Mild Cognitive Impairment

Etiology

There are various risk factors for MCI. 

Non-Modifiable Risk Factors 

Advancing age is the strongest risk factor for MCI. Other risk factors include male sex, family history of cognitive impairment, and the presence of the apolipoprotein E (APOE) allele.[6] The APOE ε4 allele is the most frequent genetic risk factor associated with the progression of MCI to Alzheimer dementia. Some studies have reported an increased risk of progression to Alzheimer dementia in both carriers and homozygotes for APOE ε4 allele, while other studies have not found any association. Hence, the clinical utility of using the APOE genotype is limited.[8]

Modifiable or Reversible Risk Factors 

Chronic Medical Conditions and Multimorbidity

Vascular risk factors such as hypertension, hyperlipidemia, coronary artery disease, and stroke are associated with MCI. A study focused on multimorbidity and MCI showed that patients with 4 or more comorbid conditions, especially 2 of the following: hypertension, coronary artery disease, hyperlipidemia, and osteoarthritis, have an increased risk of MCI.[6][8] Other chronic diseases, such as chronic obstructive pulmonary disease and diabetes mellitus, are also risk factors for MCI.[6]

Polypharmacy

Numerous classes and combinations of medications can have adverse impacts on memory. These include both prescription and over-the-counter medications. Some of the common classes are opiates, anxiolytics such as benzodiazepines, non-benzodiazepine sedatives/hypnotics such as zolpidem, muscle relaxants, antiepileptic, and anticholinergic medications.[9] Anticholinergic medications include antihistamines, antidepressants, urinary incontinence medications, and antipsychotics.[6][10] Antihypertensive medications can affect cognition by causing orthostatic hypotension. Hypoglycemia due to side effects from antidiabetic agents or hyperglycemia from inadequate treatment of diabetes can cause cognitive deficits.[6] Drug-to-drug interactions between medication classes can also cause cognitive loss. Medication side effects are reversible and can be improved if recognized promptly. 

Psychiatric Risk Factors

Depression can cause both cognitive and physical impairment and can present as MCI. The cognitive deficits can be reversed with adequate treatment of depression. Depression can also accelerate the progression of MCI to dementia.[6] Late-life anxiety has also been reported to be a risk factor for cognitive decline.[11]

Metabolic or Infectious Causes 

Hypothyroidism, vitamin B12 deficiency, dehydration, hypo or hyperglycemia, and infections such as urinary tract infections can all cause cognitive impairment and are easily treated.[6]

Sleep Disorders 

Obstructive Sleep Apnea causes daytime fatigue and, if untreated, can cause cognitive dysfunction. The affected cognitive domains include executive function, attention, verbal or visual memory, visuospatial ability, and information processing. Continuous Positive Airway Pressure (CPAP) treatment may improve cognitive symptoms.[12]

Neurological Disorder

Normal Pressure Hydrocephalus is caused by cerebrospinal fluid (CSF) accumulation in the brain's ventricular system, causing ventricular enlargement. It presents as a triad of ataxic gait, urinary incontinence, and cognitive impairment. The cognitive changes are reversible if there is early diagnosis and treatment.[6]

MCI may also represent a prodromal stage of dementia. For some conditions, the disease manifests first with cognitive impairment in the later stage of the disease course. These conditions include Parkinson Disease (PD), traumatic brain injury (TBI), Huntington disease, Human Immunodeficiency Virus (HIV) infection, and cerebrovascular accident. The Movement Disorder Society (MDS) PD-MCI criteria require that impaired cognitive domains be specified to see whether different cognitive impairments progress at different rates.[13] There are other diseases where cognitive impairment is the first manifestation of the disease process, such as Alzheimer Disease, Lewy body disease, prion disease, frontotemporal dementia, and vascular dementia. MCI can be the prodromal stage; in these cases, it will progress to dementia. Amnestic MCI may progress to AD or vascular dementia, while non-amnestic MCI commonly develops into Lewy body disease or frontotemporal dementia.[6]

Some protective factors are associated with a reduced incidence of dementia or delayed dementia onset. These factors may also be protective for MCI. Higher education, bilingualism, and cognitively stimulating activities protect cognition. Lifestyle factors such as the Mediterranean diet, physical activity, smoking cessation, mild to moderate alcohol consumption, and participation in social activities are associated with reduced risk of cognitive impairment.[11][3]

