Mild Cognitive Impairment Overview and Update
November 1, 2018
November 30, 2020
Tina Caliendo, PharmD, BCGP, BCACP
St. John's University
College of Pharmacy and Health Sciences
Olga Hilas, PharmD, MPH, BCPS, BCGP, FASHP
St. John's University
College of Pharmacy and Health Sciences
Queens, New York
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Drs. Caliendo and Hilas have no actual or potential conflicts of interest in relation to this activity.
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To provide pharmacists with an overview of mild cognitive impairment (MCI) and an update of recent treatment guidelines.
After completing this activity, the participant should be able to:
- Define and recognize signs and symptoms of MCI.
- Differentiate MCI from dementia.
- Identify risk factors for MCI and its progression.
- Determine appropriate screening tools used in the diagnosis of MCI.
- Review pharmacologic and nonpharmacologic interventions studied in persons with MCI.
ABSTRACT: Mild cognitive impairment (MCI) refers to the interim state of cognition beyond that of the normal aging process, yet not sufficient to warrant a diagnosis of dementia. This article presents an overview of the types of MCI, as well as the screening and diagnostic criteria for MCI. In addition, the 2018 Academy of Neurology Practice Guideline Update for MCI, which focuses on the prevalence, prognosis, and treatment options, is reviewed. To date, no pharmacologic therapies have proven to be effective in MCI. However, regular exercise has shown promise in positively affecting cognition and should be recommended.
Changes in cognitive function are a normal occurrence throughout the aging process. However, persistent cognitive deterioration, combined with behavioral changes and/or changes in normal functioning status, may lead to dementia (i.e., Alzheimer's disease [AD]). Early detection and recognition of the signs and symptoms of dementia by clinicians are, therefore, important to establish a baseline, rule out other etiologies or offending agents, monitor the progression of the disease, and possibly prevent further cognitive decline.
Mild cognitive impairment (MCI), also known as mild neurocognitive disorder (mNCD) as defined in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), refers to the interim state of cognition that goes beyond the normal aging process, yet insufficient to warrant a diagnosis of dementia.1 Patients with MCI are memory impaired, but are otherwise functioning well. The core clinical features that meet the criteria for diagnosis of MCI include the following: memory complaints (preferably corroborated by an informant); objective memory impairment (for age and education); normal or preserved general cognitive function; intact activities of daily living; and no presence of dementia.2,3
The threshold between MCI and dementia is often unclear; therefore, changes in functional status and the degree of impairment are typically the determining factors in distinguishing MCI from dementia.4
MCI can also be further broken down into two subgroups: amnestic MCI (aMCI) and nonamnestic MCI (naMCI). aMCI is the most common subtype and generally is associated with more memory loss than is normal for people of the same age. The ability to learn and recall new information also poses a challenge. However, behavioral changes are absent, and independent functioning status remains stable and intact.5,6
naMCI typically affects thinking skills rather than memory. Impaired executive functioning results in the inability to focus, plan, solve problems, and make sound decisions. Language skills may also be affected, and patients often find themselves at a loss for words. They find it difficult to verbally express themselves, and become frustrated. Visuospatial acuity is also compromised. Patients may exhibit movement difficulties, and may not be able to comprehend or properly judge the timing and sequence needed in order to complete a task.5,6
MCI is most commonly seen in the older adult population. The prevalence increases with advanced age. According to the most recent 2018 American Academy of Neurology Practice Guideline update for MCI, estimated prevalence by age is as follows: age 65 to 69 years: 6.4%; age 70 to 74 years: 10.1%; age 75 to 79 years: 14.8%; and age 80 to 84 years: 25.2%.4 aMCI is more commonly observed than naMCI.
Other factors associated with increased prevalence of MCI include the following: lower education level; cardiovascular disease risk factors such as hypertension, diabetes, and obesity; any past medical history of stroke or heart disease; apolipoprotein E genotype 4; and neuropsychiatric conditions such as anxiety and depression.
