Table 1: Criteria for the Diagnosis of Alzheimer's Disease
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Table 1: Criteria for the Diagnosis of Alzheimer's Disease

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Table 1: Criteria for the Diagnosis of Alzheimer's Disease Document Transcript

  • 1. Prevention of Alzheimer’s Disease Heidi D. Klepin Resident Grand Rounds November 28, 2000 Case History Mrs K. is a 58 year old white female who presents to her primary care physicians office for a yearly follow-up. She reports no problems in the last year with the exception of two episodes of poison ivy. Her review of systems is negative with the exception of some mild arthritis in the hands. PMH: osteoarthritis FH: colon cancer, CAD SH: married with 2 grown children. Does office work and remains very active physically and socially. No tobacco. Social alcohol. ALL: none Medications: HRT which she cuts into quarters. PE: normal Labs: lipid normal Health maintenance: encouraged patient to have screening colonoscopy, up to date on mammogram At the end of the interview the patient says that she recently read in Prevention magazine that vitamin E helped improve memory and prevent Alzheimer’s disease. She had also heard something about Ginkgo biloba from a friend at work. She asks if she could be advised on what to take, if anything, to prevent Alzheimer’s disease. Clinical question: Are there any medications that have been proven to help prevent Alzheimer's disease? Table of Contents: I. Definition of Alzheimer’s disease II. Pathology III. Epidemiology IV. Rationale for prevention V. Risk factors VI. Estrogen VII. Anti-inflammatory medication VIII. Anti-oxidants IX. Ginkgo biloba X. Vaccine XI. Conclusions Alzheimer’s Disease Can we prevent it? Heidi D. Klepin Internal Medicine
  • 2. November 28, 2000 I. Definition Alzheimer’s disease is a progressive neurologic disorder characterized by memory loss, cognitive dysfunction, personality changes and global functional decline. It is the most common type of dementia accounting for atleast 60% of cases18. It typically develops insidiously and progresses gradually over time. Classically, patients initially experience short term memory loss often with some impairmed orientation, judgement, problem solving and perception which may be subtle and missed by family and clinicians18. As the disease progresses patients become increasingly dysfunctional and eventually completely dependent in IADLs and ADLs. Cognitive decline is often paired with behavioral disturbance and mood disorders as well. Alzheimer’s disease is both a clinical and pathological diagnosis. Currently the most accepted diagnostic criteria for Alzheimer’s disease was introduced by the Work Group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) which is listed below. Table 1: Criteria for the Diagnosis of Alzheimer’s Disease Diagnosis Criteria Probable Alzheimer’s Disease All of the following must be present: - Dementia established by exam and objective testing - Impairment in memory and atleast one other cognitive function (ex. language and perception) - Progressive worsening of memory and atleast one other cognitive function - No disturbance in consciousness - Onest between 40 and 90 years of age - Absence of another grain disorder or systemic disease that might cause dementia In addition the diagnosis may be supported by one of the following: - Loss of motor skills - Diminished independence in ADLs and altered patterns of behavior - Family history of similar disorder - Laboratory results consistent with the diagnosis (ex. cerebral atrophy on CT scan) Possible Alzheimer’s Disease - Fulfillment of the above criteria with variation in the onset of symptoms or manifestations or in clinical course; or a single, but gradually progressive, cognitive impairment without and identifiable cause. - Another brain disorder or systemic disease that is sufficient to produce dementia, but that is not considered to be the underlying cause of the dementia in the patient. Definate Alzheimer’s disease - Fulfillment of the above clinical criteria and histiologic evidence of Alzheimer’s disease based on the examination of brain tissue at biopsy or autopsy. (NEJM Nov 25, 1999) II. Pathology The histopathology of Alzheimer’s disease includes neuritic plaques (senile plaques), neurofibrillary tangles, loss of synapses and neurons, granulovacular degeneration and amyloid angiopathy 2,4. The neuritic plaques are extracellular lesions consisting of degenerating neuronal processes (neurites) and abnormal deposits of amyloid protein 4. Neurofibrillary tangles are intraneuronal structures configured as paired helical filaments consiting primarily of abnormallly phosphorylated tau protein 2,4. The neurofibrallary tangles lead directly to cell death, although, cell death is not limited to only neurons
  • 3. containing this classical finding of Alzheimer’s disease (AD)2. The evolution and distribution of plaques and tanles in the brain is systematic in AD2,4 and correlates with the usual symptomatic progression of disease. Of note neuritic plaques have also been seen in the normal aging process while neurofibrillary tangle have been assiciated with other neurologic disorders including Parkinson’s disease , dementia pugilistica, subacute sclerosing, panencephalitis and early onset epilepsy byt not normal aging2. Loss of number of neurons and synapses is also classically seen in AD patients. One study reported a 45% decrease in presynaptic terminal density at the time of autopsy2. There is also evidence of inflammation within or adjacent to neuritic plaques2. Multiple acute phase reactants have been detected as well as activation of the complement system 2. Inflammatory activity may play a role in amyloid metabolism and subsequent cell death2. Research is currently underway regarding the beneficial effects of anti-inflammatory medication and dementia. Amyloid metabolism is felt by many researchers to be the central focus of AD pathologic changes in the brain. Many studies in vitro and in vivo have demonstrated the toxic effects of abnormal accumulation of amyloid protein on neuronal tissue2,4. The amyloid-beta protein is part of a larger molecule which itself has not demonstrated neurotoxicity. Major catabolism of this protein (APP) does not liberate amyloid- beta secondary to cleaving within the beta portion of the protein. A minor pathway requiring 2 cleavage events liberates beta-amyloid. All genetic mutations that lead to an increased risk of AD as well as normal aging and traumatic brain injury cause increased production of amyloid-beta 2. The mechanism by which this protein exerts neurotoxic effects is not clear. It is hypothesized that amyloid-beta