AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Mild degrees of cognitive impairment, particularly when self-reported by patients, pose a substantial challenge to the clinician. The physician may be dealing with a patient with a mild or transient condition, a drug-induced adverse effect, or a depressive disorder; the patient may be in the early stages of a condition that will eventually lead to a dementia; or the complaint may be due to a psychological condition rather than an organic brain disorder. Because a variety of conditions may result in such a complaint, an individualized workup for such conditions and a consensus on a therapeutic approach should be sought.

In recent years, the term minimal cognitive impairment (MCI) is commonly used to refer to a stage of cognitive impairment (and specifically a subtype with memory loss [ie, amnestic MCI]) prior to attaining clinical criteria for dementia in Alzheimer disease (AD) and related disorders. However, no completely reliable means, other than long-term follow-up and eventual autopsy, exist to distinguish between patients experiencing MCI due to preclinical AD and patients experiencing MCI due to less frequently occurring conditions (Petersen, 2001). In this context, MCI is regarded as a high-risk condition that precedes AD in a large proportion of cases. It should be emphasized, however, that considerable controversy still exists considering the formulation of the concept of MCI and the practical implementation of the diagnosis. Furthermore, there is no consensus whatsoever as to treatments for this controversial condition.

In fact, the relatively recent formulation of MCI follows previous attempts to characterize cognitive decline associated with aging, including benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline (Crook, 1986; Kral, 1962; Levy, 1994). Therefore, this relatively new concept is perhaps best considered as a stage in the difficult process of understanding and characterizing mild defects in cognition that do not fit clearly within the scope of established neurological and psychiatric disorders.

In general, many of the previous terms imply extremes in a hypothetical process of normal aging as opposed to representing a precursor to pathological aging and dementia (eg, the "malignant" senescent forgetfulness [Kral, 1962]). Thus, in contrast with many previous terms, individuals with MCI have a condition that appears to some as different from normal aging in that long-term follow-up indicates that they tend to progress as a group to AD at an accelerated rate (Petersen, 1995; Petersen, 1999). Other terms with connotations similar to MCI include isolated memory impairment, incipient dementia, and dementia prodrome, although these latter terms are not nearly as widely accepted as MCI and they should not be considered as exact synonyms of MCI.

Pathophysiology

The pathophysiology of MCI is unknown. However, if one adopts the view that it most commonly results from AD, one hypothesis is that the disorder is associated with a gradual build-up of senile plaques and neurofibrillary tangles in areas of the cerebral cortex targeted by AD (entorhinal and perirhinal cortex) before the density of these lesions reaches the threshold necessary for the histopathologic diagnosis of AD (Morris, 2001). Similarly, the development of certain neurotransmitter deficiencies, and especially a cortical cholinergic deficiency, in the most common amnestic form of MCI is hypothesized. In the few studies undertaken to date, most patients with MCI have neuropathologic changes akin to AD, while a few individuals who are clinically similar do not have significant numbers of AD-like lesions (Mufson, 1999; Price, 1999; Troncoso, 1996). However, much larger numbers of patients with MCI must be studied before definitive statements can be made about the pathobiology of MCI.

Frequency

United States

Annual prevalence estimates for MCI range from 17-34% among elderly populations (Barker, 1995; Larrabee, 1994; Petersen, 2001). However, note that only a relatively small amount of work has been conducted in the epidemiology of MCI because it is a comparatively recently characterized entity. In addition, most individuals evaluated in memory disorders facilities already meet the clinical criteria for dementia, justifying the perception that MCI is comparatively underrepresented in such populations.

Mortality/Morbidity

Amnestic MCI is said to progress to AD at a rate of 10-15% per year, as compared with healthy elderly individuals who develop AD at a rate of 1-2% per year. In addition, in a study from the Mayo Alzheimer's Disease Center, which monitored patients for over 10 years, the rate of conversion into AD was as high as 80% after 6 years of follow-up (Petersen, 1995). This is significant from the perspective that AD is often cast as the fourth leading cause of death in the United States.

Race

Virtually nothing is known about cultural and racial factors influencing the clinical manifestations of MCI.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

Patients with MCI often present with vague and subjective symptoms of declining cognitive performance, which may be difficult to distinguish from the decline in such performance affecting healthy older individuals. The most common is said to be memory loss, consistent with the prevalent view that the amnestic form is the most common type of MCI. However, some authorities affirm that the most common form of MCI affects multiple spheres of cognition. Less common presentations include language disturbance (eg, word-finding difficulty), attentional deficit (eg, difficulty following or focusing on conversations), and deterioration in visuospatial skills (eg, disorientation in familiar surroundings in the absence of motor and sensory conditions that would account for the complaint).