It is important to note that while MCI may be a precursor to AD, not everyone diagnosed with MCI will necessarily progress to AD. Patients remain stable indefinitely, or even improve. However, there is a 10% to 15% risk per year of MCI converting to AD, making it appropriate for clinicians to continue to monitor and perform assessments for any cognitive changes.7,8
SCREENING AND DIAGNOSIS
The key to assessing cognitive complaints is to first perform a clinical patient interview, noting the degree and severity of memory loss and functional impairment, if any. Changes in cognitive function are often reported by the patient, but may also be observed by a physician, close friend, relative, or caretaker.2,3 Since most of the early stages of MCI are identified by subjective signs, physicians should not rely solely on the patient or caregiver as the historian. Instead, an evaluation using a brief, validated, and comprehensive assessment tool should be utilized to determine if more in-depth cognitive testing is warranted.4 In doing so, patients can be more engaged in the decision-making process by becoming more informed about pharmacologic and nonpharmacologic treatment options, seeking out specialists and support services, and better preparing for the future. If the physician does not have the necessary experience and credentials to make a diagnosis with certainty, the patient should be referred to a specialist.4
Screening should be performed in a primary care or community setting or during a patient's Medicare Annual Wellness Visit.9 There are various brief screening instruments that have been studied for detecting cognitive impairment in the older adult.10 The most commonly used patient-assessment tools include, but are not limited to, the following: General Practitioner Assessment of Cognition (GPCOG); Mini-Cog; and Memory Impairment Screen (MIS).
Patient informant assessment tools include an eight-item Informant Interview to Differentiate Aging and Dementia; GPCOG; and Short Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).
There is no single tool considered to be superior to another. The Alzheimer's Association lists these tools specifically because they have been validated for the primary care and community setting due to their ease of use by both medical and nonmedical staff and their quick administration time (≤5 minutes); their metrics are equivalent or superior to the Mini-Mental State Exam (MMSE), and they are free of any educational, language, or cultural bias.11 The MMSE and the Montreal Cognitive Assessment are other validated tools used specifically for healthcare providers to screen for MCI and dementia, but it takes approximately 10 minutes to administer.12
Screening for independent functional status will also help determine if a patient can independently carry out activities of daily living (criteria for MCI) or if there is enough cognitive decline to require assistance with daily activities, indicating dementia. Clinicians can administer the Functional Activities Questionnaire to determine functional status from either the patient or caregiver. Patients who score six points or higher are likely to require more assistance and are therefore more likely to have dementia than MCI.12
It is important to also obtain an accurate medical history, as well as medication history. Multiple medications have been found to contribute to impaired cognition, and these should be regularly assessed for appropriateness. The most common medication offenders causing cognitive impairment include anticholinergics, benzodiazepines and nonbenzodiazepines, tricyclic antidepressants, opiates, and antiepileptics, to name a few. Strict control of blood pressure and blood glucose are also thought to contribute to cognitive decline.12
Other potentially reversible forms of MCI can be determined though laboratory testing. Obtaining a CBC, a complete metabolic panel, a thyroid panel, and a vitamin B12 with folate panel is recommended to rule out the possibility of infection, electrolyte disturbances, renal insufficiency, or vitamin deficiencies as the cause for cognitive impairment.12
Patients suspected of having MCI should have a full neurologic and psychological workup, including screening for depression. Vision, hearing, and speech should be evaluated. Any changes in gait, muscle weakness, numbness or tingling in the extremities, or dizziness should be noted to identify other underlying causes of cognitive decline, such as Parkinson's disease or stroke. Since depression can contribute to impaired cognition, it should be screened for as well. Patients can also become depressed because of their changes in cognition; therefore, depression screening should be standard practice when monitoring patients suspected of having MCI. Using the Global Depression Scale, clinicians can evaluate a patient's behaviors and ascertain if they exhibit the signs of depression. If there is still uncertainty about the diagnosis, neuroimaging can be performed, but it is not routinely recommended. Once treatment is deemed necessary, nonpharmacologic therapy should be initiated first.12
PRACTICE GUIDELINE UPDATE
The goal of the original 2001 practice guidelines for MCI by the American Academy of Neurology (AAN) was to address two clinical areas of concern: screening and diagnosis.3 They sought to determine whether MCI was a precursor to dementia and screening patients who are suspected to have MCI with a validated instrument in a certain setting will assist in determining a diagnosis of dementia.
