Image by Texas photographer Tom Hussey in campaign for Exelon.
The global prevalence of dementia is 24 million, and is predicted to double every 20 years until at least 2040. Alzheimer disease is the leading cause of dementia.
93, 86, 79, …
AN1792, Elan Pharmaceuticals vaccine. Antibody production was quite variable.
Note disconnect between amyloid and cognitive levels.
The gi side effects of donepezil are mostly transient.Rivastigmine is available as capsules or via a patch.bm: bowel movements; pronunciation of memantine (ma man TINe, long I) donepezil (dawn ep ah zil)
AChE & BuChE convert ACh into choline where it can be transported into the axon. AChE is found in gut, skeletal muscle, red blood cells, platelets, and at high levels in areas that receive cholinergic input. BuChE may also be present in amyloid plaques.
Donepezil is made by a Japanese (Eisai) and American (Pfizer) companies and is a selective & reversible AChE inhibitor. The gi side effects (nausea, diarhea, abdominal pain) of donepezil are typically temporary.
Rivastigmine is made by Novartis, a Swiss company based in Basel, Switzerland.Rivastigmine is apseudoirreversible (reverses itself over hours) nonselective cholinesterase inhibitor. The patch is useful for this population as they may forget to take their meds and gi upset is an appreciable source of medicine nonadherance for AChE inhibitors.
Galantamine is found in the bulbs and flowers of daffodil (left),Caucasian snowdrop (middle), snowflake, andRed Spider Lily. Galantamine causes the channel to open more frequently.
LTP: Long-Term Potentiation; Calcium is the ion whole levels must be very carefully controlled.
LTP: Long-Term Potentiation; There are a wide variety of pro-oxidant enzymes (hydroxylases, oxidases, oxygenases, peroxidases and synthases) that may be activated by Ca to form free radicals. Low levels of free radical formation may cause dendritic pruning but higher levels result in neuron death.
The low affinity of Memantine to the magnesium binding site on the NMDA receptor results in binding and removal from the channel.
Mean MMSE at baseline was 7.9; Age = 76. ADL includes bathing, using bathroom, dressing, kitchen, & tv. More patients receiving placebo than memantine discontinued the study prematurely because of adverse events (17 versus 10 %)!
Chorea (pronounced kor EE ah or like nation Korea) is abnormal writhing movements. The medium spiny neurons of the striatum are most severely affected.
Genetically verified HD patients (N = 111, Age = 48, mean illness duration = 5.5) completed annual interviews over 4 years. Interestingly, these patients were attending a clinic and rates may have been higher without psychiatric meds. 99% of patients endorsed at least one item.
Non-selectivity includes 5-HT2C antagonist and binding to several liver enzymes. Effects on NET may only occur at high doses.
FDA: orphan disease effects less than 200K; Janovik from Texas spent 3 decades getting tetrabenazine FDA approved. It is the only currently approved drug for HD. VMAT2 inhibition results in larger effects on dopamine than norepinephrine.
SAE included 1 suicide by drowning, 1 fall, & 1 suicidal ideation requiring hospital visit. Study drugs were withdrawn after week 12. Other research has noted that as many as 2% of HD patients attempt suicide.
Right image is of theoretical physicist Stephen Hawking on the “Vomit Comet” in 2007. Hawking has a disease related to ALS. Most patients die of pneumonia after 2 years!dysarthria: disorder of articulation, as stammering or stutteringdysphagia: pronounced dis-fey-juh; difficulty swallowing
Pronounced RIL yoozol. Riluzole is the only currently approved drug for ALS. In vitro studies indicate that Riluzole increases activity of the Glutamate Transporters and decreases presynaptic release. Adverse effects result in 10% of patients stopping treatment.Pronounced as-thee-nee-uh and defined as lack of strength and weakness.
About half of ALS patients die within 3 years of developing symptoms. Bottom two lines are from a separate study with much older and more severely effected at study onset (not included in Pooled mean). All shown studies used oral 100 mg/day.
Spasticity refers to an increased muscle tone. Baclofen may be administered orally (5 mg upto 200 mg/day) or intrathecally.
Pharmacotherapies for neurodegenerative disorders
Pharmacotherapies of Neurodegenerative Disease:Alzheimer’s, Huntington’s, & ALS Brian J. Piper, Ph.D., M.S.
Goals• Describe mechanism & efficacy of pharmacotherapies for AD.• List drug therapies used for symptomatic management of HD & ALS.
Alzheimer’s Prevalence Dementia cases in U.S. Year Patients (millions) 2010 5.8 2020 6.8 2030 8.7 2040 11.8 2050 14.3Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128.
Aloysius ”Alois” Alzheimer • German psychiatrist • Described symptoms + pathology – Neuronal loss 1864-1913 – Plaques – Tangles • Presentation to SW German Psychiatrist meeting ignored but Emil KraeplinCipriani et al. (2011) Neurological Sciences, 32(2), 275-279. Auguste Deter, 1851-1906
Test of Neurocognitive Function • Mini-Mental State Exam (MMSE) – Where are we in? – Count backwards by 7 starting with 100 – Remember 3 words – Copy drawing • Executive functionFolstein, Folstein, & McHugh (1975). J Psychiatric Research, 12, 189-198.
Executive Function Test: Trail Making Test: Part A
Efficacy & Great Tolerability of Memantine • Double-blind randomized controlled trial of memantine (20 mg/day). • Participant age >50 with MMSE 3-14 • Dependent measures include Activities of Daily Living scale (Max = 78) completed by the caregiverReisburg et al. (2003). New England J Medicine, 348(14), 1333-1341.
Huntington’s Chorea• Autosomal dominant (Huntingtin) 1912 - 1967• # CAG repeats predicts onset• motor -> personality/dementia H h h Hh hh h Hh hhExample patient (1 min): http://www.youtube.com/watch?v=JzAPh2v-SCQWoody Guthrie (1 min): http://www.youtube.com/watch?v=wxiMrvDbq3s
Thompson et al. (2012). Journal of Neuropsychiatry & Clinical Neuroscience, 24(1), 53-60.
Fluoxetine • depression & anxiety • Not selective – SERT – 5-HT2C – NET – Sigma (σ)Stahl (2008). Essential Psychopharmacology, p. 533.
Clinically Significant Reduction in Chorea • Participants were randomized to placebo (N=30) or individualized dose of tetrabenazine (N=51) for 12 weeks. • Unified Huntington’s Disease Rating Scale interview was conducted blind.Huntington’s Study Group (2006). Neurology, 66, 366-372.
Slight, but Significant, Benefits• Meta-analysis of 4 studies (N Riluzole = 974, N Placebo = 503)• Likelihood of surviving one year was ↑10%• Overall survival was – Placebo 11.8 months – Riluzole 14.8 monthsMiller et al (2012). Cochrane Database Systematic Reviews.