Mild Cognitive Impairment

Britton Ashley Arey, MD, MBA

Introduction

As the United States population ages, mild cognitive impairment (MCI) is a clinical condition that is receiving increasing attention due to growing interest in the early diagnosis, treatment, and prevention of dementia. MCI is a heterogeneous entity, representing decrements in cognitive functioning in various domains which do not meet the diagnostic threshold for dementia.

There are three types of MCI that have been proposed by Portet and colleagues:¹

(1) Amnestic MCI, which may progress to Alzheimer's disease
(2) MCI characterized by a slight impairment of multiple cognitive domains, which may progress to Alzheimer's disease or vascular dementia, or may represent a normal cognitive decline with age
(3) MCI with isolated impairment of a cognitive domain other than of memory
(‘‘single-domain non-memory MCI''), which may progress to non-Alzheimer-type dementia.

The best characterized form of MCI is amnestic MCI, which is defined as the presence of impaired memory function for age and education without dementia, as evidenced by preserved general cognitive function and intact activities of daily living.² For the purposes of this review, the designation MCI will refer to amnestic MCI unless otherwise indicated.

The criteria proposed by Petersen and colleagues² for amnestic MCI are as follows:
(1) not demented,
(2) memory complaint,
(3) preserved general cognitive function,
(4) intact activities of daily living, and
(5) impaired memory for age and education.

Properly diagnosing MCI identifies a subset of patients that is at increased risk for dementia.² These patients may then be carefully monitored, and may be candidates for interventions that can improve functioning and quality of life. Several guidelines and consensus statements exist regarding MCI. These include the report of the Current Concepts in Mild Cognitive Impairment conference,² and the American Academy of Neurology's (AAN) practice parameters for mild cognitive impairment¹ and diagnosis of dementia.² Together, these guidelines answer a number of questions about the current state of knowledge regarding MCI, and provide expert opinion on its diagnosis and impact.

Objectives of the American Academy of Neurology's Practice Parameters

To summarize the current state of knowledge in MCI diagnosis, epidemiology, consequences, and management, the AAN's practice parameters address a number of questions related to the diagnosis of dementing illness in general and MCI in particular. These questions provide a framework for reviewing the current data on MCI. Those most relevant to a discussion of MCI include the following:

• Does the presence of mild cognitive impairment predict the development of dementia?
• Does screening at-risk subjects with a specific instrument in a specific setting accurately lead to the diagnosis of dementia?
• What comorbidities should be screened for in elderly patients undergoing an initial assessment for dementia?
• What are important directions for future research?

QUESTION 1
Does the presence of mild cognitive impairment predict the development of dementia?

MCI is best understood as part of a continuum between normal aging and dementia. Controversy exists over the definition of diagnostic criteria that accurately differentiate between normal aging, MCI, and dementia; however, evidence points to the likely validity of defining MCI as a transitional state between normal age-related cognitive changes and dementia. The rate of progression from MCI to Alzheimer's Disease is between 6 and 25% per year. This is in comparison to rates in the general population of 0.2% in the 65 to 69 year age range to 3.9% in the 85 to 89 year range.³ Additional data estimates that among individuals diagnosed with MCI, 60 to 80% will progress to dementia within six years.² Thus, patients with MCI are at high risk for developing a dementing illness such as Alzheimer's disease, and these patients should be monitored regularly for cognitive and functional declines consistent with dementia.³

A variety of evidence supports the view of MCI as part of a continuum of dementing conditions, and may ultimately help to refine our understanding of the progression from MCI to Alzheimer's disease. For instance, MCI is characterized by increased hippocampal atrophy compared to controls, and the degree of hippocampal atrophy can predict the rate of conversion from MCI to Alzheimer's disease.² Hippocampal atrophy appears to occur at the same rate in individuals who progress from normal cognition to MCI as in individuals who go from MCI to Alzheimer's disease, further suggesting a transition along a disease spectrum.²

Neuropathologic evidence also points to the validity of MCI as a transitional state between normal aging and Alzheimer's disease. Several studies have indicated that subjects who died while meeting clinical criteria for MCI had pathologic changes that appeared to be transitional between the changes expected in normal aging and those of mild Alzheimer's disease.⁵ These changes include early deposition of neurofibrillary tangles and beta-amyloid plaques, as well as changes in total tau protein, hyperphosphorylated tau protein and amyloid beta42 protein that may help distinguish MCI and early or symptomatic Alzheimers from patients undergoing normal aging, those with depression, and those with Parkinson's disease.¹ Additionally, there is evidence that MCI may present with imaging abnormalities which may also point to early neuropathologic evidence of Alzheimers, including volumetric changes in the entorhinal and hipocampal-amygdala regions, as well as functional changes in the tempo-parietal cortex and posterior cingulate areas .¹ However, at this time, despite the neuropathological similarities to Alzheimer's and the potential utility of imaging in the future, MCI remains a purely clinical diagnosis.