The clinical studies reviewed in these guidelines revealed that a significant percentage of patients with certain signs of impaired cognition (without meeting the clinical criteria for dementia, specifically MCI), demonstrated a continuous decline over time, ultimately leading to a diagnosis of AD. Therefore, it was advised that patients who had already met the criteria for MCI (and were at greater risk for progression to dementia) be monitored closely for further decline in cognition.3
When evaluating studies to determine the usefulness of screening instruments for cognitive impairment in its earliest stages, guideline authors reviewed the MMSE, the Kokomen Short Test of Mental Status, the 7-Minute Screen, and the MIS. These screening tools proved suitable for detecting dementia in individuals with suspected cognitive impairment. Brief cognitive screening tools such as the Clock-Drawing Test and the Time and Change Test may also be considered. However, due to the limitations of these tools (based on specificity and sensitivity), they should not be used to independently screen for MCI. Informant-based instruments such as the IQCODE, Clinical Dementia Rating scale (CDR), or the Blessed Dementia Rating Scale are also appropriate and optional. These are interviewbased methods for obtaining information regarding the cognitive status of a patient from an informed source other than the patient. Finally, neuropsychological batteries, which are a combined set of tests used to assess cognitive function in various areas, are also useful in identifying possible patients at risk for cognitive impairment, specifically in the area of memory loss.3
The current 2018 practice guideline update for MCI focuses on the diagnosis and treatment of MCI, specifically idiopathic or neurodegenerative MCI.MCI related to reversible causes (metabolic) or disease states (i.e., Parkinson's disease) was not included. In this update, the authors addressed four additional concerns: 1) the prevalence of MCI; 2) the prognosis for patients with MCI progressing to dementia; 3) effective pharmacologic treatments; and 4) effective nonpharmacologic treatments for MCI.4
In reviewing the studies identified, it was redetermined that MCI is more common in the olderadult demographic, and the incidence increases with age and lower education level. Once diagnosed with MCI, patients were found to be at increased risk for converting to dementia. Patients may improve, remain the same, or progress to dementia, which warrants close routine monitoring for any further decline, thereby altering the diagnosis and treatment management.4
If a patient, family member, or close contact voices concern, the physician should assess for MCI and not assume the problem is due to normal aging. Relying solely on the patient to report his or her memory concerns is not advised. Rather, validated assessment tools should be utilized to confirm suspected cognitive impairment. In addition to cognition, functional status should be assessed. In doing so, one can distinguish between a diagnosis of MCI with that of dementia based on the severity of the functional impairment. Any reversible or modifiable causes of MCI should be identified, and if the physician is not equipped to properly diagnose the patient, the patient should be referred to a specialist. It was also noted that there are no biomarkers that can accurately predict MCI progression. Since this is an evolving area, interested patients may be referred to research centers to be enrolled into clinical trials.4
Currently, there are no FDA-approved medications for the treatment of MCI. Patients and their families should be advised that no long-term studies have been conducted to demonstrate the improvement of MCI with pharmacologic or dietary agents. Cholinesterase inhibitors, such as donepezil, have been studied for off-label use in MCI. However, clinically significant improvement with these agents has not been established, despite statistically significant improvements reported with the use of certain cognitive scales. If physicians choose to prescribe a cholinesterase inhibitor, patients and families should be made aware of the lack of data supporting benefits of therapy. Patients may also be connected with trial centers should they be willing to try new treatment options being studied.4
In addition, the importance of exercise and its positive effects on cognition was highlighted in the new practice guideline update. It is recommended that patients exercise regularly, at least twice weekly, as part of their treatment. Exercise has many overall health benefits, with limited risk to the patient. Although the studies are not long-term (spanning over a 6-month period), regular exercise should be advocated and recommended. Nonpharmacologic recommendations should be considered and recommended over pharmacologic therapy. The importance and usefulness of cognitive interventions, such as CBT, are widely documented in literature and should also be considered to help minimize the progression from MCI to dementia.4
The updated guideline reviewed 14 studies that evaluated the use of various agents as treatment options for MCI. A brief overview of each of these studies and their primary findings is given below.