Dissociating purely cognitive symptoms from those attributable to various degrees of sensory deprivation (eg, hearing loss, loss of visual acuity) that tend to coexist in the same patient population is often difficult and may be compounded by motor deficits that also beset the same individuals. In any case, the defining element of MCI as postulated by Petersen is a single sphere of slowly progressive cognitive impairment not attributable to motor or sensory deficits, to which other areas of involvement may eventually be added, before social or occupational impairment supervenes (because this marks the onset of dementia). Virtually nothing is known about the average duration of these manifestations before they are usually (if ever) brought to medical attention.

Physical

No feature of the general physical examination is characteristic of MCI. However, a physical examination should be performed as part of the general evaluation in an effort to determine whether conditions capable of causing MCI are present (eg, signs of thyroid disease, cobalamin deficiency, or venereal disease) and whether sensory and motor deficits are present, which could explain or compound the symptoms.

Causes

MCI is a heterogeneous condition due to numerous different causes, which may overlap in individual patients. In an attempt to distinguish among patient groups, emphasis is often placed on whether memory is involved or single nonmemory domains are involved instead. Thus, the most common form of MCI is thought to be amnesic MCI, in which the single domain affected is memory. A large percentage of these patients appear to progress to AD.

While accounts of MCI often revolve around the amnestic form because it is said to be the most common, other forms exist that are considerably less well characterized. Thus, a theoretically less common form of MCI is one in which multiple cognitive domains are affected; this is said to be associated with atypical variants of AD and dementia associated with cerebrovascular disease. Some epidemiological studies suggest that the multidomain form of MCI is more common than the amnestic form.

A third postulated type is one in which a single nonmemory domain is affected. Such a condition is believed to evolve frequently into frontotemporal dementia, Lewy body dementia, primary progressive aphasia, dementia in Parkinson disease, and other atypical variants of AD.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

MCI is due to numerous, potentially overlapping, and diverse conditions not limited to AD, cerebrovascular disease, Parkinson disease, frontotemporal degeneration, primary progressive aphasia, cobalamin deficiency, thyroid disease, lues, HIV infection, and neuroborreliosis. Additional potential causes include depression, metabolic and endocrine disease, adverse central nervous system effects of drugs and toxicants, cerebral infection, traumatic brain injury, cognitive adverse effects of sleep disorders, and chronic psychological stress.

Depressive disorders are particularly prevalent in older adults (approximately 15%) who frequently exhibit vague somatic symptoms and anxiety and report inability to concentrate and poor memory. Such patients typically deny a sad mood but often endorse sleep symptoms, lack of interest in things they used to enjoy, loss of appetite, and lack of motivation. A clinically useful distinguishing feature is that patients with pseudodementia readily report memory loss but, at the same time, often provide correct responses when pressed for an answer during cognitive testing. Such examinations may be painstaking because the patients tend to be slow in responding and tend to provide brief monosyllabic or 2- to 3-word responses.

The onset of such cases is typically within a few months and is relatively abrupt. By contrast, the patients with MCI describe only specific cognitive deficits, deny neurovegetative signs of depression, and have a more subtle and gradual onset. Patients with depression respond well to antidepressants as a general rule, although a subset of depressed patients aged 60 years or older become truly demented within 2 years, and, in the majority of this subset, the dementia is due to AD.

An unresolved dilemma persists in distinguishing between MCI and normal results of aging. Part of this dilemma is the still prevalent myth among lay persons and health care providers that substantial memory loss is a normal aspect of aging. This false belief, particularly among caregivers and family members, often explains the long delays between symptom onset and requests for medical evaluation and intervention.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• No specific laboratory studies are indicated for MCI. Most practitioners perform at least a basic workup to rule out treatable conditions that may cause dementia, such as thyroid disease, cobalamin deficiency, and lues. These are not mandatory, however. A search for biological markers of MCI that may help distinguish among the many conditions that lead from this syndrome to full-blown dementia is ongoing. However, no unanimous agreement exists as of yet, and potentially useful markers such as functional and structural abnormalities found on imaging studies (eg, hippocampal atrophy, cerebral hypoperfusion) and putative biochemical markers (eg, apolipoprotein E epsilon 4 allele) remain controversial.

Imaging Studies

• Brain imaging with computed tomography scanning or magnetic resonance imaging (preferably) is often performed in patients with MCI. No practice parameters have been recommended in this regard. However, findings indicate that hippocampal atrophy may correlate with MCI (Jack, 1999), although no established parameters exist to implement this correlation for the routine diagnosis and management of MCI.

Other Tests

• Neuropsychological testing is probably useful in MCI, but this has not been conclusively demonstrated. While the value of such testing has been proven in AD and other dementias and is helpful to distinguish among dementing conditions, neither AD nor MCI can be diagnosed solely by using neuropsychological tests. The potential validity and utility of such tests will be determined in presently ongoing studies of large cohorts of patients with MCI. These ongoing studies will help define whether existing tests are useful in this context as well as in the design of new tests specifically adapted to patients with MCI.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

At present, no treatment for MCI exists. Several trials are currently underway to determine whether cholinesterase inhibitors, anti-inflammatory agents, and antioxidants may be beneficial in MCI. Smaller scale studies suggest that at least some cholinesterase inhibitors may improve the memory loss (Freo, 2001), although larger scale studies are necessary to ascertain this more rigorously. Unfortunately, results presented so far with donepezil have been disappointing, but the results of a large-scale trial with rivastigmine have not been released yet.