Epidemiology

MCI is a heterogeneous syndrome as there is a wide variation of cognitive and functional severity within the MCI definition. There are no standardized criteria for the diagnosis of MCI that have high clinical reliability and validity and provide consistent estimates across various studies. Hence, multiple studies have reported varying incidence and prevalence estimates.[14] The 2018 American Academy of Neurology (AAN) guideline update on MCI found that its prevalence is high among the older adult population and increases with age. The prevalence estimate was 6.7% in the 60-64 year age group and increased to 25.2% for ages 80-84.[15] Other studies have reported prevalence rates of up to 22% in community-dwelling older adults above 71 years of age and 40% among older adults in memory care practices.[8] Lower educational level was associated with a higher prevalence, while most studies found a similar prevalence in men and women.[15] Other studies have reported a higher prevalence in men.[9] The differences in the reported prevalence of MCI worldwide are due to the lack of standardized cut-off for neuropsychology test scores, use of population versus clinic-based cohorts, and algorithmic (non-informant-based) versus clinical approaches to assign the MCI diagnosis.[14] European studies reported a lower prevalence estimate than those reported by the US studies. Prevalence estimates were higher for those US studies conducted in urban settings and those that included ethnic groups other than Caucasians.[14] A recent study from China estimated that MCI prevalence was 15.5 % among Chinese adults.[16] There are fewer studies on the incidence rate of MCI. The reported incidence rate of MCI varies from 5.1 to 168 (1000 person-years), while that of A-MCI is estimated between 10 to 14 (1000 person-years).[14]

Pathophysiology

MCI can have several outcomes, with the most important being the progression to dementia. Other cases may revert to normal or remain stable in the MCI stage.

A meta-analysis demonstrated that the cumulative incidence of dementia development was 14.9% for MCI patients older than 65 years who were followed for 2 years. The relative risk for all types of dementia was 3.3 at 2 to 5 years in a cohort of MCI patients and age-matched controls, while the relative risk for the development of Alzheimer Disease was 3.0. People with MCI are at a higher risk of progressing to dementia than age-matched controls.[15] The annual progression rate can be 12% in the general population and up to 20% in high-risk populations.[8] The risk factors for the development of MCI are not consistently associated with progression to dementia. Markers of cerebral dysfunction and those indicating the severity of underlying pathology are more consistently related to the risk of progressing to dementia.[14] More significant functional impairment, neuropsychiatric symptoms at the time of MCI diagnosis, lower neuropsychological test scores, and abnormalities on structural magnetic resonance imaging (hippocampal atrophy) are associated with a greater risk of conversion to dementia.[14] Some studies have noted that advanced age and amnestic MCI were associated with faster progression to dementia.[8] A stepwise multivariate regression analysis study reported that parietal glucose metabolic rate and total Tau proteins could predict progression from MCI to Alzheimer-type dementia.[17] The presence of APOE ε4 allele is also associated with a higher risk of Alzheimer-type dementia in MCI patients.[8]

Studies have shown that the reversion rate to normal can vary from 14.4% to 55.6%.[15] An average of 20% of individuals with MCI may revert to normal cognition; however, they remain at higher risk of progression back to MCI or dementia than those who were never diagnosed with MCI.[14][15] Factors associated with reversion to normal include male sex, younger age, single domain MCI, non-amnestic MCI, better scores on objective cognitive instruments (higher Mini-Mental State Examination score or lower CDR sum of boxes score), less functional deficits, lower burden of medical disease, and presence of reversible factors (such as infection).[14]

MCI does not have a linear trajectory for progression toward dementia or reversion to normal. Patients with stable MCI can change subtypes, revert to normal, convert to MCI, or progress to dementia.[18][19]

Histopathology

The neuropathology of MCI also displays considerable heterogeneity.

Gross Morphology 

It is difficult to distinguish between no cognitive impairment and mild cognitive impairment on autopsy. One study observed a widening of sulci in amnestic MCI and mild AD as compared to no cognitive impairment (NCI) or non-amnestic MCI.[20]

Amyloid Pathology 

Amyloid beta (Aβ) plaques are a characteristic lesion seen in MCI. These plaques appear similar in patients with normal cognition and those with MCI and cannot be used to distinguish between these two states.[20] Plaque density increased with progressing dementia, and the morphology changed from diffuse to neuritic.[20] The Rush Religious Orders Study (RROS) found that although the Aβ-amyloid burden in MCI was intermediate between normal controls and early AD, the difference was not statistically significant, suggesting that β amyloid deposition does not define the pathological transition to MCI.[21]