Donepezil: Donepezil was investigated in the following three studies for its potential effectiveness in the treatment of MCI.
Salloway et al conducted a study to evaluate the efficacy and safety of donepezil in persons with MCI.13 Two hundred and seventy participants were enrolled in this multicenter, randomized, doubleblind, placebo-controlled, parallel-group study for a duration of 24 weeks. Participants received either donepezil 5 mg daily for 42 days, then 10 mg daily, or placebo daily. Primary efficacy measures included the New York University Paragraph Delayed Recall test scores and least squares mean Clinical Global Impression of Change Scale for MCI scores. At the study endpoint, no significant differences were found between donepezil and placebo in either measure. However, participants in the donepezil group reported more adverse events as compared with the placebo group.
In Petersen et al, investigators aimed to evaluate the progression to clinically possible or probable AD in persons with MCI.14 A total of 769 participants were enrolled in this multicenter, double-blind, placebo-controlled, parallel-group study, and were randomly assigned to receive either 2,000 IU of vitamin E daily (after initiation of 1,000 IU daily for 6 weeks); 10 mg of donepezil daily (after initiation of 5 mg daily for 6 weeks); or placebo daily, for 3 years. A multivitamin consisting of 15 IU of vitamin E was also given to all study participants.
The rate of progression from MCI to AD was determined to be 16% annually, with clinically possible or probable AD developing in 212 participants.13 No significant differences in progression to AD were seen in the vitamin E group or the donepezil group (hazard ratio [HR] 0.8, 95% CI 0.57 to 1.13; P = .42) compared with the placebo group at the study endpoint. Progression to AD was seen to be lower in the donepezil group over the first year of the study; however, this reduction in progression was not maintained at 3 years.
Doody et al also conducted a multicenter, randomized, double-blind, placebo-controlled, parallelgroup study to investigate whether acetylcholinesterase inhibitors could improve symptoms in persons with MCI.15 A total of 821 participants received placebo (single-blind) for a 3-week run-in period, followed by either donepezil 5 mg daily for 6 weeks and then 10 mg daily for 42 weeks, or placebo daily for 48 weeks. The primary efficacy endpoints were changes from baseline in the modified AD Assessment Scale-cognitive subscale (ADAS-Cog) and the Clinical Dementia Rating Scale-sum of boxes (CDRSB). At the study endpoint, a small, yet favorable, decrease (−0.90, SE 0.37) in the modified ADAS-Cog scores from baseline was reported in the donepezil group (P = .01). CDR-SB score changes from baseline were minimal and not significantly different between the groups throughout the duration of the study. Greater rates of adverse events were seen in the donepezil group.
Galantamine: Winblad et al conducted two studies to assess the safety and efficacy of galantamine in persons with MCI.16 These studies were multicenter, randomized, double-blind, placebo-controlled studies that included 2,048 participants. Participants received either galantamine 16 to 24 mg daily (4 mg twice daily for 1 month, then 8 mg twice daily for 1 month, then 12 mg twice daily, if well tolerated) or placebo daily for 24 months. The primary efficacy endpoint was the number (%) of participants who progressed from MCI to dementia (defined as a CDR >1.0) at 24 months. The results from both studies were reported together, and showed no significant differences in MCI-to-dementia conversion rates between the galantamine and placebo groups (Study 1: 22.9% vs. 22.6 %, respectively, P = .146; and Study 2: 25.4% vs. 31.2%, respectively, P = .619). Mild-to-moderate adverse events were reported more frequently in the galantamine groups, but serious events occurred at the same rate in both groups.
