Mild Cognitive Impairment

In mild cognitive impairment (MCI), the changes in cognition exceeds the normal, expected changes related to age. In one classification of MCI, the amnestic form is distinguished from the nonamnestic form. The amnestic form often precedes Alzheimer disease.

Signs and symptoms

Symptoms of mild cognitive impairment (MCI) are often vague and include the following:

• Memory loss

• Language disturbance (eg, difficulty in finding words)

• Attention deficit (eg, difficulty in following or focusing on conversations)

• Deterioration in visuospatial skills (eg, disorientation in familiar surroundings in the absence of motor and sensory conditions that would account for the complaint)

Ronald C. Petersen postulated that the defining element of MCI is a single sphere of slowly progressive cognitive impairment that is not attributable to motor or sensory deficits and to which other areas of involvement may eventually be added, before social or occupational impairment supervenes (because this occurrence marks the onset of dementia). ^[1]

Diagnosis

Although no single feature of the general physical examination characterizes MCI, the following should be included in the overall assessment of the patient:

• Evaluation of mental status

• Examination for the presence of potential causative comorbid conditions

• Examination for the presence of sensory and/or motor deficits as potential causes or exacerbating factors

No specific diagnostic studies exist for mild cognitive impairment. However, most clinicians perform a basic workup at minimum to exclude potential treatable causes (eg, thyroid disease, cobalamin deficiency). Research is ongoing in the search for biologic markers that may help differentiate between the large number of conditions that may progress from MCI to full dementia.

Brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) is often performed in patients with MCI. In general, MRI is preferred, as whole brain and hippocampal volume on MRI can predict progression from MCI to Alzheimer disease (AD). ^[2] However, there are no established parameters to integrate this finding into the routine diagnosis and management of MCI. In addition, there is also some preliminary evidence for the use of baseline FDG-PET of the brain in conjunction with episodic memory assessment to predict conversion to AD. ^[3]

There are no stipulated neuropsychological tests for patients with MCI, nor are there predetermined cutoff points (eg, 1.0, 1.5, or 2 standard deviations below the mean). However, clinicians use the results from standardized memory and cognitive tests to determine whether these data represent significant changes from a patient’s presumed baseline. In general, serial testing is required to establish whether the patient’s cognitive function is improving, staying stable, or progressing to full-blown clinical dementia.

Management

Although no established treatment exists for MCI, donepezil delays the progression to AD in MCI patients with depression without affecting their depressive symptoms, and some evidence suggests that cognitive interventions may have a positive effect. ^[4] Cholinesterase inhibitors have not been found to delay the onset of AD or dementia in MCI. ^[5]

Identify and monitor patients with MCI, because of their increased risk for AD (and, to a lesser extent, other dementing conditions). In addition, to the extent possible, correct any sensory and motor manifestations that compound their cognitive symptoms.

Diet and activity may have some positive effects in patients with MCI. The risk of developing MCI is lower in individuals who consume a Mediterranean diet, ^[6] and interactive, mentally challenging activities as well as moderate exercise have the potential to be helpful in MCI. ^[7]

Various terms have been employed to characterize the cognitive decline associated with aging, including benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline. ^{[8, 9, 10]} The term mild cognitive impairment (MCI) is intended to represent an intermediate stage between normal aging and the development of pathologic aging and dementia (eg, malignant senescent forgetfulness ^[9] ).

Other terms with connotations similar to those of MCI include isolated memory impairment, incipient dementia, and dementia prodrome. However, these terms are not nearly as widely accepted as MCI and should not be considered exact synonyms.