increases production of H2O2 leading to oxidative cell damage and cell death2. The potential role of free radicals has prompted research into the theraputic benefits of antioxidants. Amyloid beta protein also disturbs calcium metabolism and increases the intrneuronal calcium concentrations that may lead to cell death by activating intracellular proteases and lipases, abnormal phosphorylation of protein resulting in neurofibrillary tangles and direct damage to cell mitochondria2. The potential role of calcium channel blockers in AD is also being explored. Neurotransmitter disturbances have been well documented in Alzheimer’s disease and have been the focus of most drug related research. Acetylcholine (ACh) levels are consistently decreased in AD patients. This is secondary to neuronal destruction in the nucleus basalis of Meynert in the basal forebrain where most ACh is synthesized, which occurs early and consistently in AD. Choline acetyltransferase (CAT) which synthesizes Ach is reduced by 58-90% in AD patients and correlates with the severity of dementia2. The acetylcholinesterase inhibiters including tacrine and donepazil were developed to target this aspect of AD pathology. Muscarinic (M1) and nicotinic cholinergic recepters have also been found to be decreased in AD2. Other neurotransmitters not related to the cholinergic system including serotonin, GABA, somatostatin, norepinephrine have been shown to be reduced in AD as well and may play a role in cognitive dysfunction. III. Epidemiology Alzheimer’s disease is the most common form of dementia in the United States. Is is estimated to affect 4 million people. The incidence of AD is estimated at 0.5% per year at age 65 and 8% per year after the age of 85. Since average survival with disease is 10 years, the prevalence of AD increases from 3% at 65 years of age to approximately 47% at 85 years of age. The proprtion of the US poulation greater than 80 years old is expected to double in 10 years with significant implications for the number of patients suffering from this disease. In addition to the social and psychological stresses produced by this disease process, patients with AD are at increased risk for many medical problems. They suffer from an increased incidence of neurologic complications, infections, hip fractures and malnutrition. Specifically, these patients have been shown to be at higher risk for stroke, myoclonus, urinary tract infection and aspiration pneumonia6. Furthermore, as neurologic function declines most patients require increasingly intensive supervision and care, most often resulting in nursing home placement. The financial burden of AD is impressive. In 1991, the estimated cost of caring for and individual with AD was $47,000 per year. The combined direct and indirect colst including medical care, loss of
  • 4. productivity, resource loss and family care for all patients with AD in the US is estimated at 100 billion dollard per year. Alzheimer’s disease is already a significant public health problem and will continue to become more prominent over the next few decades as the population ages. A recent paper by Brookmey et al. Projected that the prevelance of AD would quadruple in the next 50 years. They used a prevalence estimated of 2.3 million people with AD (1997) and projected a 3 fold increase in the number of patients afflicted by the year 2047. They calculated that a delay in onset of disease by 5 years would decrease the prevalence of AD by 1.15 million people 10 years later and 4 million people 50 years later. Even a 1 years delay in onset of symptoms could decrease the number of patients with AD by 210,000 at 10 years and 770,000 at 50 years. The calculated economic benefit of such a preventative measure would be about 10 billion dollars 10 years after initiation of intervention (using a yearly cost of $47,000 x 210,000 fewer patients7. IV. Risk Factors V. Estrogen A. Mechanism of Action The benefit of estrogen on cognitive function and potential role for estrogen in the treatment and prevention of dementia has intrigued scientists for years. Basic science research has provided the groundwork for recent clinical trials. Multiple mechanisms have been proposed which might contribute to a decreased risk of dementia and specifically AD. Animal models have shown that chronic estrogen deficiency affects behavior and cognitive function, specifically decreasing performance on tasks of memory and learning16. This has been associated with decreased cholinergic activity and is improved with estrogen replacement. Estrogen appears to modulate mutiple neurotransmitters within the brain. It has been shown to increase choline acetyltransferase, increase release of acetylcholine and prolong survival of cholinergic neurons. Estrogen has also been shown to decrease monoamine oxidase activity which is results in decreased catabolism of catecholimines. In vitro studies have also shown that estrogen stimulates neurite growth and synapse formation 17. In vitro studies have shown that estrogen increases metabolism of amyloid precurser protein (APP) into nontoxic peptides, which could have signigicant impact on Alzheimer’s disease pathology17. Estrogen may also influence inflammatory repsonses via effects on interleukin-6, a cytokine postulated to participate in neuritic plaque formation17. Estrogen improves regional blood flow in the brain and may be protective against cerebral ischemia 17. Estrogen may also influence genetic predispostition to Alzheimer’s disease. Studies have suggested that estrogen modulates expression of apolipoprotein E gene and may supress the expression apo E-4 in rodents. Summary of pathophysiologic benefits of estrogen • increased cholinergic activity • decreased catabolism of catecholamines secondary to inhibition of MAO • stimulation of neurite growth and synapse formation • decreased production of toxic beta-amyloid protein • antiinflammatory effect • improved regional blood flow • supression of apoE-4 expression
  • 5. C. Clinical Trials The effect of estrogen on cognition has been the subject of numerous trials. This paper will consider trials that looked at the effect of estrogen directly on cognition as well as studies that addressed the association between estrogen and AD directly. There have been 7 large observational trials addressing the effect of estrogen on cognitive function. Conclusions: Effect of estrogen on cognitive function Observational trials • Contradicory results with no consistantly reproducible benefit of estrogen use on cognitive function • Prospective trials did not show improvement in cognitive decline with estrogen use Observational trials limited by lack of randomizatiom and potential inherent differences between study groups