Rivastigmine: In another multicenter, double-blind, placebo-controlled study, this one conducted by Feldman et al, rivastigmine was evaluated for its efficacy in delaying progression of MCI to AD.17 Primary efficacy endpoints included time to clinical diagnosis of AD and rate of cognitive decline (measured by change in performance on a cognitive test battery). One thousand and eighteen participants were randomized to receive either rivastigmine 3 mg to 12 mg daily (based on tolerability) or placebo daily, for up to 48 months. Over 3 to 4 years, investigators found no significant differences between the rivastigmine and placebo groups in mean time to diagnosis of AD (1,318 days vs. 1,289 days, respectively), the mean changes of standardized Z scores from baseline to endpoint for the cognitive test battery (−0.10, 95% CI −0.63 to 0.44; P = .726), or the percentage of participants who progressed to AD (17.3% vs. 21.4%, respectively [HR 0.85, 95% CI 0.64 to 1.12; P = .225]). Adverse events were reported more frequently in the rivastigmine group; however, serious adverse events were reported by more participants in the placebo group than in the rivastigmine group (30.5% vs. 27.9%, respectively).
B Vitamins: Smith et al conducted a single-center, double-blind, placebo-controlled study to investigate whether B vitamins can slow the rate of brain atrophy in persons with MCI due to their lowering of plasma homocysteine.18 A total of 271 participants over the age of 70 years were randomized to receive folic acid 0.8 mg daily, vitamin B12 0.5 mg daily and vitamin B6 20 mg daily, or placebo daily for 24 months. The primary efficacy endpoint was the group mean rate of change of atrophy of the brain per year, which was assessed using MRI scans.
One hundred and sixty-eight participants completed the MRI scans during the study period.17 Results showed that the mean rate of brain atrophy per year was lower in the vitamin group (0.76%, 95% CI 0.63 to 0.90) than in the placebo group (1.08%, 95% CI 0.94 to 1.22; P = .001). In addition, treatment response was found to be related to homocysteine levels. Although these findings seem promising, the current AAN guideline on MCI cautions that there is insufficient evidence to support or refute the use and clinical significance of homocysteine-lowering agents in persons with MCI.4
Vitamin E: As previously discussed, Petersen et al conducted a placebo-controlled study evaluating the progression of MCI to clinically possible or probable AD in participants receiving vitamin E 2,000 IU daily, donepezil 10 mg daily, or placebo.14 No significant differences in progression to AD was seen in the vitamin E group (HR 1.02, 95% CI 0.74 to 1.41; P = .91) or the donepezil group compared with the placebo group. Therefore, it was concluded that vitamin E provided no benefit in persons with MCI.
Vitamin E and Vitamin C: In a single-center, doubleblind, placebo-controlled study, Naeini et al sought to determine the effects of vitamin E and vitamin C on cognitive performance among elderly persons with MCI.19 Two-hundred and fifty-six participants (aged 60 to 75 years) were randomly assigned to receive either vitamin E 300 mg daily and 400 mg vitamin C daily or placebo daily for 1 year. Cognitive function was measured by MMSE scores at 6 and 12 months. After covariate adjustments, it was concluded that there were no significant differences between the study groups at either point in time.
Flavanols: Desideri et al investigated the effects of dietary flavanols on cognitive function in persons with MCI.20 A single-center, double-blind, parallelarm study was conducted in 90 older adults with MCI. Participants were randomized to receive a high cocoa flavanol–containing drink of approximately 990 mg daily; an intermediate cocoa flavanol–containing drink of approximately 520 mg daily; or a low cocoa flavanol–containing drink of approximately 45 mg daily for a total of 8 weeks. The MMSE, Trail Making Tests A and B, and verbal fluency test were measures used to evaluate cognitive function. At the conclusion of the study, there were no significant differences in MMSE scores between the groups (P = .13); however, time needed to complete Trail Making Tests A and B was significantly lower in the high cocoa– flavanol and intermediate cocoa–flavanol groups compared with the low cocoa–flavanol group (P <.05). In addition, verbal-fluency test scores were significantly better in participants within the high cocoa–flavanol group compared with those in the low cocoa–flavanol group (P <.05). Although this study suggests that the regular consumption of intermediate to high flavanols may be effective in improving cognitive function in persons with MCI, the 2018 practice guideline states that the evidence provided by this study alone is insufficient to support or refute the potential cognitive benefits of flavanols.