A practice parameter recommendation by the American Academy of Neurology states that patients with MCI should be identified and monitored because of their increased risk for AD and, to a lesser extent, other dementing conditions. Obviously, correcting (to the extent possible) any sensory and motor manifestations compounding the cognitive symptoms is important to minimize their impact on MCI.

Activity

Because physical, social, and mental activity are often recommended for patients with AD and MCI often heralds AD, many experts have thought that mentally challenging activities, such as crossword puzzles and "brain teasers" may be helpful in MCI. While definitive proof of the efficacy of these exercises is unavailable at the time of this writing, recommending them to patients with MCI seems advisable. Keep such exercises within reasonable levels of difficulty for the patient. Exercises should preferably be interactive rather than passive, and they should also be administered in a fashion that does not cause excessive frustration. Social isolation can be minimized through referral to senior community centers or a day treatment program. Cognitive retraining/rehabilitative strategies offer considerable promise in MCI (D. Loewenstein, PhD, oral communication, March 2005) and are therefore being explored.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• The American Academy of Neurology recommends that patients with MCI be identified and monitored because of their increased risk for AD and, to a lesser extent, other less frequently occurring dementing conditions.

Patient Education

• For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education article Possible Early Dementia.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Most patients with MCI eventually experience progressive deterioration in their abilities to perform activities of daily living, cognition, and behavior. This often leads to a dementia, said to be most commonly a dementia of the Alzheimer type. Caution with this formulation is based on epidemiological studies, which indicate that individuals with MCI can revert to normal levels of cognitive performance or oscillate between normal and impaired cognition throughout the timeline of observation.
• Particular attention should be given to the need to make a legal statement about the competency of patients to handle their own affairs. Because patients with MCI are by definition not demented, assignment of power of attorney is usually unnecessary, in contrast with patients who have AD and who eventually do need such help.
• Basic safety evaluation should include inquiry regarding weapons, driving, and home fires (eg, cigarettes, stove, fireplace), and interventions should include removal of guns and other weapons, evaluation of driving abilities, assistance with meal preparation, and encouraging cessation of tobacco use or its use only under supervision.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

• Barker A, Jones R, Jennison C. A prevalence study of age-associated memory impairment. Br J Psychiatry. Nov 1995;167(5):642-8. [Medline].
• Crook T, Bartus RT, Ferris SH. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change. Dev Neuropsychol. 1986;2:261-276.
• Freo U, Carbonin C, Ori C, Pizzolato G. Effects of acetylcholinesterase inhibition in mild cognitive impairment (MCI): preliminary results with rivastigmine. Soc Neurosci Abstr. 2001;677.
• Grundman M, Petersen RC, Ferris SH, et al. Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol. Jan 2004;61(1):59-66. [Medline].
• Jack CR, Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. Apr 22 1999;52(7):1397-403. [Medline].
• Kral VA. Senescent forgetfulness: benign and malignant. Can Med Assoc J. Feb 10 1962;86:257-60. [Medline].
• Larrabee GJ, Crook TH. Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr. 1994;6(1):95-104. [Medline].
• Levy R. Aging-associated cognitive decline. Working Party of the International Psychogeriatric Association in collaboration with the World Health Organization. Int Psychogeriatr. 1994;6(1):63-8. [Medline].
• Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. Mar 2001;58(3):397-405. [Medline].
• Mufson EJ, Chen EY, Cochran EJ, et al. Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol. Aug 1999;158(2):469-90. [Medline].
• Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. Dec 2001;58(12):1985-92. [Medline].
• Petersen RC, Smith GE, Ivnik RJ, et al. Apolipoprotein E status as a predictor of the development of Alzheimer''s disease in memory-impaired individuals. JAMA. Apr 26 1995;273(16):1274-8. [Medline].
• Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. Mar 1999;56(3):303-8. [Medline].
• Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer''s disease. Ann Neurol. Mar 1999;45(3):358-68. [Medline].
• Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol Aging. May-Jun 1996;17(3):365-71. [Medline].
• von Gunten A, Kovari E, Rivara CB, et al. Stereologic analysis of hippocampal Alzheimer's disease pathology in the oldest-old: evidence for sparing of the entorhinal cortex and CA1 field. Exp Neurol. May 2005;193(1):198-206. [Medline].
• Wolf H, Jelic V, Gertz HJ, et al. A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurol Scand Suppl. 2003;179:52-76. [Medline].

Article Last Updated: Jul 28, 2005