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

Year Patients (millions)

2010 5.8

2020 6.8

2030 8.7

2040 11.8

2050 14.3

Dementia cases in U.S.

Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128.

Aloysius ”Alois” Alzheimer

• German psychiatrist• Described symptoms + pathology

– Neuronal loss– Plaques– Tangles

• Presentation to SW German Psychiatrist meeting ignored butEmil Kraeplin

Cipriani et al. (2011) Neurological Sciences, 32(2), 275-279.

1864-1913

Auguste Deter, 1851-1906

1st, but possibly, atypical case

Healthy Alzheimer’s Disease

AD, external aspect

AD, coronal cross section

Genetic Risk Factors

• Apolipoprotein E:– Chromosome 19– 299 amino acids– E3 > E2 > E4

Isoform 112 158

E2 Cysteine Cysteine

E3 Cysteine Arginine

E4 Agrinine Agrinine

Apolipoprotein E & Alzheimer’s Disease

• ε4– 1 copy: 2.5x– 2 copies: 7x

Corder et al. (1993). Science, 261, 921-3.

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 function

Folstein, Folstein, & McHugh (1975). J Psychiatric Research, 12, 189-198.

Executive Function Test: Trail Making Test: Part A

Trail Making Test: Part B

Amyloid Plaque

• Amyloid Beta Peptide: 40/42 amino acids• Amyloid Plaque: clusters of Beta amyloid +

Alzheimer’s Vaccine?

• Immunization against AB42 peptide produced antibodies

• MMSE– 30: maximum– 21-24: mild– 10-20: moderate– <9: severe

• Brain versus behavior

Holmes et al. (2008). Lancet, 372, 216-223.

Alzheimer’s Vaccine?

• Immunization against synthetic AB42 produced antibodies

• MMSE– 30: maximum– 21-24: mild– 10-20: moderate– <9: severe

• Brain versus behavior

Holmes et al. (2008). Lancet, 372, 216-223.

Pharmacotherapies for ADDonepezil(Aricept)

Galantamine(Razadyne)

Rivastigmine(Exelon)

Memantine(Namenda)

FDA Approved for:

mildmoderatesevere

mildmoderate

mildmoderate moderate

severe

Mechanism cholinesteraseinhibitor

cholinesteraseinhibitor

cholinesteraseInhibitor

NMDAantagonist

Adverse effects nauseavomiting↓ appetite↑ bm

nauseavomiting↓ appetite↑ bm

nauseavomiting↓ appetite↑ bm

headacheconstipationconfusiondizziness

http://wps.prenhall.com/wps/media/objects/3775/3866436/proto/donepezil.wav

Acetylcholine Breakdown

AChE: actylcholinesterase– brain (neurons)

BuChE: butyrylcholinesterase (pseudo)

– plasma– liver– gut– brain (glia)

Stahl (2008). Essential Psychopharmacology, p. 915.

Mechanism of Donepezil

Stahl (2008). Essential Psychopharmacology, p. 925.

Mechanism of Rivastigmine

Stahl (2008). Essential Psychopharmacology, p. 926-929, http://www.youtube.com/watch?v=Pk89_b3FI5E

Mechanism of Galantamine

• Found in several plants including daffodil

• AChE inhibitor & nACh Positive Allosteric Modulator

Stahl (2008). Essential Psychopharmacology, p. 919.

Galantamine

Stahl (2008). Essential Psychopharmacology, p. 929-31.

Response to Cholinesterase Inhibitor

Stahl (2008). Essential Psychopharmacology, p. 924.

AChEInhib

BuChEInhib

nAChPAM

Donepezil yes no no

Rivastigmine yes yes no

Galantamine yes no yes

Glutamateric Transmission in Health

• Excitatory amino acid• Important for cognition

Stahl (2008). Essential Psychopharmacology, p. 302, 933.

Glutamateric Transmission & Neurotoxicity

• Free radicals– superoxide (O2-)

– hydrogen peroxide (H2O2)– hydroxyl (OH)

Stahl (2008). Essential Psychopharmacology, p. 933.

Low affinity NMDA binding

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 caregiver

Reisburg et al. (2003). New England J Medicine, 348(14), 1333-1341.

Huntington’s Chorea

• Autosomal dominant (Huntingtin)

• # CAG repeats predicts onset• motor -> personality/dementia

Woody Guthrie (1 min): http://www.youtube.com/watch?v=wxiMrvDbq3s

1912 - 1967

H h

h Hh hh

h Hh hh

Example patient (1 min): http://www.youtube.com/watch?v=JzAPh2v-SCQ

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.

Tetrabenazine

• Tx: chorea• MOA: reversible VMAT2 inhibitor• Adverse Effects: depression/suicidal ideation

Joseph Janovik, MD

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.

Amyotrophic Lateral Sclerosis

• Symptoms: weakness, muscle atrophy, dysarthria, dysphagia, respiratory compromise

• Pathophysiology: glutamate excitotoxity in upper (motor cortex) & lower (ventral horn) motor neurons

1903-1941 1942 -

Riluzole

• Tx: disease progression (?)• MOA: ↓ glutamate

release & ↑ uptake; • Adverse Effects: nausea &

asthenia• Cost: $10K/year

http://www.howjsay.com/index.php?word=riluzole&submit=Submit

Cifra et al. (2012-in press). Neuroscientist, 1-8.

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 months

Miller et al (2012). Cochrane Database Systematic Reviews.

Baclofen

• Tx: ALS spasticity• MOA: GABAB agonist• Adverse Effects:

– drowsiness & fatigue (oral)– somnolence, dizziness (intrathecal)

Pump 2:05 to 4:10 min: http://www.youtube.com/watch?v=NDys_6lPa5U

Terminology• dysarthria (p. 624): disorders of articulation, as stammering or stuttering• dysphagia (p. 624): pronounced dis-fey-juh; difficulty swallowing

http://dictionary.reference.com/browse/dysphagia?s=t