Nicotine: In a multisite, double-blind, placebo-controlled, parallel-group study conducted by Newhouse et al, 74 nonsmoking participants with aMCI were randomized to receive either 15 mg daily of transdermal nicotine (initiated at 5 mg daily and titrated to 15 mg by day 21) or placebo daily for a period of 6 months.21 The primary efficacy endpoint was attention improvement assessed using the Conners Continuous Performance Test (CPT). At the end of the study period, participants who received nicotine treatment had significant improvement in CPT compared with placebo (P = .0003). Investigators concluded that transdermal nicotine may aid in improving cognitive test performance in nonsmokers with aMCI; however, additional evidence is needed to further determine the clinical significance of this treatment option.
Growth Hormone–Releasing Hormone: Baker et al conducted a single-center, double-blind, placebocontrolled study investigating the effect of growth hormone–releasing hormone on cognitive function in older adults with MCI and healthy older adults aged 55 to 87 years over 20 weeks.22 Sixty-one participants with MCI and 76 healthy participants completed the study, in which they were randomized to receive either tesamorelin 1 mg subcutaneous injection daily or placebo daily for 20 weeks. The primary efficacy measures were executive function, verbal memory, and visual memory. Investigators reported a favorable effect of growth hormone– releasing hormone on cognition (P = .002) and executive function (P = .005), with a favorable trend in verbal memory (P = .08). Although growth hormone–releasing hormone demonstrated a possible benefit on cognitive measures in persons with MCI, additional studies with higher confidence in the evidence are needed.
Rofecoxib: In a multicenter, double-blind, placebocontrolled, parallel-group study conducted by Thai et al, investigators sought to determine whether rofecoxib delays AD diagnoses in adults aged >65 years with MCI.23 A total of 1,457 participants were randomized to receive either rofecoxib 25 mg daily or placebo daily for up to 4 years. The primary efficacy endpoint was the percentage of participants who progressed from MCI to clinical AD. Results showed that although both groups had lower annual AD diagnosis rates than the expected 10% to 15%, the rate for the rofecoxib group over the 4-year study period was greater than that of the placebo group (14.8% vs. 11.2%, respectively; HR 1.46, 95% CI 1.09-1.94; P = .011). Therefore, rofecoxib may possibly increase the risk of progression from MCI to AD. (In 2004, rofecoxib was voluntarily withdrawn from the market worldwide. Studies investigating other anti-inflammatory agents in persons with MCI are lacking.)
Piribedil: Nagaraja and Jayashree conducted a singlecenter, double-blind, placebo-controlled study that aimed to determine whether piribedil (a dopamine receptor agonist) improves global cognitive function in persons with MCI and MMSE scores of 21 to 25.24 The primary efficacy endpoint was change in MMSE score from baseline. Sixty participants were randomly assigned to receive either piribedil 50 mg daily or placebo daily for a total of 90 days. Investigators found improvement in MMSE scores (>26) at 3 months in 63.3% of the piribedil group and 26.7% of the placebo group. They also reported significantly greater response rates and mean increases in MMSE scores with piribedil at 90 days; however, specific data were not presented. Therefore, additional data are necessary to evaluate the role of piribedil in persons with MCI.
V0191: A multicenter, double-blind, placebo-controlled, parallel-group study was conducted by Dubois et al to evaluate the efficacy and safety of V0191 (a novel procholinergic agent) in persons with prodromal AD.25 Two hundred and forty-two participants were included in this study and randomized to receive either 1,500 mg of V0191 daily or placebo daily for a total of 24 weeks. The primary endpoint was change in global cognitive functioning using the ADAS-Cog (response rates). At the conclusion of the study, investigators found that there were no statistically significant differences between the V0191 and placebo groups in response rates or cognitive function.
