Medication Therapies in the Treatment of Alzheimer s Disease

1. Medication Therapies in the Treatment of Alzheimer�s Disease Alvin C. Holm, MD, FACP

3. I will begin at the very beginning. This is a photograph of the medical record of Auguste D. She was 51 y/o when she was admitted to the insane asylum at Frankfurt, Germany on 11/25/1901. Her attending physician was a psychiatrist named Alois Alzheimer. Dr. Alzheimer cared for Auguste until 1903 when he moved to the Royal Psychiatric Clinic in Munich. From Munich, Dr. Alzheimer continued to follw her course until her death on 4/8/06 from sepsis due to a decubitus ulcer after which he studied the pathological characteristics of her illness. His original manuscript was published in 1907. Dr. Kraepelin, in his 8th edition of the Handbood of Psychiatry was the first to use the term "Alzheimer's disease"I will begin at the very beginning. This is a photograph of the medical record of Auguste D. She was 51 y/o when she was admitted to the insane asylum at Frankfurt, Germany on 11/25/1901. Her attending physician was a psychiatrist named Alois Alzheimer. Dr. Alzheimer cared for Auguste until 1903 when he moved to the Royal Psychiatric Clinic in Munich. From Munich, Dr. Alzheimer continued to follw her course until her death on 4/8/06 from sepsis due to a decubitus ulcer after which he studied the pathological characteristics of her illness. His original manuscript was published in 1907. Dr. Kraepelin, in his 8th edition of the Handbood of Psychiatry was the first to use the term "Alzheimer's disease"

4. This is one of two photographs found in the chartThis is one of two photographs found in the chart

5. Dementia and its Relationship to Age

6. Global Aging

7. Cognition All aspects of thinking, remembering and perceiving

8. Dementia An acquired disorder of intellectual impairment produced by a dysfunctional brain

9. The Clinical Spectrum of Dementia

10. Clinical Criteria for Definite, Probable, and Possible Alzheimer�s Diaease Definite Alzheimer�s Disease: 1. Clinical criteria for probable AD 2. Histopathological evidence of AD (autopsy or biopsy) Probable Alzheimer�s Disease: 1. Dementia established by clinical examination and documented by mental status exam 2. Dementia confirmed by neuropsychologic testing 3. Deficits in two or more areas of cognition 4. Progressive worsening of memory and other cognitive functions 5. No disturbance of consciousness 6. Onset between ages 40 and 90 7. Absence of systemic disorders or other brain diseases capable of producing a dementia Possible Alzheimer�s Disease: 1. Presence of a systemic disorder or other brain disease capable of producing dementia but not thought to be the cause of the dementia 2. Gradually progressive decline in a single intellectual function in the absence of any other identifiable cause Unlikely Alzheimer�s Disease 1. Sudden or apoplectic onset 2. Focal neurologic signs 3. Seizures or gait disturbance early in the course of the illness

11. An Operational Definition of Alzheimer�s Disease:

12. Dementing Illnesses as Proteinopathies DAT: beta amyloid => posterior cortex FTD: tau => anterior cortex (frontal/temporal) DLB: alpha synuclein => limbic system / midbrain / brain stem / cortex 

13. Neuritic Plaques

14. Neurofibrillary Tangles

15. Evidence Supporting Beta Amyloid as the Putative Toxic Agent in Alzheimer�s Disease The clinical phenotype of AD corresponds to impairment in brain regions with the highest plaque burdens The degree of intellectual impairment in AD directly correlates with AB plaque burden Beta amyloid deposition is associated with reduced dendritic arborization, synaptic connectivity, and neurotransmitter availability Beta amyloid deposition is associated with inflammatory changes in the cerebral cortex including cell death Most cases of familial AD are caused by mutations in genes regulating expression ofpresenilin (active component of gamma secretase) Alzheimer�s disease occurs uniformly in patients with Down�s syndrome (trisomy 21) at an early age

16. DAT: Distribution of Neuritic Plaques

17. DAT: Distribution of NFT

20. Flurodeoxyglucose (FDG) PETnormal DAT

21. Amyloid Cascade Hypothesis

22. Metabolism of the Amyloid Precursor Protein

23. Proteolysis of the APP APP + alpha secretase + gamma secretase = P3 (soluble) 17   40-42 APP + beta secretase + gamma secretase = AB (insoluble)  1 40-42

24. Treatment Strategies to Lower AB/Plaque Load in DAT

25. Characteristics of Drugs for the Treatment of AD

26. Alternative Drug Therapies for the Treatment of Alzheimer�s Disease Antioxidant therapies: Vitamin E Coenzyme Q10 Ginkgo biloba  Cholinesterase inhibition: Huperzine A  Anti-inflammatory Ginkgo biloba nonsteroidal anti-inflammatory therapy ( ibuprofen ) Unknown: Omega-3 fatty acids Phosphatidylserine

27. Behavioral Disturbances in Alzheimer�s DiseaseRelated to Time of Diagnosis Peak Incidence Social withdrawl/Apathy > 30 months ptd Depression 24 months ptd Suspiciousness 18 months ptd Anxiety 8 months ptd Diurnal rhythm disturbance 8 months ptd Delusions 8 months ad Wandering 10 months ad Agitation 12 months ad Hallucinations 18 months ad Physical aggression 24 months adptd = prior to diagnosisad = after diagnosis Adapted from Jost, BC, Grossberg, GT, JAGS, 1996.

28. Agitation in DAT as Related to CDR So the anticipated growth in the number of patients with dementia and the high frequency of NP sxs in these patients combine to define an emerging reality: not only are we beginning to experiencing an epidemic of dementia in our society but and epidemic in neuropsychiatric illness at a time when our healthcare system is neither configured or prepared to deal with this challenge.So the anticipated growth in the number of patients with dementia and the high frequency of NP sxs in these patients combine to define an emerging reality: not only are we beginning to experiencing an epidemic of dementia in our society but and epidemic in neuropsychiatric illness at a time when our healthcare system is neither configured or prepared to deal with this challenge.

29. Behavioral Disturbances in DAT as Defined by the NPI

30. Relationship Between Psychosis and Stage of Dementia

31. Bethesda Hospital ExperienceGeriatric Behavior Program Outcome Study ~60% of admissions exhibited predominant signs/symptoms of depression ~20% of admissions exhibited predominant signs/symptoms of a mixed mooddisturbance ~10% of admissions exhibited predominant signs/symptoms of a delirium ~8% of admissions demonstrated a predominant need for increased structuralinterventions and a reduction in psychotropic therapies

32. Behavioral Syndromes in the Disturbed Dementia Patient Delirium Depression  Anxiety  Psychosis Mania

33. Treatment of Behavioral Disturbances in Dementia(Empirical Approach) An iterative process  Based on the determination of clinical need in a multidimentional assessment Generates reasonable hypotheses regarding the etiology of dysfunctional behavior Employs a process whereby hypotheses are tested by strategic introduction ofboth drug and non-drug therapies Therapeutic approached supported by longitudinal assessment of broad based clinical outcomes (cognitive, functional, and behavioral)

34. Treatment of Behavioral Disturbances in Dementia