Published in UAB Insight, Summer 2004
Alzheimer Disease: Diagnosis and Prevention
ABSTRACT: Efforts are under way to improve diagnosis of Alzheimer disease and prevent its development or progression
CME OBJECTIVE: The reader will appreciate diagnostic and preventive approaches to patients with cognitive impairment.
Lindy E. Harrell, MD, PhD, no conflicts of interest.
Alzheimer disease (AD) is not a normal consequence of aging, but increasing age is the greatest risk factor for the disorder, which robs individuals of their memories and independence.
One in 10 individuals aged 65 years and older have AD, and the condition affects nearly half of those aged 85 years and older. "As the number of Americans older than 65 doubles over the next 2 decades, the prevalence of Alzheimer disease will dramatically increase," says Lindy E. Harrell, MD, PhD, director of UAB's Alzheimer Disease Center. "We now have some preventive strategies and emerging tools for early diagnosis, such as PET scans. Delaying disease onset by just 5 years could cut occurrence in half."
Difficult Diagnosis
Early recognition and accurate assessment of cognitive decline can identify patients at risk for progression to AD. The Memory Impairment Study (Arch Neurol. 2004;61:59-66) found 10% to 15% of individuals with mild cognitive impairment, a transitional state of cognition and functionality between healthy aging and mild AD, progress to clinically probable AD each year.
Distinguishing between mild cognitive impairment, AD, and other forms of dementia challenges physicians, Harrell says. "First, correctable conditions, such as medication overuse, must be excluded. Most experts believe 60% of dementia cases are caused by Alzheimer disease, 15% by vacular insults, and the remainder by other factors.
"Many other conditions and some medications can produce symptoms mimicking Alzheimer disease, including substance abuse, thyroid disease, severe vitamin B12 deficiency, depression, normal pressure hydrocephalus, blood clots, syphilis, Huntington disease, and brain tumors," she notes.
A combination of diagnostic tools, including medical history, physical examination, and neuropsychological assessment, are useful for diagnosing AD; yet, Harrell maintains, observations by the patient's caregiver provide the most valuable diagnostic evidence. "Relatives and spouses have years of experience with the individual's personality and provide the most accurate picture of mental decline and functional loss. It is crucial to interview caregivers alone as they are often reluctant to discuss deterioration in front of their loved one."
A recent study (Ann Intern Med. 2004;140:501-509) found the lifespan of individuals diagnosed with AD is reduced by about 50%, compared with those of similar age without the disease, and that certain factors help predict long-term survival. Larson and colleagues found survival was reduced most among individuals aged 85 years and older with a history of wandering, abnormal gait, diabetes, and congestive heart failure. "Alzheimer disease is a devastating diagnosis," Harrell says. "Being able to better predict rate of decline helps caregivers plan for the future.
Diagnostic Neuroimaging
Magnetic resonance imaging and computed tomography can rule out stroke, blood clots, tumors, or normal pressure hydrocephalus. Recently, positron emission tomography (PET) has emerged as a tool for diagnosing early AD.
"Neurofibrillary tangles and beta amyloid accumulation, which forms neuritic plaques and inhibits acetylcholine production, are primary factors involved in Alz-heimer disease development," Harrell says. "PET scans detect reductions in regional brain metabolism associated with these damaged neurons."
PET scans accurately predicted AD development in 90% of cases and correctly identified the disease in 94% of diagnoses later confirmed by autopsy, according to a study (JAMA. 2001;286: 2120-2127). A more recent study outlined a new PET technique measuring AD-related processes leading to altered brain connections between the entorhinal cortex and both brain hemispheres (J Nucl Med. 2004;45:382-392). Located in the ventromedial temporal lobe, the entorhinal cortex is an integral component of the medial temporal lobe memory system.
"PET scans may facilitate early diagnosis by revealing functional alterations during initial stages of the disease process," she says. "However, no one measure is accurate enough for an unequivocal diagnosis of Alzheimer disease."
The national Alzheimer's Association only endorses PET scanning if diagnosis remains unclear after a complete workup. Harrell notes in June, the Centers for Medicare and Medicaid Services announced it would cover costs for PET scans for the diagnosis of suspected Alzheimer's disease for Medicare patients when a specific diagnosis remains uncertain despite a thorough clinical evaluation. Because of the potential benefit of PET scans, Medicare will also cover PET in other patients with early dementia or unexpected memory loss who are enrolled in clinical trials. Private insurers are likely to follow.
Slowing Decline
Although there are no proven methods for preventing AD, several strategies may reduce risk and slow progression.
"Vitamin E, and to a lesser extent vitamin C, has been associated with slowing of memory loss, and some nonsteroidal anti-inflammatory drugs, particularly ibuprofen, may prevent beta amyloid accumulation," Harrell says. "Low-fat diets also may be protective, and studies have shown regular exercise and staying mentally active are important tools for preventing cognitive decline."
Four cholinesterase inhibitors — donepezil, rivastigmine, galantamine, and tacrine — are approved for treatment of mild-to-moderate AD. All are designed to improve memory and slow mental decline by raising levels of acetylcholine and protecting the cholinergic system.
"These drugs do not affect the basic disease process, and many patients and caregivers notice only moderate gains in memory and daily functionality," Harrell says. "Yet, even small improvements, such as individuals being able to dress themselves and recall the layout of their home, can translate into substantial benefits for patients and caregivers and may delay the need for nursing home care."
Memantine — used in Germany for treatment of dementia since 1982 — recently became the first drug approved by the Food and Drug Administration for moderate-to-severe AD.
"Memantine is an NMDA receptor antagonist that blocks glutamate, a neurotransmitter disrupted by beta amyloid accumulation," she explains. "Overstimulation of glutamate allows calcium to enter brain cells and damage neurons important for learning and memory. Memantine appears to modestly enhance daily functioning and cognition.
"There is a definite need for better understanding of the degenerative processes involved in Alzheimer disease," Harrell concludes. "UAB's Alzheimer Disease Center is recruiting participants for trials aimed at slowing disease progression and for genetic studies that may yield critical clues in the fight against this devastating disease."
UAB Alzheimer Disease Center Trials
Treatment of Agitation/Psychosis in Dementia/Parkinsonism
Summary: Placebo-controlled trial of efficacy and tolerability of quetiapine for psychosis and/or agitation in AD patients with parkinsonism.
Candidates: Aged >50 years; diagnosis of probable AD; presence of the following: resting tremor, bradykinesia, limb rigidity, shuffling, short-stepped gait.
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Cholesterol-lowering Agent to Slow Progression of AD
Summary: Safety and efficacy of simvastatin to slow AD progression.
Candidates: Aged >50 years; mild-to-moderate AD patients free of life-threatening disease who do not require lipid-lowering treatment. Score of 12-26 on Mini-Mental State Exam. Stable medical condition >3 months prior to screening. Residence in a community dwelling.
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Vitamins to Slow AD (homocysteine study)
Summary: Study investigating whether reduction of homocysteine levels with high-dose folate and vitamin B6 and B12 slows rate of cognitive decline in AD patients.
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Multi-institutional Research in Alzheimer’s Genetic Epidemiology
Summary: Evaluate association between genetic and nongenetic AD risk factors.
Candidates: Probable AD diagnosis and living sibling willing to participate.
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For more information
Dr. Lindy Harrell
1.800.UAB.MIST
mist@uabmc.edu