In the 2018 practice guideline update, seven studies involving nonpharmacologic interventions in the treatment of MCI were identified and evaluated.4,26-32 Two of these studies aimed to determine whether exercise improved cognition in older adults with MCI.2,3 Both demonstrated improvement in cognitive measures after 6 months of exercise (e.g., resistance training and multicomponent exercises, including aerobic, muscle strength training, and postural-balance retraining). The updated practice guideline has recognized the potential benefit of exercise in the treatment of MCI and states that 6 months of exercise training is likely to improve cognitive measures.
The five remaining studies focused on cognitive intervention strategies, such as cognitive rehabilitation and training, in persons with MCI.28-32 Although some improvements in cognitive measures were observed in these studies, the practice guideline update states that there are insufficient data to support or refute a recommendation in persons with MCI based on the level of evidence, findings, and limitations of the available studies.
According to the 2018 Practice Guideline Update for Mild Cognitive Impairment, pharmacologic agents do not currently possess strong evidence for recommendation in the treatment of MCI. However, nonpharmacologic interventions, such as exercise training for 6 months, have shown promise for the improvement of cognitive measures. Overall, the management of persons with MCI is a field that is challenging and constantly changing, as more research is continually being conducted. It is important that pharmacists stay up-to-date on the evidence in order to educate patients and provide appropriate evidence-based recommendations for the optimal management of MCI.
- Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
- Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303-308.
- Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology. 2001;56(9):1133-1142.
- Petersen RC, Lopez O, Armstrong SJ, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:126-135.
- Alzheimer's Association. Mild cognitive impairment (MCI). www. alz.org/alzheimers-dementia/what-is-dementia/related_conditions/ mild-cognitive-impairment. Accessed August 1, 2018.
- National Institute on Aging. Symptoms and diagnosis of Alzheimer's disease: what is mild cognitive impairment? www.nia.nih.gov/ health/what-mild-cognitive-impairment. Updated May 17, 2017. Accessed August 1, 2018.
- Petersen RC, Knopman DS, Boeve BF, et al. Mild cognitive impairment: ten years later. Arch Neurol. 2009;66(12):1447-1455.
- Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatric Med. 2013;29(4):10.1016/j.cger.2013.07.003.
- Lin JS, O'Connor E, Rossom RC, et al. Screening for cognitive impairment in older adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159:601-612.
- Cordell CB, Borson S, Boustani M, et al. Alzheimer's Association recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting. Alzheimers Dement. 2013;9(2):141-150.
- Alzheimer's Association. Cognitive assessment. www.alz.org/professionals/healthcare-professionals/cognitive-assessment. Accessed August 1, 2018.
- Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA. 2014;312(23):2551-2561.
- Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004;63:651-657.
- Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-2388.
- Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology. 2009;72:1555-1561.
- Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008;70:2024-2035.
- Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurology. 2007;6:501-512.
- Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5:e12244.
- Naeini AM, Elmadfa I, Djazayery A, et al. The effect of antioxidant vitamins E and C on cognitive performance of the elderly with mild cognitive impairment in Isfahan, Iran: a double-blind, randomized, placebo-controlled trial. Eur J Nutrition. 2014;53:1255-1262.
- Desideri G, Kwik-Uribe C, Grassi D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly patients with mild cognitive impairment: the Cocoa, Cognition and Aging (CoCoA) study. Hypertension. 2012;60:794-801.
- Newhouse P, Kellar K, Aisen H, et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012;78:91-101.
- Baker LD, Barsness SM, Borson S, et al. Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol. 2012;69:1420-1429.
- Thai LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005;30:1204-1215.
- Nagaraja D, Jayashree S. Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment. Am J Psychiatry. 2001;158:1517-1519.
- Dubois B, Zaim M, Touchon J, et al. Effect of six months of treatment with V0191 in patients with suspected prodromal Alzheimer's disease. J Alzheim Dis. 2012;29:527-535.
- Nagamatsu LS, Handy TC, Hsu CL, et al. Resistance training promoted cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Inter Med. 2012;172:666-668.
- Suzuki T, Shimada H, Makizako H, et al. Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 2012;12:128.
- Kinsella GJ, Mullaly E, Rand E, et al. Early intervention for mild cognitive impairment: a randomised controlled trial. J Neurol Neurosurg Psychiatry. 2009;80(7):730-736.
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