Neurofibrillary Tangle (NFT) Pathology 

NFTs are composed of hyperphosphorylated aggregates of the tau protein. NFT deposition is increased in certain anatomical brain regions (such as the Entorhinal cortex and Inferior Parietal Cortex) in MCI patients compared to normal controls, suggesting that NFTs could mark the transition from normal aging to MCI.[20] Studies have also shown that NFTs are present in both amnestic and non-amnestic MCI subtypes, whereas about 52% of MCI cases did not have neuritic plaques.[22] Studies have shown that amnestic MCI is similar to early AD based on NFT distribution.[23][24]

Neuronal Loss  

Various studies have examined the neuronal changes in MCI, focusing on the medial temporal lobe (MTL), particularly the Entorhinal Cortex (ERC). The RROS study showed neuronal reduction in the ERC and ERC atrophy in MCI patients.[20] ERC atrophy was also correlated with impairments in the MMSE, indicating that ERC neurodegeneration influences the progression of MCI.[25][26]

Synaptic Degeneration in the Hippocampus

The hippocampus shows reduced synaptic plasticity in MCI.[20] The number of synapses is reduced in MCI when compared to controls with NCI, and people with early AD have a significantly lower number of synapses when compared with MCI and NCI groups. The number of synapses also correlated with MMSE and delayed recall scores.[27]

Cholinergic System and Acetylcholine Receptors

Reduction in the cholinergic activity in the cortex and loss of neurons in the cholinergic basal forebrain (CBF) has been proposed as a potential mechanism for AD. In MCI, deposition of NFTs was noted in the CBF; however, the number of CBF nucleus basalis (NB) neurons that express choline acetyltransferase enzyme (ChAT) or the acetylcholine transporter was stable.[20] Cholinergic receptor binding in ERC is lower in MCI than in NCI, while it is lower in the hippocampus in AD than in MCI, leading to cognitive deficits. This indicates that cholinergic system dysfunction could be responsible for cognitive changes seen in MCI.[28]

Other Neuropathologies 

Lewy Bodies (LB), cerebral white matter rarefaction (CWMR), infarcts, and cerebral amyloid angiopathy (CAA) are some of the other findings observed in neuropathology studies. Non-amnestic MCI shows a greater distribution of LBs in the temporal lobes than amnestic MCI.[22] CWMR and CAA are equally common in both amnestic and non-amnestic MCI; however, cases with executive dysfunction had a higher frequency of CWMR and CAA.[22] Multiple studies have shown that mixed pathologies are a common feature of MCI.

History and Physical

Cognitive disorders are diagnosed clinically. Obtaining a comprehensive history from the patient or a reliable informant is important. Sometimes, the patients or their family members or caregivers are concerned about memory loss and may request an evaluation. At other times, neither the patient nor their families report concerns unless the physician asks them directly. Patients with memory loss may have poor insight into their impairment. Hence, it is necessary to obtain collateral information from someone who knows the patient well to obtain an accurate history. Sometimes, the patient's physician or a clinical staff member may be the first to recognize cognitive challenges when a patient misses their appointments, forgets to refill their medications, or gets confused by simple instructions. Periodically, the initial complaint may be a mood or behavioral problem rather than a cognitive one. Anxiety, depression, apathy, and other personality changes may prompt a request for the assessment. 

Information about the onset and progression of symptoms should be noted. Usually, the symptoms are gradual in onset and progressive. Sometimes, the patients or their families may attribute these to normal aging. The AAN recommends that all memory concerns be assessed for MCI and not assumed to be due to normal aging.[15]

The purpose of the evaluation is to distinguish MCI from normal aging or dementia and to ascertain if any reversible factors may be responsible for the presentation. When determining a patient's baseline function, it is important to gather and consider information about their educational level and occupation. 

A detailed assessment can identify affected cognitive domains. The complaint should represent a change from the baseline for the patient. The table below shows some examples.[11]

The cognitive history should be followed by a detailed functional history inquiring about instrumental activities of daily living (IADLs) and basic activities of daily living (BADLs). Changes in complex functions such as difficulty managing finances, medications, or driving should be asked about. In MCI, the patients may report functional independence alongside their cognitive complaints. It can sometimes be challenging to determine if the IADLs are impaired. Patients with higher educational levels or those in cognitively challenging occupations (such as physicians) may report mild changes that affect their professional performance. In contrast, those with lifelong lower-skill jobs may not report any problems.[29] Assessing functional impairment related to cognition is vital to distinguish MCI from dementia.[15]

A detailed medication review involving prescription and over-the-counter medications is integral to the evaluation. The Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults, developed by the American Geriatrics Society, is useful for identifying medications that can contribute to cognitive impairment.[10]

Neuropsychiatric symptoms are quite common in MCI, with 35-85% of patients showing at least one neuropsychiatric symptom.[30] Depression, apathy, anxiety, irritability, sleep problems (difficulty falling asleep, early morning waking, wandering at night), agitation, appetite or eating disorder, and disinhibition can be seen commonly in MCI. Hallucinations and delusions are unusual in MCI patients but associated with worse outcomes if present.[31] It can sometimes be difficult to evaluate if depression and anxiety are a cause of MCI or associated. Screening for sleep-disordered breathing such as OSA, asking questions about vision, hearing, gait, history of falls, recent hospitalizations, tingling/numbness, urinary incontinence, tremors, and speech problems are included in the history. 