Of the normal memory functions, some decline substantially with increasing age, and some do not. Memory functions that remain relatively stable with increasing age include the following:

• Semantic memory - Facts and general knowledge about the world; although this function generally remains stable with age, especially if the information is used frequently, ^[11] retrieval of highly specific information (eg, names) typically declines

• Procedural memory – Acquisition and later performance of cognitive and motor skills ^[11]

Memory functions that decrease with age include the following:

• Working memory - Holding and manipulating information in the mind, as when reorganizing a short list of words into alphabetical order ^[11] ; verbal and visuospatial working speed, memory, and learning, with visuospatial cognition more affected by aging than verbal cognition ^[12]

• Episodic memory – Personal events and experiences ^[11]

• Processing speed ^[13]

• Prospective memory – The ability to remember to perform an action in the future (eg, remembering to fulfill an appointment or take a medication ^[11] )

• Ability to remember new text information, to make inferences about new text information, to access prior knowledge in long-term memory, and to integrate prior knowledge with new text information ^[14]

• Recollection ^[15]

To demonstrate that a patient’s cognitive function is worse than would normally be expected for his or her age, neuropsychological testing is necessary so that the patient’s performance can be compared with that of an age-matched (and, ideally, education-matched) control group.

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 a complaint of cognitive impairment, an individualized workup for such conditions and a consensus on a therapeutic approach should be sought. To date, no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of MCI.

For patient education resources, see the Dementia Center, as well as Possible Early Dementia.

In mild cognitive impairment (MCI), cognitive impairment exceeds the normal expected age-related changes, but functional activities are largely preserved; thus, MCI does not meet the criteria for dementia. ^[1] Different subtypes of MCI are recognized. One common classification distinguishes between amnestic and nonamnestic forms of MCI.

Amnestic MCI, in which memory impairment predominates, is often a precursor of clinical Alzheimer disease (AD). Nonamnestic forms of MCI are characterized by a variety of cognitive impairments, the most common of which is probably impaired executive function. A substantial number of patients with MCI may be judged to have normal cognition on follow-up visits.

The pathophysiology of MCI is multifactorial. Most cases of amnestic MCI result from pathologic changes of AD that have not yet become severe enough to cause clinical dementia. ^[16] At least in specialty research populations, autopsies done on amnestic MCI patients have found the neuropathology to be typical of AD. ^[17] Nonamnestic MCI may be associated with cerebrovascular disease, frontotemporal dementias (as a precursor), or no specific pathology.

Mild cognitive impairment (MCI) is heterogeneous both in its clinical manifestations and in its etiology. Given that amnestic MCI often results from Alzheimer disease (AD) pathology, it is not surprising that most patients with amnestic MCI progress to clinical AD within 6 years. Nonamnestic forms of MCI may be due to cerebrovascular disease, Lewy body dementia, Parkinson disease, frontotemporal dementias, atypical Alzheimer disease, or no specific underlying pathology.

Mood disorders, medical illness, and medications may affect cognition in such a way that a patient will meet criteria for MCI (usually nonamnestic MCI). Many such patients have normal neuropsychological test results when reevaluated a year later.

According to a large population-based study conducted in 2016, there is no significant link between exposure to general anesthesia and the development of MCI in individuals aged 40 years and older. Anesthesia exposure, assessed as a dichotomous variable, was not associated with MCI nor was there was a link between the number of anesthesia exposures and MCI. ^[18] A study in 2013 also had similar findings; those results showed exposure to general anesthesia during medical procedures after age 45 years is not a risk factor for dementia. ^[19]  However, these data do not exclude the possibility that anesthetic exposures occurring later in life may be associated with an increase in the rate of incident MCI.

Annual prevalence estimates for mild cognitive impairment (MCI) range from 12% to 18% in persons older than 60 years, a finding reflected in multiple international studies. ^{[20, 21, 22, 23]} Among community-dwelling African Americans, the estimated prevalence is 19.2% for those aged 65–74 years, 27.6% for those aged 75–84 years, and 38% for those aged 85 years and older. ^[24]

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. ^[25] Many studies indicate that the risk of Alzheimer disease (AD) is significantly higher in women than in men, and it is therefore presumed that the likelihood of developing MCI is greater in women than in men. Virtually nothing is known about cultural and racial factors influencing the clinical manifestations of MCI.

Patient 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 typical performance decline in healthy older individuals. The most common symptom is said to be memory loss, in keeping with the prevalent view that amnestic MCI is the most common type. However, some authorities affirm that the most common form of MCI affects multiple spheres of cognition.

Less common presentations of MCI include language disturbance (eg, difficulty in finding words), attention deficit (eg, difficulty in 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 or 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 that is not attributable to motor or sensory deficits and to which other areas of involvement may eventually be added, before social or occupational impairment supervenes (because this occurrence marks the onset of dementia). ^[1] Virtually nothing is known about the average duration of these manifestations before they are brought to medical attention (if they ever are).

Clinicians should rely on their own judgment in deciding when safety-related questions that are appropriate for patients with dementia—for example, about weapons, driving, and possible home fires involving cigarettes, stoves, or fireplaces—should also be asked of patients with MCI.

Physical examination

No feature of the general physical examination is characteristic of MCI. Nevertheless, a thorough physical examination should be performed as part of the general evaluation in an effort to determine whether any conditions capable of causing MCI (eg, thyroid disease, cobalamin deficiency, or venereal disease) are present and whether there are any sensory and motor deficits that could explain or compound the symptoms. Mental status examination is also important for documenting the degree of cognitive dysfunction.

Mild cognitive impairment (MCI) may result from virtually any disorder that causes brain dysfunction. Common causes include the following:

• Alzheimer disease (AD)

• Cerebrovascular disease

• Parkinson disease

• Frontotemporal degenerations

• Thyroid disease

• HIV infection

• Depression

• Metabolic and endocrine disease ^[26]

• Adverse central nervous system effects of drugs and toxicants

• Cerebral infection

• Traumatic brain injury

• Cognitive adverse effects of sleep disorders

• Cobalamin deficiency

• Chronic psychological stress

According to an analysis of 5150 patients aged 65 years or older from the Cardiovascular Health Study, patients with atrial fibrillation (AF) reach clinical thresholds for cognitive impairment and dementia at an earlier age than patients without AF, even in the absence of clinical stroke. ^{[27, 28]}

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 admit to 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.

The association between depression and AD and other dementias is likely to be complex, and depression may be misdiagnosed in the realm of dementia. Framingham data have helped bolster the epidemiologic association, documenting a 50% increase in AD and dementia in those who were depressed at baseline. ^[29] During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia, compared with 16.6% of those who were not depressed.

In another related study, recurrent depression was noted to be particularly pernicious: having 1 depression episode conferred an 87–92% increase in dementia risk, whereas having 2 or more episodes nearly doubled the dementia risk (but did not increase the risk of incident MCI). ^[30]

No specific laboratory studies are indicated for mild cognitive impairment (MCI). 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 assessments are not mandatory, however.

A search for biologic markers of MCI that may help distinguish among the many conditions that lead from MCI to full-blown dementia is ongoing. As yet, however, no unanimous agreement has been reached, and potentially useful markers, such as functional and structural abnormalities found on imaging studies (eg, hippocampal atrophy and cerebral hypoperfusion) and putative biochemical markers (eg, apolipoprotein E epsilon 4 allele), remain controversial.

Neuropsychological testing is required in instances of mild cognitive impairment (MCI) to demonstrate that the patient is below some cutoff point on standardized memory tests (as well as other cognitive tests). However, the exact cutoff 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 MCI patients have undergone baseline testing on these measures before the onset of the impairment, 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 establish whether the patient’s cognitive function is improving, staying stable, or progressing to full-blown clinical dementia. A useful aspect of this testing is the ability of the neuropsychologist to establish a profile for the patient based on their gender, age, and education, and to then evaluate if their level of function is adequate for that profile.

The Alzheimer's Association released guidelines, including an algorithm, to help clinicians in the primary care setting detect cognitive impairment and determine whether referral or further testing is needed. ^[3] The algorithm includes the following components ^{[2, 3]} :

• Review of patient health risk assessment (HRA) information

• Patient observation

• Use of unstructured queries

• Use of structured cognitive assessment tools for patients and informants

The following 3 cognitive assessment tools are recommended for routine use by primary care physicians ^[9] :

• General Practitioner Assessment of Cognition (GPCOG)

• Mini-Cog

• Memory Impairment Screen (MIS)

Additionally, the Alzheimer’s Association recommends the following 3 cognitive assessment tools for use with the patient's spouse, family, or friends ^{[8, 9]} :

• Informant General Practitioner Assessment of Cognition (informant GPCOG)

• AD 8-Question Screen (AD8)

• Short Informant Questionnaire on Cognitive Decline in the Elderly (short IQCODE)

Medical care

At present, no established treatment exists for mild cognitive impairment (MCI). Cholinesterase inhibitors have not been found to delay the onset of Alzheimer disease (AD) or dementia in individuals with MCI; however, donepezil has been found to delay the progression to AD in MCI patients with depression without affecting their symptoms of depression. ^[5] There is some evidence to suggest that cognitive interventions may have a positive effect. ^[4]

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 for minimizing their impact on MCI.

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, they usually do not need to assign power of attorney to anyone else—unlike patients with AD, who eventually will need such help.

The results of a study that included 361 subjects with AD, vascular dementia, or mixed dementias suggested that centrally acting angiotensin-converting enzyme inhibitors (CACE-Is) may reduce the rate of cognitive decline in patients with dementia, regardless of blood pressure levels at the time of their hypertension diagnosis. ^{[31, 32]} The rate of cognitive change was slowed in the first 6 months after dementia patients started taking these drugs.

Diet

Roberts et al found that the risk of developing MCI is lower in individuals who consume a Mediterranean diet, which is high in vegetables and unsaturated fats. ^[6]

A randomized, double-blind, placebo-controlled trial involving 25 elderly subjects with MCI determined that dietary supplementation with an oily emulsion of docosahexaenoic acid (DHA)-phospholipids containing melatonin and tryptophan yielded significant improvements in several measures of cognitive function as compared with supplementation with the placebo. ^[33]

According to one study of 663 adults in Singapore 60 years of age and older, consuming more than two standard portions of mushrooms per week may reduce odds of developing MCI by as much as 50%. ^[34]

Activity

Because physical, social, and mental activity are often recommended for patients with AD and because MCI often heralds AD, many experts have suggested that mentally challenging activities (eg, crossword puzzles and brain teasers) may be helpful for patients with MCI. Although there is no definitive proof that these exercises are efficacious, recommending them to patients with MCI seems advisable.

Such exercises should be kept to a level of difficulty that is reasonable for the patient. Ideally, they should be interactive rather than passive, and they should be administered in a fashion that does not cause excessive frustration. If an activity is not enjoyable or stimulating for the patient, it is unlikely to offer much cognitive benefit. In such cases, searching for other similar cognitive activities may be beneficial.

Social isolation can be minimized through referral to senior community centers or a day treatment program. Cognitive retraining and rehabilitative strategies offer considerable promise in MCI ^[35] and are therefore being explored.

A growing body of evidence suggests that physical activity and exercise are beneficial for brain health. A prospective study suggested that engaging in moderate exercise of any frequency in midlife or late life was associated with reduced odds of having MCI. ^[7]  According to one study, aerobic exercise was associated with a slight improvement in cognition. ^[36]  The 2017 update of the American Academy of Neurology guideline on mild cognitive impairment (MCI), which is endorsed by the Alzheimer's Association, recommends that patients with MCI exercise regularly as part of an overall approach to managing their symptoms. ^[37]  However, a 2018 study published in BMJ suggests rigorous exercise is not effective against dementia. Researchers assigned 329 participants to an aerobic and strength exercise program and 165 to usual care (n=494). The primary outcome was score on the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, health-related quality of life, and carer quality of life and burden. Results show mean ADAS-cog score had increased to 25.2 (SD 12.3) in the exercise arm and 23.8 (SD 10.4) in the usual care arm, which indicates greater cognitive impairment in the exercise group, but the clinical significance of this finding is uncertain. Overall, the study found that a moderate to high intensity aerobic and strength exercise training program does not slow cognitive impairment in people with mild to moderate dementia. ^[38]

Another study showed certain activities to lower risk of MCI in cognitively normal individuals older than 70 years. These included playing games, reading magazines, being engaged in crafts, computer use, and social activities. Among these, being social and using computers were shown to reduce risk of MCI in people who were APOE4 carriers as well. ^[39]

Many patients with mild cognitive impairment (MCI) eventually experience progressive deterioration in their abilities to perform activities of daily living, cognition, and behavior.

