pathophysiology: alzheimer's disease

Alzheimer’s Disease

Brian J. Piper, Ph.D., M.S.

October 24, 2012

PiB PET scan

Disease Identifier Frequency in US Genetic Patho-physiology

Neurochem

PharmManagement

Parkinson’s JamesParkinson1817

500 K low nigra-striatal

DA common

Alzheimer’s AloysiusAlzheimer1906

5.4 million moderate diffusecortex

ACh? common

Huntington’s GeorgeHuntington1872

30 K high striatum ? uncommon

ALS JeanMartinCharcot

25 K low motorneurons

Glut? common

ACh: acetylcholine; DA: dopamine; Glu: glutamine; sym: symptom management

Neurodegenerative Disorders

Aloysius ”Alois” Alzheimer

• German psychiatrist• Described symptoms + pathology

– Neuronal loss– Plaques– Tangles

• Presentation to SW German Psychiatrist meeting about Auguste Deter ignored butEmil Kraeplin

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

1864-1913

1st, but possibly, atypical case Auguste Deter, 1851-1906

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.

Healthy Alzheimer’s Disease

AD, coronal cross section

AD, external aspect

AD ≠ Aging

Smith & Jobst (1996). British Medical Bulletin, 52(3), 575-586.

Rate of Decline

Smith & Jobst (1996). British Medical Bulletin, 52(3), 575-586.

Alzheimer’s Disease (AD)

• nucleas basilis is one region affected early• somas for acetylcholine system

Stahl (2008). Essential Psychopharmacology. p. 921.

Genetic Risk Factors

• Late Onset AD• 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.

Behavior & Brain

Smith & Jobst (1996). British Medical Bulletin, 52(3), 575-586.

Executive Function Test: Tower of London• Developed by Tim

Shallice in 1982 as a simplified version of the Tower of Hanoi

• Test of problem solving which is sensitive to brain damage

Screen shot from Piper et al. (2012). Behavior Research Methods, 44(1), 110-123.

DSM5 Criteria For Neurocognitive Disorder

http://www.dsm5.org/ProposedRevision/Pages/proposedrevision.aspx?rid=421

Amyloid Plaque

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

Pittsburg Compound B (PIB): A Future Diagnostic Biomarker for AD?

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.