Presented by Meagan Koepnick, Josh McDonald, Abby Narayan, Jared Szabo Mentored by Dr. Doorn

Transcription

1 Presented by Meagan Koepnick, Josh McDonald, Abby Narayan, Jared Szabo Mentored by Dr. Doorn

2 Objectives What agents do we currently have available and what do we ideally need? What biomarkers exist for Parkinson s Disease? What is lacking in regards to treatment of Parkinson s Disease?

3 Progressive disease which results in movement disorders due to loss of dopaminergic neurons in the brain It is a very slowly progressing disease Detection is key to efficacy of treatment Visible manifestations of the disease - Clinical (motor) Biomarkers Incontinence Rigid mucles Tremors Drooling Hyposmia

4 Genetic mutations SNCA LRRK2 GBA MAPT Environmental and Non modifiable causes Age*** Head injury Occupational exposures

5 There are several biomarkers that are associated with PD α-synuclein, Lewy Bodies, Parkin etc.. None of identified biomarkers are completely specific to PD Testing for biomarkers is expensive or invasive or both Other easy to assess biomarkers are highly nonspecific i.e depression or constipation

6 Levodopa Mechanism: Converted to dopamine via DOPA decarboxylase Gold standard of therapy Characterized by on/off periods Dopamine Agonists Mechanism: Stimulates dopamine receptors Common as monotherapy in early disease; combo in later disease Example agents: pramipexole, bromocriptine, ropinirole Kalia LV, Lang AE. Parkinson s disease. Lancet. 2015;386: Review

7 Ruottinen HM, Rinne UK. COMT inhibition in the treatment of Parkinson s disease. J Neurol Nov;245(11 Suppl 3):P Review. PubMed PMID: COMT Inhibitor Mechanism: Inhibit COMT to increase available dopamine levels Increases on-time and decreases off-time Example agents: tolcapone, entacapone MAO Inhibitor Mechanism: Inhibit of monoamine oxidase B to increase levels Example agents: rasagiline, selegiline Figs Goodman & Gilman. 12ed. McGraw Hill

8 Anticholinergics Mechanism: Blocks action of acetylcholine Used to treat tremor associated with PD Example agents: benztropine, trihexphenidyl Anti-spasticity agents Mechanism: bind to neuronal receptors Used to treat movement symptoms Example agents: baclofen, tizanidine

9 4 properties of biomarkers that guide informed selection of neuroprotective therapy 1. How certain are we this marker can identify PD 2. How specific is the marker? Occur in PD or as a normal part of aging? 3. Lead time - length of time between a detected marker and onset of clinical PD 4. Cost to assess markers/time commitment (is it practical?)

10 Olfactory dysfunction Large amount of PD patients have lost sense of smell Loss of smell is a normal with aging Other disease states (I.E. MS, AD) Subtle motor signs Highly variable between patients No uniform way of measuring motor changes If you see motor signs -> the disease has probably hit the clinical PD phase -> damage has been done

11 REM sleep behavior disorder strong evidence here. studies show 80-90% with RBD confirmed by polysomnography (records brain waves) develop PD. only ½ to ⅓ with early PD have RBD, Time consuming, expensive ($500-5k) Kalia & Lang. (2015) Lancet. 386, 896

12 Many biomarkers including restless leg syndrome, color vision loss, cognitive impairment, mood and affective disorders. Limited number of studies Present in many disease states Medications More studies need to be done but REM-RBD testing may have a place in therapy/be a good place to start, if the cost is reduced

13 Kalia & Lang. (2015) Lancet. 386, 896

14 Loss of dopaminergic neurons in substantia nigra pars compacta -> motor symptoms: bradykinesia, rigidity, and tremor Nonmotor symptoms main part of prodromal phase A-synuclein protein RBD Olfactory loss Dorsal motor nucleus Prodromal phase is about 10 years -> other originating factors

15 Deposition of a-synuclein proteins in: GI tract -> constipation gut-> enteric nervous system -> brainstem Nicotine - alpha 3 nicotinic receptors & Caffeine - adenosine receptors Both increase GI motility History of smoking and caffeine use Vagal nerve Cranial nerve X vagotomy Caveat

16 No current treatments provide neuroprotection Origin of PD may not be set in stone Further research is needed into new drug targets for PD

17 Survey Link: