Mild Cognitive Impairment Introduction 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 disorde r. Because a variety of conditions may result in a complaint of cognitive impairment, an individualized workup for such conditions and a consensus on a therapeutic approach should be sought. Normal expected age-related memory functions Memory functions that remain relatively stable with increasing age Semantic memory - Facts and general knowledge about the world; remains stable with age, especially if the information is used frequently1 (However, retrieval of highly specific information, such as names, typically declines.) Procedural memory Acquisition and later performance of cognitive and motor skills1 Memory functions that decrease with age Working memory - Holding and manipulating information in the mind such as reorganizing a short list of words into alphabetical order1; verbal and visuospatial working speed, memory, and learning, with visuospatial cognition more affected by aging than verbal cognition2 Episodic memory Personal events and experiences1 Processing speed3 Prospective memory The ability to remember to perform an action in the future such as remembering an appointment or to take a medication1 To demonstrate that cognitive function is worse than expected for age, neuropsychological testing is necessary so that a patients performance can be compared with that of an agematched (and ideally education-matched) control group. Mild cognitive impairment (MCI) represents a stage of cognitive impairment that exceeds the normal expected age-related changes, but functional activities are largely preserved and so MCI does not meet the criteria for dementia.4 Different subtypes of MCI are recognized. One common classification distinguishes between amnestic and nonamnestic forms of MCI. The amnestic form, where memory impairment predominates, is often a precursor for clinical Alzheimers disease. A variety of types of cognitive impairments may occur in nonamnestic forms of MCI, with the most common impairment probably being executive function. This form of nonamnestic MCI may be associated with cerebrovascular disease or may be a precursor for some frontotemporal dementias. A substantial number of patients with MCI may be judged as having normal cognition on follow-up visit.

Ultimately, long-term follow-up and eventual autopsy are necessary to distinguish between patients experiencing MCI due to preclinical Alzheimers disease and patients experiencing MCI due to less frequently occurring conditions. However, some factors can be helpful in predicting the likelihood of progression. The severity of memory impairment is predictive of progression to Alzheimers disease; those patients with more severe memory impairment are more likely to progress. Patients with nonamnestic MCI (ie, impairment in language, executive function, or visuospatial skills, in addition to memory) have been found to have higher rates of mortality compared with patients with memory-only (amnestic) MCI.5 Whole brain and hippocampal volume on MRI imaging has been shown to be predictive of progression from MCI to Alzheimer's disease6, as has apolipoprotein E (ApoE) status7; however, ApoE testing is not recommended for routine clinical use. No medications have been FDA approved for the treatment of MCI. Previous attempts have been made to characterize cognitive decline associated with aging, including benign senescent forgetfulness, age-associated memory impairment, and ageassociated cognitive decline.8, 9, 10 The term MCI is intended to represent an intermediate stage between normal aging and the development of pathological aging and dementia (eg, the malignant senescent forgetfulness9). 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. Pathophysiology The pathophysiology of mild cognitive impairment is multifactorial. Most cases of the amnestic form of MCI result from the pathological changes of Alzheimers disease that are not yet severe enough to cause clinical dementia.11 At least in specialty research populations, autopsies in amnestic MCI have found the neuropathology to be typical of Alzheimers disease.12 Nonamnestic MCI may be associated with cerebrovascular disease, frontotemporal dementias, or no specific pathology. Frequency United States Annual prevalence estimates for mild cognitive impairment range from 3-4% in the eighth decade13 in the general population and 19.2% for ages 65-74 years, 27.6% for ages 75-84 years, and 38% for ages 85 years and older14 among community-dwelling African Americans. See Medscapes CME activity Mild Cognitive Impairment Affects 22% of Those 71 Years of Age and Older. Mortality/Morbidity Subtypes of mild cognitive impairment progress to Alzheimer's disease at different rates. A study by Roundtree et al showed that the conversion rate to Alzheimer's disease for amnestic MCI was 56%, for amnestic-subthreshold MCI was 50%, and for nonamnestic MCI was 52%.15 For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to Alzheimer's disease was 46% (11% annually).15 This was compared with healthy elderly individuals who develop Alzheimer's disease at a rate of 1-2% per year. Boyle et al reported that patients with MCI are almost 7 times more likely to develop Alzheimer's

disease compared with older individuals without cognitive impairment.16 Of patients with MCI, 80% are said to progress to dementia after approximately 6 years. This is significant from the perspective that Alzheimer's disease 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 mild cognitive impairment. Sex Many studies indicate that the risk of Alzheimers disease is significantly higher in women than in men, and it is therefore presumed that the likelihood of developing mild cognitive impairment is greater in women than in men. Age The prevalence of mild cognitive impairment increases with age. The prevalence is 10% in those aged 70-79 years and 25% in those aged 80-89 years.17 Clinical History Patients with mild cognitive impairment (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 symptom is said to be memory loss, consistent with the prevalent view that the amnestic form of memory loss 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).4 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 mild cognitive impairment (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 that could explain or compound the symptoms. Mental status examination is also important to document the degree of cognitive dysfunction.

