Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 22 Alzheimer’s Disease

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Alzheimer’s Disease  Devastating illness  Progressive memory loss  Impaired thinking  Neuropsychiatric symptoms  Inability to perform routine tasks of daily living  Alzheimer’s disease (AD) affects 4.5 million Americans  4th leading cause of death – 100,000 deaths per year

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pathophysiology  Degeneration of neurons  Early in hippocampus Memory Memory  Later in cerebral cortex Speech, perception, reasoning, and other higher functions Speech, perception, reasoning, and other higher functions

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pathophysiology  Reduced cholinergic transmission  Levels of acetylcholine (ACh) 90% below normal Important neurotransmitter Important neurotransmitter Critical to forming memories Critical to forming memories  Loss of cholinergic function not the whole story

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pathophysiology  Beta-amyloid and neuritic plaques  Form outside of neurons  Spherical bodies composed of beta-amyloid core  Neurofibrillary tangles and tau  Form inside neurons  See Figure 22-1

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Histologic changes in Alzheimer’s disease.

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pathophysiology  Apolipoprotein E4 (apoE4)  May also contribute to AD  Endoplasmic reticulum–associated binding protein  Present in high concentrations in AD patients  Homocysteine  Elevated plasma levels of homocysteine associated with increased risk for AD

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Risk Factors  Major risk factors  Advancing age  Family history  Possible risk factors  Female  Head injury  Low educational level  Production of apoE4  High levels of homocysteine  Low levels of folic acid  Estrogen/progestin therapy  Nicotine in cigarette smoke  Sedentary lifestyle

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Symptoms  Memory loss  Confusion  Feeling disoriented  Impaired judgment  Personality changes  Difficulty with self-care

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Symptoms  Behavior problems (wandering, pacing, agitation, screaming)  “Sundowning”  Inability to recognize family members  Inability to communicate

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Progressive Symptoms  Symptoms typically begin after age 65 years, but may appear as early as age 40 years.  Life expectancy from symptom onset may be 20 years or longer, but is usually 4 to 8 years.

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diagnosis  NINCDS and ADRDA criteria based on patient’s age and clinical evaluation  Under the proposed new definition of AD, a patient must have episodic memory impairment plus at least one AD biomarker, as determined by MRI scan, PET neuroimaging, or CSF analysis. Note that overt dementia need not be present.

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diagnosis  2007 international group of AD experts proposed new diagnostic criteria for AD.  Added technologies and tests that provide data for evaluation of characteristic changes of AD:  MRI: atrophy of brain areas  PET: altered patterns in the brain  Cerebrospinal fluid analysis: presence of abnormal proteins

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Goal of treatment is to improve symptoms and reverse cognitive decline.  Available drugs cannot do this.  Five drugs are approved for AD dementia (none are very effective).

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Neuronal receptor blocker  Memantine  Cholinesterase inhibitors  Donepezil  Galantamine  Rivastigmine  Tacrine

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Treatment of AD with these drugs can yield improvement that is statistically significant but clinically marginal.  Equivalent to taking a “weight loss drug” and losing ½ pound after 6 months of therapy  It is not recommended that all patients receive these drugs because of the modest benefits.

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Cholinesterase inhibitors may delay or slow progression of disease, but will not stop it.  Drugs that block cholinergic receptors (first- generation antihistamines, TCAs, conventional antipsychotics) can reduce responses to cholinesterase inhibitors.

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Cholinesterase inhibitors  Indicated for mild to moderate AD  Prevent breakdown of ACh  May help to slow progression of disease  Only three are recommended for use and have equivalent benefits: Donepezil Donepezil Galantamine Galantamine Rivastigmine Rivastigmine  Not recommended (causes liver damage): Tacrine Tacrine

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Cholinesterase inhibitors (cont’d)  Adverse effects Cholinergic side effects Cholinergic side effects GI GI Dizziness Dizziness Headache Headache Bronchoconstriction Bronchoconstriction Liver injury (tacrine) Liver injury (tacrine)

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy  Memantine (Namenda, Namenda XR)  First drug in a new class, the NMDA receptor antagonists  Indicated for moderate to severe AD  Better tolerated than cholinesterase inhibitors  Adverse effects Dizziness Dizziness Headache Headache Confusion Confusion Constipation Constipation

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Memantine mechanism of action.

22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Treatments  Drugs for neuropsychiatric symptoms  Symptoms experienced by 80% of AD patients  Include agitation, aggression, delusions, hallucinations  Atypical antipsychotics  SSRIs for depression (not AD symptoms)