Several features have been identified which may predict the rate of progression from MCI to Alzheimer's disease. These include apolipoprotein E4 (ApoE4) carrier status, cognitive features such as inability to benefit from semantic cues, degree of hippocampal atrophy, FDG ([11C]flumazenil and [2-18F]2-deoxy-2-fluoro-D-glucose ([18F]) PET markers, and CSF amyloid beta (Αβ) and tau levels. However, the clinical utility of these measures has yet to be established.⁵

QUESTION 2
Does screening at-risk subjects with a specific instrument in a specific setting accurately lead to the diagnosis of dementia?

Diagnosing MCI is complicated by disagreement on the definition of normal aging and the degree of cognitive change that is nonpathologic.² Nonetheless, a number of screening tools and more extensive diagnostic batteries exist to help clinicians evaluate and characterize cognitive function in individuals in whom cognitive impairment is suspected due to a subjective complaint of memory impairment. These tools are of variable diagnostic utility, and are especially helpful in cases of MCI and mild dementia in which functional and behavioral impairment may be minimal. In such cases, symptoms may not be obvious, and objective screening tools can pick up more subtle symptoms.

General cognitive screening instruments are among the most useful tools in detecting MCI and mild dementia in clinical settings. Of these, the Mini-Mental State Examination and the Memory Impairment Screen are supported by the strongest evidence, and there is also evidence supporting the utility of the Kokmen Short Test of Mental Status and the 7-Minute Screen. These instruments are most useful in populations that are at elevated risk for cognitive impairment, either due to age or to subjective complaints of memory dysfunction. ³ Impairments on these instruments warrant further assessment and monitoring, as described below.

Attempts have also been made to develop screening tools that can be administered in a briefer time frame. However, these assessments, such as the Clock Drawing Test and the Time and Change Test, focus on limited aspects of cognitive function and are therefore less reliable.³

Neuropsychological batteries, and especially neuropsychological instruments emphasizing memory function, are also useful in objectively differentiating dementia from mild cognitive impairment and normal aging. These instruments, often administered by neuropsychologists, can provide a more in-depth and quantitative assessment of cognitive functioning than can more general screening instruments. As with general screening instruments, these tests are most useful when administered to a population at risk for cognitive impairment.³

Neuropsychological tests alone are not sufficient to diagnose MCI or Alzheimer's disease. The results of these tests can be influenced by multiple factors, including education, age, cultural background, and other illnesses. Moreover, patients with different types of dementia may have overlap in neuropsychological profiles. Therefore, test results must always be supplemented by clinical judgment.²

Inconclusive evidence supports instruments that rely on interviewing collateral sources such as relatives and caretakers, such as the Blessed Dementia Rating Scale, Clinical Dementia Rating, and Informant Questionnaire on Cognitive Decline in the Elderly. Nonetheless, corroborating information about a patient's cognitive and functional status can be clinically useful in identifying candidates for additional screening.²

While neuroimaging studies cannot differentiate MCI from dementia or normal aging, they can help to evaluate for structural or vascular causes of cognitive impairment. Therefore a baseline noncontrast CT or MRI is indicated in the initial workup of patients with cognitive complaints.⁴

QUESTION 3
What comorbidities should be screened for in elderly patients undergoing an initial assessment for dementia?

Several conditions which occur commonly in the elderly are of particular interest in patients with memory complaints, as they may either cause cognitive difficulties secondarily, or may worsen preexisting dementing illness. Therefore, patients who present with memory complaints require screening for common comorbidities.

Depression. The relationship between cognitive impairment and depression is bidirectional. While depression can produce symptoms that mimic cognitive impairment, true cognitive impairment is also a risk factor for depression. Patients with depression and coexisting cognitive complaints have a high likelihood of dementia on longitudinal follow-up.⁴ Moreover, in one study approximately 12% of patients with dementia had comorbid depression.⁴ Because depression can either be a cause or a result of cognitive difficulties, routine screening for depression is indicated in patients with evidence of MCI.

