The number of people in the United States aged 65 years and older increased from 12 million to 37 million from 1950 to 2005.1 As advancing age brings an increasing probability of memory loss, PAs in primary care, as well as those in most specialties, will encounter patients with cognitive deficits. Failure to identify and correctly diagnose the cause of these deficits can lead to suboptimal care of other medical conditions, adverse reactions to medications or environmental changes, improper planning for the patient's future, and a lack of understanding of why patients are not adhering to treatment. Approximately 40% of people aged 65 years or older have age-associated memory loss, and 10% have mild cognitive impairment (MCI). Age-associated memory loss progresses to dementia in only 1% of patients, whereas MCI progresses to Alzheimer's disease (AD) in nearly 15% of patients with the condition.2 Memory loss is a common complaint. Therefore, clinicians need to distinguish between age-associated memory loss, MCI, and dementia when evaluating older patients. A diagnosis of MCI is an opportunity to identify the patient at increased risk for developing dementia and to initiate treatment that can delay further cognitive decline.3,4
DEFINITION AND INCIDENCE
In the simplest terms, MCI is the transitional state between age-related cognitive decline and dementia or AD.4 Unfortunately, there is no consensus among researchers and clinicians on a definition of MCI.5 However, the literature demonstrates that a diagnosis of MCI can be made with the following criteria:
• The patient is neither cognitively normal nor demented.6 MCI does not meet the diagnostic criteria for dementia defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision.5
• Evidence of cognitive decline is apparent. Specifically, the patient complains of memory loss and impaired objective memory for his or her age and education level.5,6
• General cognition is relatively preserved. Patients with MCI usually fail to meet the diagnostic criteria for dementia because only one cognitive domain is affected, the symptoms are mild, and social and occupational functions are preserved.5 Patients with MCI are not disabled and usually suffer no cognitive deficits other than memory loss.7
• Activities of daily living (ADLs) are intact, but complex instrumental functions may be minimally impaired.
In summary, MCI is a syndrome in which cognitive decline is greater than expected for a person's age and educational level but does not notably interfere with ADLs.6
With the variation in definitions, the prevalence of MCI is reported to be 3% to 19%, with an incidence of 8 to 58 per 1,000 persons per year.6 However, when using the criteria outlined here, the incidence of MCI is approximately 3%. Patients who meet these criteria have the highest likelihood of progressing to dementia.4
ASSESSMENT
The US Preventive Services Task Force found insufficient evidence to recommend routine screening for dementia in asymptomatic elderly patients;8 however, patients older than 50 years with complaints of memory loss should be evaluated. A thorough history should be obtained from either the patient or an informant to assess cognitive function. The differential diagnosis based on a complaint of memory loss falls on a wide spectrum, ranging from normal age-associated memory loss to dementia. The differential for dementia is extensive and includes AD, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia, as well as potentially treatable conditions such as normal pressure hydrocephalus, sleep apnea, hypothyroidism, and depression. In clinical practice, the distinction between the stages of cognitive decline can be subtle. Defining the boundaries of normal aging from MCI or MCI from mild AD can be challenging. Numerous distinctions are determined by the degree of impairment.6 Learning ability and memory should not decline before age 60 years. Cognitive function should remain relatively stable up to age 80 years, showing no more than a 10% decline from baseline. An older person experiencing age-related memory loss may process thoughts more slowly but should still be able to recall facts and experiences when cues are given.5
Patients experiencing memory loss and their informants should be questioned about the patient's ability to perform ADLs. Studies show that patients with MCI will show subtle difficulties with complex hobbies and handling finances 2 years before dementia is diagnosed. A lack of awareness of deficits and decreased ability to perform common activities—such as using the telephone, taking medications, and orientation to direction and place—suggests progression to dementia.6 When MCI is suspected, neuropsychological tests should be performed.
Currently, there are no universally accepted screening tests for MCI.9 The Mini-Mental State Examination (MMSE) is often used to screen patients for dementia; however, the test is only 18% sensitive for detecting MCI. Most patients with MCI would score within the normal range.10 A more sensitive test for MCI is the Montreal Cognitive Assessment (MoCA), a 10-minute cognitive screening tool available at www.mocatest.org.10,11 The MoCA is 90% sensitive and 87% specific for MCI. The test assesses eight cognitive domains: short-term memory recall, visuospatial abilities, executive functions, attention, concentration, working memory, language, and orientation to time and place. Unlike the MMSE, the MoCA features more words; fewer learning trials; longer delays before recall for assessing memory; and more numerous and demanding tasks for assessing executive function, visuospatial abilities, and language.10 The Computer-Administered Neuropsychological Screen for MCI (CANS-MCI) has also been validated.12,13 CANS-MCI is a 30-minute computerized touch-screen battery test that measures executive function, language fluency, and memory. The test is administered, scored, and interpreted from a computer, which allows for consistent administration and scoring. CANS-MCI provides any assistance necessary, and many patients complete the test without difficulty, regardless of their computer skills.13 If office-based test results are inconclusive, the patient can be referred to a neuropsychologist for a more extensive battery of cognitive tests.
Currently, neuroimaging and electrophysiologic tests are used only in the research setting. MRI can demonstrate atrophy in patients with MCI compared to healthy controls, and positron emission tomography can show synaptic loss from neurofibrillary tangles.5,6 Plaques and tangles are neuropathologic changes that occur in the normal aging process; however, they occur more often in patients with MCI and they are hallmarks for dementia.7 High levels of total tau, phospho-tau epitopes, and amyloid isoforms in CSF and the presence of the apolipoprotein APOE*E4 on genetic testing also may indicate progression to AD.5
TREATMENT
As with many other diagnoses, patients with MCI are often aware of their deficits and seek information. Patients must be educated about the nature of the disorder, risks, coping strategies, and prognosis. Patients and their families should be encouraged to discuss advance directives and to make plans for the patient's future needs. They need to know that the patient should be closely monitored for any cognitive or functional changes; knowing that their health care provider is supportive is also important.
