L2 Motor System Disorders Flashcards
2 groups of neurodegenerative diseases
- Conditions affecting memory and conditions related to dementia
- Conditions causing problems with movements
Examples of NDDs
Alzheimer’s, vascular dementia, Parkinson’s, Huntington’s
What do NDDs have in common?
- Role of aging
- Glutamate excitotoxicity
- Mitochondrial dysfunction → oxidative stress
- Apoptosis
- Protein misfolding & aggregation
- Disruption of intracellular transport
- Neuroinflammation
Average age of onset of PD
55
What percentage of PD cases are familial?
~10%
What genes are involved in autosomal dominant PD cases (rare)?
LRRK2
SNCA (encodes for α-synuclein production)
What genes are involved in autosomal recessive PD cases?
Parkin, PINK-1, DJ-1
Exposure to what toxin induces Parkinson’s-like symptoms?
MPTP
Neuronal pathways affected by PD
Selective loss of dopaminergic neurons (therefore less GABA inhibition), while cholinergic neurons remain intact
Main treatment for PD until L-DOPA was discovered
Atropine and related drugs
What reestablish the balance between DA and ACh?
Muscarinic receptor antagonists
What is the problem with anti-muscarinics?
Associated with troublesome side effects and are therefore now rarely used, except to treat Parkinsonian symptoms in patients on anti-psychotics (DA receptor antagonists → nullify effect of L-DOPA)
Treatment strategies for PD to increase DA signalling
- Increasing DA synthesis: L-DOPA (administered with DDC inhibitor)
- Inhibiting DA catabolism: Selegiline (MAOB inhibitor), COMT inhibitors (Tolcapone, Entacapone)
- Blocking uptake & enhancing release of DA: Amantadine
- DA receptor agonists: Bromocriptine & Pramipexole
Examples of DDC inhibitors
- Carbidopa
- Benserazide
- Methyldopa
What type of disease is Huntington’s?
AD inherited NDD (no sporadic form)
What causes HD?
An insertion of multiple CAG repeats in the huntingtin (HTT) gene, resulting in an N-terminal polyglutamine expansion of HTT
What does disease severity in HD depend on?
the length of the polyQ stretch
What suggests that HTT has a central role in cell functioning?
- HTT is highly conserved from Drosophila to humans
- HTT KO mice die at embryonic stage
Neuronal pathways affected by HD
Some cholinergic neurons may be lost, but even more GABAergic neurons degenerate → more DA signalling
Approved treatment for chorea (and hyperkinetic disorders similar to HD)
Tetrabenazine
How does Tetrabenazine work?
Mainly as a VMAT-2 inhibitor, promoting the degradation of monoamines (in particular, DA)
What was the first deuterated drug to have received FDA approval (in 2017)?
Deutetrabenazine (Austedo)
All anti-psychotic drugs block __ receptors
D2
200mg daily of what NMDA receptor antagonist likely moderately decreases HD chorea?
Riluzole
Use of Amantadine in HD
Likely effective in decreasing chorea, but high doses can worsen cognitive function
What is the most common motor neuron disease?
Amyotrophic lateral sclerosis
What do most ALS patients die from?
Respiratory failure (usually within 3-5 yrs from onset of symptoms)
True or False: Most ALS cases are sporadic.
True
What is the only probable risk factor identified for ALS?
Smoking
Most common causative gene mutation in ALS
SOD1
Only approved drug for ALS in Europe
Riluzole
How does Riluzole work?
- blocks NMDA receptors (inhibits Glu release, stimulates reuptake)
- blocks voltage-gated Na⁺ channels
What is Edaravone?
A potent radical scavenger used to treat ALS in Japan & US
What is Albrioza?
Sodium phenylbutyrate and taurursodiol combination used to treat ALS
4 main types of multiple sclerosis
- Progressive relapsing (PRMS)
- Relapsing remitting (RRMS): ~80% of patients
- Secondary progressive (SPMS)
- Primary progressive (PPMS)
What cells of MS patients are more reactive toward myelin components?
T cells (Th1, Th17)
Examples of disease-modifying therapies for MS
- Fingolimod (Gilenya)
- IFN-β (Avonex, Betaferon)
- Nataliuzumab (Tysabri): anti-VLA4 mAb
- Alemtuzumab (Lemtrada): anti-CD52 mAb
Only FDA-approved DMT for PPMS
Ocrelizumab (Ocrevus): anti-CD20 mAb
Agents targeting nucleic acid metabolism
- Mitoxantrone (Novantrone) infusion: topoisomerase II inhibitor
- Oral Cladribine (Mavenclad): purine analog
- Oral Teriflunomide (Aubagio): active metabolite of leflunomide, inhibits de novo pyrimidine synthesis
Synthetic protein that mimics myelin basic protein
Glatiramer acetate (Copaxone) - induces switch from pro- to anti-inflammatory pathways
What DMT for MS is based on a psoriasis treatment and induces a Th2 phenotype to cause immunosuppression?
Dimethyl fumarate (Tecfidera)
__ are major targets for effective immunotherapy in relapsing MS
Memory B cells