Vitamin B12 deficiency. While B12 deficiency is common in the elderly, and is associated with slight decrements in cognitive performance, there is no evidence that nondemented individuals with B12 deficiency are at higher risk to later develop dementia. Evidence for improvement of cognitive function with treatment of B12 deficiency is equivocal. Moreover, the prevalence of dementia caused by B12 deficiency appears to be very low.⁴

Hypothyroidism. Hypothyroidism, also common in the elderly, may cause cognitive deficits in nondemented individuals. While elevated TSH levels carried an increased risk for dementia in one study, the prevalence of dementia attributed solely to hypothyroidism was very low.⁴

Syphilis. There have been no reported cases of tertiary syphilis in North America in the last 20 years, and therefore syphilis screening in patients with cognitive impairment is not indicated unless the patient is at high risk, has a prior history of syphilis, or lives in one of the few areas in the United States with high rates of syphilis.⁴

Summary of comorbidities. Depression, B12 deficiency, and hypothyroidism are common in the elderly in general and in patients with cognitive difficulties in particular. Screening for and treatment of these disorders is indicated in patients with cognitive complaints, even though treatment may not completely reverse cognitive impairment. Syphilis screening is not indicated except in patients from high risk groups.⁴

QUESTION 4
What are important directions for future research?

Further studies are needed in order to clarify the distinctions between normal aging, MCI, and early dementia.⁴ The relationship between MCI and the various categories of dementia, such as Alzheimer's disease, vascular dementia, frontotemporal dementia, and Lewy body dementia are incompletely understood.² Increased understanding of the pathophysiology of MCI may help to establish this relationship. Further assessment is also needed to determine whether treating MCI can prevent or delay the progression of dementia.² Biomarkers are needed that can predict the development of dementia in asymptomatic patients or those with MCI in order to further guide early detection and treatment.⁴

Implications for Management

Awareness of the diagnostic implications described above can help to guide the care of patients with MCI. At present, there are no Food and Drug Administration-approved treatments for MCI. Several clinical trials have looked at the efficacy of pharmacologic treatment in slowing the rate of progression from MCI to Alzheimer's disease. One randomized controlled trial found that treatment of MCI with a cholinesterase inhibitor reduced rates of progression to Alzheimer's disease at 12-month but not at three year follow up. Trials of other agents have not shown a statistically significant treatment benefit.⁵

While there is no established benefit to pharmacologic treatment of patients with MCI, accurate diagnosis can guide the counseling and monitoring of these patients. Patients should be counseled that they are at risk for developing dementia, but that it is also possible that their condition will not progress. Patients with MCI may also benefit from lifestyle changes such as increasing exercise, intellectual activities, and social connectedness, and modifying their diet to optimize cardiovascular health.⁵ Moreover, there is evidence that spouses of patients with MCI exhibit elevated caregiver burden and symptoms of anxiety and depression, and therefore may benefit from supportive services.⁶ Finally, patients with MCI should be monitored clinically for signs of functional impairment consistent with dementia, so that treatment options for Alzheimer's disease may be considered as needed.

Conclusions

An increasing body of evidence suggests that MCI is a useful clinical construct, representing an intermediate state between normal aging and dementia. Patients diagnosed with MCI have an increased risk for progression to Alzheimer's disease. Use of clinical screening instruments and neuropsychological testing can improve recognition of MCI in patients with subjective memory complaints. These patients should also be screened for common comorbidities which may complicate the diagnosis. Patients with MCI should be counseled about the condition's implications, and healthy lifestyle modifications should be encouraged. Patients with MCI should be monitored closely for signs of progression to dementia. Further research is needed to further refine the diagnosis of MCI, better predict the risk of progression to dementia, and evaluate the utility of treatment to delay progression and improve quality of life.

References

1. Portet, F., Ousset, P.J, Visser, P.J., Frisoni, G.B., Nobili, F., Scheltens, P.H, Vellas, B.,Touchon, J. & MCI Working Group of the European Consortium on Alzheimer's Disease.(EADC) (2006). Mild cognitive impairment (MCI) in medical practice: A critical review of theconcept and new diagnostic procedure. Report of the MCI Working Group of the EuropeanConsortium on Alzheimer's Disease. Journal of Neurology, Neurosurgery, and Psychiatry, 77(6),714-718.
2. Petersen RC et al, Current Concepts in Mild Cognitive Impairment. Arch Neurol, 2001; 58: 1985-1992.
3. Petersen RC et al, Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 2001; 56(9):1133-42.
4. Knopman DS et al, Practice parameter: Diagnosis of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 2001; 56:1143-1153.
5. Petersen RC, Mild Cognitive Impairment: Current Research and Clinical Implications. Seminars in Neurology, 2007; 27: 22-31.
6. Small BJ et al, Early identification of cognitive deficits: Preclinical Alzheimer's disease and mild cognitive impairment. Geriatrics, 2007; 62: 19-23.