See Medscapes CME activity Everyday Cognition Questionnaire Helps Assess Cognitive Function in Older Adults. Causes Mild cognitive impairment is heterogeneous both in its clinical manifestations and in its etiology. Amnestic MCI often results from Alzheimers disease pathology, and most patients with amnestic MCI progress to clinical Alzheimers disease within 6 years. Nonamnestic forms of MCI may be due to cerebrovascular disease, Lewy body dementia, or Parkinson's disease, frontotemporal dementias, atypical Alzheimer's disease, or no specific underlying pathology. Mood disorders, medical illness, and medications may affect cognition such that a patient will meet criteria for MCI (usually nonamnestic MCI). Many such patients have normal neuropsychological testing when reevaluated a year later. Differential Diagnoses Other Problems to Be Considered Mild cognitive impairment may be due to virtually any disorder that causes brain dysfunction. Common causes are Alzheimers disease, cerebrovascular disease, Parkinson disease, frontotemporal degenerations, thyroid disease, HIV infection, 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, cobalamin deficiency, 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. These 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. Depression may certainly be accompanied by cognitive dysfunction that abates with successful treatment of the depression. For more information, see Medscapes Depression Resource Center. Workup Laboratory Studies No specific laboratory studies are indicated for mild cognitive impairment. Most practitioners perform at least a basic workup to rule out treatable conditions that may cause dementia, such as thyroid disease and cobalamin deficiency. These are not mandatory, however. A search for biological markers of mild cognitive impairment that may help distinguish among the many conditions that lead from MCI 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 (CT) scanning or magnetic resonance imaging (MRI) (preferred) is often performed in patients with mild cognitive impairment. No practice parameters have been recommended in this regard. Whole brain and hippocampal volume on MRI has been shown to be predictive of progression from mild cognitive impairment to Alzheimers disease,6 although no established parameters exist to implement this correlation for the routine diagnosis and management of mild cognitive impairment. Other Tests Neuropsychological testing is needed in instances of mild cognitive impairment to demonstrate that the patient is below some cut-point on standardized memory tests (as well as other cognitive tests). The cut-point (be it 1.0, 1.5, or 2 standard deviations below the mean) and the particular neuropsychological tests to be used are not stipulated. Because few patients have had baseline premorbid testing on these measures, the clinician will have to determine whether a particular score represents a significant change from a patient's presumed baseline. Such determinations are inexact, and serial testing eventually will be needed to show whether a patient is improving, staying stable, or progressing to full-blown clinical dementia. Treatment Medical Care At present, no treatment exists for mild cognitive impairment (MCI). A systematic review of the literature by Raschetti et al studied 8 randomized controlled trials of 3 cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) in MCI.18 No delay in the onset of Alzheimers disease or dementia was seen; however, the trend was toward slowing the progression of MCI to Alzheimers disease.19, 20, 21 The rate of death was higher in patients with MCI who took galantamine.20 This increased risk of death with the use of galantamine has not been reported when used in patients with Alzheimer's disease. 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 Alzheimers disease 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 the impact on MCI. Activity Because physical, social, and mental activity are often recommended for patients with Alzheimers disease, and since mild cognitive impairment often heralds Alzheimers disease, many experts have thought that mentally challenging activities, such as crossword puzzles and brain teasers may be helpful for patients with MCI. Although definitive proof of the efficacy of these exercises is unavailable, 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. If the patient does not enjoy the activity or find it stimulating, the activity would likely be of limited cognitive benefit. Searching for other similar cognitive activities would perhaps be beneficial.

Social isolation can be minimized through referral to senior community centers or a day treatment program. Cognitive retraining/rehabilitative strategies offer considerable promise in MCI22 and are therefore being explored. A growing body of evidence suggests that physical activity and exercise are beneficial for brain health. A retrospective study suggested that engaging in moderate exercise 2-5 times per week (brisk walking, hiking, aerobics, strength training, golfing without a cart, swimming, doubles tennis, moderate use of exercise machines, yoga, martial arts, or weight lifting) in those aged 50-65 years may significantly reduce the risk of developing MCI.17 Follow-up Further Outpatient Care The American Academy of Neurology recommends that patients with mild cognitive impairment be identified and monitored because of their increased risk for Alzheimers disease 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 Medicolegal Pitfalls Many patients with mild cognitive impairment (MCI) eventually experience progressive deterioration in their abilities to perform activities of daily living, cognition, and behavior. 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 Alzheimers disease and who eventually do need such help. Clinicians should use their judgment about when inquiries appropriate for patients with dementia regarding weapons, driving, and possible home fires (eg, cigarettes, stove, fireplace) should also be asked of patients with MCI.