DNL343: eIF2B Agonist
Emerging Small-Molecule Therapies

5. Mechanisms of Action of Emerging
Therapies in ALS1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/ZXV40
1. Jiang J et al. Front Pharmacol. 2022;13:1054006. 2. Yuan J et al. Nat Rev Neurosci. 2019;20:19-33. 3. Sun L et al. 2022 International Symposium on ALS/MND. Abstract CLT-09.
4. https://clinicaltrials.gov/ct2/show/NCT05006352?term=DNL343&draw=2&rank=2. 5. Robberecht W, Philips T. Nat Rev Neurosci. 2013;14:248-264. 6. Miller T et al. N Engl J Med. 2020;383:109-119.
Emerging Small-Molecule Therapies
Antisense oligonucleotides
• Are administered intrathecally
• Are widely distributed throughout the CSF
• Duration of action is between 1 to 3 months
Tofersen: Antisense Oligonucleotide Targeting SOD1 ALS
DNA mRNA
SOD1
protein
Antisense
oligonucleotide
Enzymatic
degradation
Oligomers and pre-aggregates
DNA
Mutant SOD1
gene
Modified SOD1
protein
SOD1 mRNA
Aggregates
SOD1 ALS Is Thought to Be GOF Mechanism
Pathogenic Mechanism of Mutant SOD1-Induced Toxicity
Dysfunction in
the cytoplasm
and toxicity