College of Psychiatric and Neurologic Pharmacists

Etiology of Alzheimer’s disease

• A single factor is unlikely to be responsible for inducing dementia and behavioral changes.
• Amyloid-b (Ab) plaques, neurofibrillary tangles, phosphorylated tau (P-tau), inflammation and neuronal cell death are all observed during the course of the disease.
• Onset of the illness is variable, however, most patients have cellular level damage occurring by age 30-50 onward.

Amyloid and Tau hypotheses

• Amyloid hypothesis posits that the accumulation of Ab-rich plaques in the brain of Alzheimer’s disease (AD) patients leads to the cognitive impairment that eventually results in severe dementia.
• Cerebrospinal fluid (CSF) levels of Ab provide a potential biomarker for drug effects in early clinical trials.
• Tau aggregation and folding create neurofibrillary tangles either independently or in tandem with amyloid deposition.
• Disease course modification therapies will manifest as both durable symptomatic interventions and also alter the course of the illness as reflected in biomarker (lack of) progression.

Biomarkers are useful tools in developing better diagnostics & drugs

• Biomarkers are classified as ‘known’ or ‘probable’ validity.
• Biomarkers have the potential of providing a surrogate end point that is more efficient in speed and ease of measurement, thus reducing trial duration, size and related expenses.
• The ideal surrogate marker would completely mediate the relationship between clinical outcome and treatment.

CSF as a matrix for biomarkers

• CSF is in direct contact with brain tissue and has the potential to be an excellent source of clinically important biomarkers for AD.
• Sampling of CSF allows access to the central compartment and can be expected to provide a better matrix than plasma for assessing drug concentrations near the site of action.
• CSF Ab42 appears to reflect the deposition of Ab into plaques, while tau levels indicate the degree of neuronal degeneration and P-tau is related to the formation of tangles.
• CSF levels of Ab42 are decreased in AD patients, while levels of tau and P-tau are increased.
• A recent longitudinal study found very stable levels of all three biomarkers in individual patients.

Neuroimaging as a source of biomarkers

• Methods such as those being stud­ied in ADNI will provide a direct view of the AD brain that can be correlated with biomarkers like Ab and tau as well as cognitive and functional assessments. Some of these imaging techniques visualize amyloid deposits within the brain, while others examine brain function and atrophy. PET imaging with Pittsburg Compound B (PIB), a radiotracer that binds fibrillar amyloid, demon­strates promise as a method of evaluating amy­loid plaque burden in vivo.
• Functional MRI can be used to assess disruptions in brain activity in patients with AD and other dementias while structural MRI evaluates brain atrophy.

Dynabridging

• Continuous CSF collections are accomplished through an indwelling catheter placed in the lumbar sac by an experienced clinician.
• California Clinical Trials has developed this technique as a valuable tool during early drug development.
• The CSF is analyzed for drug and metabolite concentrations as well as biomarker measures of drug activity (Ab, tau, cholinesterase activity etc) with simultaneous monitoring of peripheral pharmacokinetic/pharmacodynamic parameters.
• The value of CSF Ab level monitoring in these studies is in using the AUC approach and the percentage change detected over time in correlation with drug administration.

Data (public domain) from drug development studies

• Drug therapy can be either or both symptomatic and disease course modifying.
• Therapeutic interventions which show promise include alpha-7 nicotinic modulators, BACE and Gamma Secretase inhibitors, amyloid aggregation inhibitors and clearance facilitators,  vaccines (passive and active), and a variety of molecular

Future perspective

• Corroborative approaches using CSF biomarkers, neuroimaging and cognitive assessments will be developed, leading to improvement in diagnostics, clinical trials and basic research.
• Proteomic research promises to identify new CSF biomarkers.

1. Analyze the current state of the art for disease modifying drugs.
2. Explain research design methodology with a focus on Alzheimer’s disease.
3. Describe leading biosurrogate markers in the area of Alzheimer’s disease.
4. Analyze case illustrations for early drug development as targets for the therapeutics of Alzheimer’s Disease.

Activity Dates: 04/21/2010 - 04/21/2013
ACPE Contact Hours: 1.0
ACPE Number: 0284-0000-10-017-H01-P (Knowledge)
Nursing Credit Reminder: Note that ACPE and ACCME credit is accepted for certification renewal.

This course is provided online at cpnp.org and consists of the speaker audio and slides. A PDF file of the slides is also provided and access is available to participants indefinitely although ACPE credit is available only through the course expiration date.

Participants in this course must complete an examination and achieve a score of 60% or greater. Successful completion of the course also requires the completion of a course evaluation. ACPE statements of credit can be retrieved by participants online at cpnp.org immediately upon successful completion of the course.

If you are a pharmacist, nurse practitioner or other healthcare professional involved in the medication therapy management of psychiatric and/or neurological patients, we invite you to participate in this online course.

This programming was supported in part by grants from Bristol-Myers Squibb, Otsuka America Pharmaceutical, Inc., Lilly USA, LLC, AstraZeneca and Cyberonics.