Subtypes of MCI progress to Alzheimer disease (AD) at different rates. A study by Rountree et al showed that the conversion rate to AD was 56% for amnestic MCI, 50% for amnestic-subthreshold MCI, and 52% for nonamnestic MCI. ^[40] For all MCI subtypes, the 4-year conversion rate to dementia was 56% (14% annually), and that to Alzheimer disease was 46% (11% annually).In comparison, healthy elderly individuals develop AD at a rate of 1-2% per year.

Boyle et al reported that patients with MCI are almost 7 times more likely to develop AD than are older individuals without cognitive impairment. ^[41] Of patients with MCI, 80% are said to progress to dementia after approximately 6 years. This is a significant finding, given that AD is often cited as the fourth leading cause of death in the United States.

At least one well-designed study has shown MCI, as identified by the Short Portable Mental Status Questionnaire, to be an independent predictor of mortality. ^[42] Wilson et al reported that in both African American and white patients, the risk of death was increased by about 50% among individuals with MCI and was nearly 3 times higher among those with AD. ^[43]

Ultimately, long-term follow-up and eventual autopsy are necessary to distinguish between patients experiencing MCI due to preclinical AD and patients experiencing MCI due to less frequently occurring conditions. However, there are some factors that can be helpful in predicting the likelihood of progression.

The severity of memory impairment is predictive of progression to AD: patients with more severe memory impairment are more likely to progress. There are certain neuroradiologic features that predict progression of MCI. These include MRI findings of atrophy and volume loss in the medial temporal lobe as well as a hypometabolic pattern on FDG-PET scan. ^{[44, 45, 3]} In addition, APOE4 genotype carriers are at higher risk of progression, but APoE4 testing is not recommended for routine use. ^[46] A new modality that might prove useful in predicting and monitoring progression of MCI is a new PET tracer focusing on the role of tau. Early data suggests that spread of tau laterally, outside the medial temporal lobe, may predict a poor prognosis and a more rapid progression. ^[47]

Alzheimer’s Association

The Alzheimer's Association guidelines, including an algorithm, help clinicians in the primary care setting detect cognitive impairment and determine whether referral or further testing is needed. ^{[8, 9]} The algorithm includes the following components ^{[8, 9]} :

• Review of patient health risk assessment (HRA) information

• Patient observation

• Use of unstructured queries

• Use of structured cognitive assessment tools for patients and informants

The following 3 cognitive assessment tools are recommended for routine use by primary care physicians ^{[48, 49]} :

• General Practitioner Assessment of Cognition (GPCOG)

• Mini-Cog

• Memory Impairment Screen (MIS)

Additionally, the Alzheimer’s Association recommends the following 3 cognitive assessment tools for use with the patient's spouse, family, or friends ^{[48, 49]} :

• Informant General Practitioner Assessment of Cognition (informant GPCOG)

• AD 8-Question Screen (AD8)

• Short Informant Questionnaire on Cognitive Decline in the Elderly (short IQCODE)

American Academy of Neurology

The 2017 update of the American Academy of Neurology guideline on mild cognitive impairment (MCI), which is endorsed by the Alzheimer's Association, recommends that patients with MCI exercise regularly as part of an overall approach to managing their symptoms. ^[37] The guideline also advises clinicians to do the following:

• assess for MCI using validated tools in appropriate scenarios (level B);

• evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (level B);

• monitor cognitive status of patients with MCI over time (level B);

• stop cognitively impairing medications where possible, and treat behavioral symptoms (level B);

• consider not offering cholinesterase inhibitors (level B), and if offering, first discuss lack of evidence (level A);

• recommend regular exercise (level B);

• consider recommending cognitive training (level C);

• discuss diagnosis, prognosis, long-term planning, and the lack of effective drug options (level B); and

• consider discussing biomarker research with patients with MCI and families (level C).