Once the diagnosis of MCI is established, can it be treated? The current management of MCI is nonspecific; it includes restricting certain medications, controlling vascular risk factors, and treating comorbid conditions. Using anticholinergic medications, especially in patients with cognitive decline, is troublesome because the risk of medication-induced cognitive impairment is higher in these patients than in the average population.14
Anticholinergic drugs further inhibit acetylcholine, causing detrimental effects on cognition. Additionally, any medication that crosses the blood-brain barrier should be used with caution in patients with MCI. Whether these patients will experience adverse effects depends on their baseline cognition, the pharmacokinetics and pharmacodynamics of the drug, and the drug load.14
Controlling risk factors for cerebrovascular disease is an important part of preventing further cognitive decline. White matter lesions and small infarcts must be identified and treated. Patients should be assessed for possible underlying causes of memory impairment such as hypothyroidism, anemia, sleep apnea, infection, and vitamin deficiencies. Screening for anxiety and depression is also important. These comorbid conditions need to be carefully managed in patients with MCI.
Currently, the FDA has not approved any pharmacologic agents for the treatment of MCI; however, numerous regimens have been studied or are under investigation. Because the symptoms of MCI are mild compared to those of AD, recent attention has been given to the tolerability and risk-benefit ratio of treatment.5 Clinical drug trials focus on treatments that are proven effective for AD, with a majority of the studies involving cholinesterase inhibitors (ChEIs) (see Table 1). Preliminary evidence indicates that donepezil (Aricept) may delay progression of MCI to AD.15 Additional studies on ChEIs have demonstrated only short-term benefits seen as improved secondary measure test scores, with no studies showing statistically significant long-term benefits.
Researchers have also looked at the effectiveness of antioxidants, estrogen replacement therapy (ERT), and cyclooxygenase-2 (COX-2) inhibitors for possible treatment options.5 Antioxidants such as vitamin E are proposed to protect against oxidative stress, which is thought to be involved in the mechanism of neurodegeneration.16 Recently the Alzheimer's Disease Cooperative Study conducted a 3-year, double-blind, controlled trial on the effects of vitamin E in 769 patients with MCI. Throughout the study, no statistical difference in the rate of progression from MCI to AD was seen between the vitamin E and placebo groups.15
ERT is hypothesized to play a role in nerve cell survival through intrinsic antioxidant activity as well as stimulation of estrogen receptors in the brain, leading to a cascade of positive protective events.16 In recent studies, however, neither estrogen nor estrogen-progestin therapy was clinically beneficial for patients with MCI.5 Anti-inflammatory drugs, such as COX-2 inhibitors, reportedly respond to the inflammatory cascade. The increase in cytokines, acute-phase proteins, and complement-phase proteins in the inflammatory cascade appears to contribute to the formation of amyloid plaques.16 However, COX-2 inhibitors have no significant effects as therapeutic agents for MCI.17
Several pharmaceutical agents currently under investigation for their efficacy in treating MCI are galantamine (Razadyne), donepezil, and ampakine CX516 (Ampalex), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor modulator. The manufacturer's study on galantamine is in phase III.18 The National Institute of Mental Health completed its 12-month randomized, double-blind, placebo-controlled study of donepezil in 2004; the results have not yet been released.19 The manufacturer's study of ampakine CX516 is in phase II.20
CONCLUSION
Recognizing MCI is an important opportunity to identify persons with cognitive impairment that is at risk of progressing to AD. When a PA suspects that a patient with memory loss has MCI, the MoCA assessment, a simple 10-minute test, can confirm the diagnosis. If the office-based evaluation is inconclusive or the PA-physician team is not comfortable making the diagnosis, referral should be made to a neuropsychologist, a geriatrician, or a neurologist for an extensive evaluation. If the diagnosis of MCI is made, treatment options can be discussed. Currently, donepezil is the only medication in this class that has slowed down the progression of MCI to AD; however, despite the limited proven benefit, cost and side effects prohibit its routine use. PAs should discuss the benefits, cost, and risk-benefit ratio of donepezil with the patient and family. Therapy can be started as an 8-week trial period. If the patient or family report improvement or stabilization, donepezil can be continued.21 After the patient is stabilized, scheduled follow-up visits should occur at least every 6 months, including a review of all medications and monitoring for signs of disease progression.
MCI is an emerging topic in medicine, and ongoing research should help create a greater understanding of the disease. A consensus on and a validation of the definition of MCI will allow for more uniformity in research. Studies with longer durations should also more definitively show whether the progression to dementia can be delayed, as well as demonstrate the safety of long-term ChEI therapy. Some current drug trials are focusing on neurotransmitter deficits; future studies will likely look further up the hierarchy of events, to the molecular level, and focus on strategies to intercept plaques, neurofibrillary tangles, and the loss of cholinergic neurons.16 The hope for the future is not only to find a means of slowing memory loss but also to stop the progression of MCI to more serious disease. JAAPA
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Andrea Pace practices in the emergency department at Riverside Methodist Hospital, Columbus, Ohio. Karen Graham is assistant professor in the PA program at the University of Toledo and practices at the University of Toledo Medical Center's Center for Neurological Disorders, Toledo, Ohio. The authors have indicated no relationships to disclose relating to the content of this article.