A complete neurological examination should be performed. This should include assessments for cranial nerves, focal weakness, coordination, ability to stand from a chair without using hand rests, gait, and speech evaluation to look for dysarthria and orthostatic hypotension to identify potential contributors to the cognitive complaint.[9]

The history and physical exam help identify conditions such as stroke, NPH, PD, or neuropathy due to vitamin deficiency as a cause of the symptoms. 

Evaluation

A standardized cognitive assessment is mandatory to establish a diagnosis of MCI. Standard screening tools that are used include the Montreal Cognitive Assessment (MOCA), the Saint Louis University Mental Status Examination (SLUMS), and the Mini-Mental State Exam (MMSE). A history of subjective memory concerns is insufficient to diagnose MCI, and further assessment with a validated tool is required per the AAN practice guidelines.[15]

The MOCA is a 30-point questionnaire specifically designed to detect MCI, takes about 10 minutes to administer, tests multiple cognitive domains, and is validated in multiple languages. The MOCA also accounts for educational level, granting an additional point for patients with less than 12 years of education.[32] Using a cut-off score of 25- 26, MOCA had a sensitivity of 80-100% and specificity of 50-76% for detecting MCI.[9] The MMSE is also a 30-point questionnaire but is less sensitive than the MOCA for detecting MCI, with a sensitivity of 45-60% when using a cut-off score of 27-28.[9] MOCA's assessment tasks are more varied and challenging and can better distinguish patients with mild changes in executive function, complex visuospatial function, and language abilities than the MMSE.[33] 

Correcting the MMSE score for education can create a ceiling effect for people with low education levels and a floor effect for those with higher educational levels.[34] This means that the MMSE can overestimate the extent of cognitive dysfunction in poorly educated populations and underestimate the highly educated ones. Another limitation of MMSE is that its use is copyrighted. The SLUMS is a 30-point questionnaire with an administration time of 10 minutes. It is more sensitive to detect defects in executive function, commonly impaired in MCI, hence a better screening tool for MCI than the MMSE. The SLUMS has cut-off scores for MCI based on the educational level (unlike the MMSE), is better validated for detecting MCI, and is free to use.[35] 

The DSM-V or the NIA-AA MCI criteria do not specify the use of a particular screening test; however, the scores need to be 1 to 2 standard deviations below the education and age-adjusted normative means. The scores are used as guidelines and not firm cut-offs for diagnosing MCI.[5] Referral for neuropsychology testing can be considered to specify the type and extent of cognitive deficits, and it is instrumental in cases where the deficits are subtle.

Clinicians can also collect information on cognitive function from informants using standardized tools such as the Informant Questionnaire on Cognitive Decline in the Elderly(IQCODE), the Dementia Severity Rating Scale (DSRS), and the AD8.[9] Geriatric Depression Scale can be used to screen for depression, with a score of ≥6 suggesting depression.[36]

After establishing the diagnosis of MCI based on clinical examination and cognitive testing, diagnostic tests are ordered to determine the etiology of the deficits and identify treatable causes. 

Routine laboratory testing includes tests for complete blood counts, thyroid function, vitamin B12, folate, and metabolic panel to check electrolytes, glucose, and renal function to identify reversible causes of MCI. Tests for liver function, syphilis, HIV, hepatitis (B or C), and Lyme disease may be ordered based on clinical suspicion. 

The clinical utility of biomarker studies is limited due to a lack of standardized techniques and cut-off scores for diagnosis. The most common biomarkers detect pathological changes in AD characterized by low cerebrospinal fluid levels of Aβ 42 and elevated levels of the tau protein.[6] These may help identify MCI patients at high risk of progressing to AD, but biomarkers are not recommended as part of the evaluation.[9][15]

Structural neuroimaging studies include magnetic resonance imaging (MRI) or computerized tomography (CT) brain scans. These can help rule out conditions such as stroke, brain tumors, NPH, or subdural hematoma as a cause of cognitive dysfunction. They can also show small vessel ischemic changes or white matter hyperintensities, which usually indicate cognitive impairment due to vascular dementia.[6] Volumetric MRI can show hippocampal atrophy correlated with progression to dementia. This imaging modality is selectively available at institutions, limiting its clinical use.[6] 

Functional neuroimaging studies such as positron emission tomography (PET) scans with F-fluorodeoxyglucose (FDG) or single photon emission computed tomography (SPECT) evaluate brain function. FDG-PET measures areas of glucose hypometabolism in the brain, indicating neurodegeneration, while SPECT measures cerebral blood flow.[6] These studies are limited to research settings.

Genetic testing for the APOE genotype is not recommended as a diagnostic test.[37]

MCI is a clinical diagnosis, as there are no definitive screening tests. Periodic clinical assessments are needed to monitor the trajectory of the condition.[15] The AAN guidelines also recommend referral to a cognitive specialist if the clinicians do not have experience treating patients with cognitive impairment.[15]

Treatment / Management

Treatment of reversible causes should be prioritized; conditions such as OSA, depression, hypothyroidism, vitamin deficiency, and polypharmacy are easily treated and may lead to the reversal of cognitive impairment. Vascular risk factors such as hyperlipidemia, hypertension, diabetes mellitus, atrial fibrillation, and tobacco and alcohol use should be addressed to slow down ischemic damage. 

Currently, there are no FDA-approved agents for the treatment of MCI. Several pharmacological agents have been studied for efficacy in treating MCI. These include acetylcholine esterase inhibitors donepezil, galantamine, and rivastigmine, homocysteine-lowering B vitamins, flavonoid-containing drinks, vitamin E, vitamin C, transdermal nicotine patch, piribedil, rofecoxib, tesamorelin injections, and V0191. Donepezil and other medications used for AD are not effective in reducing the progression of MCI.[1] 

The 2018 AAN practice guidelines advise against pharmacologic or dietary agents for MCI treatment.[15] The guidelines recommend that clinicians discuss with the patient before choosing not to offer cholinesterase inhibitors or prescribing them off-label. Patients should also be provided information about relevant clinical trials if they are interested in pharmacologic treatment.[15](A1)

Non-pharmacologic interventions such as exercise and cognitive training have also been studied for MCI treatment. A six-month randomized controlled trial resistance training exercise twice weekly showed improved cognitive function compared to weekly balance and tone exercises.[2] Another study showed that multicomponent exercise could improve cognitive function in MCI. A systematic review and meta-analysis have shown the usefulness of cognitive interventions on metacognition and activities of daily living.[1] Cognitively stimulating activities, such as crossword puzzles, card games, and frequent socialization, can help prevent the progression of MCI.[6] The AAN guidelines recommend regular exercise (twice per week) and cognitive interventions as part of management for general health benefits and low risk.[15](A1)

The inherent uncertainty about the progression of MCI and the lack of effective pharmacologic agents necessitates that physicians educate patients about the progression to dementia and engage in planning for the future. Patients should be encouraged to designate medical and financial power of attorneys and complete advance directives or living wills if they cannot make such decisions in the future. Potentially hazardous circumstances such as driving, gun safety, and vulnerability to financial scams can be discussed.[6][15] In addition to discussing long-term planning, the AAN recommends assessing and treating neuropsychiatric symptoms when indicated.[15](A1)

Optimizing visual and auditory function is important, as untreated problems can lead to cognitive decline.[38] Targeted interventions to improve gait and balance to reduce the risk of falls should be recommended.[9] Caregivers can experience distress and have conflicting feelings towards the patient in response to the cognitive and behavioral changes seen in MCI. It is important to provide support and services to the caregivers depending on their needs.[7]

Differential Diagnosis

It is important to differentiate MCI from both normal aging and dementia. Subjective reports from the patient or a reliable caregiver, a history of functional decline, and objective assessment with a standardized cognitive screening tool help to distinguish these conditions. Reversible causes of MCI, such as depression and OSA, need to be ruled out. MCI can represent the prodromal stage of different types of dementia, and the subtype of MCI can provide important clues about the etiology. 

AD can present from all 4 MCI subtypes - single or multiple domain A-MCI, single or multiple domain NA-MCI. Depression can present as amnestic MCI. FTD can present as a single domain NA-MCI. Vascular cognitive impairment can present as multiple-domain amnestic or non-amnestic MCI. Lewy body dementia can present as multiple-domain NA-MCI.[2] In Parkinson Disease, a single-domain NA-MCI is usually seen.[1]

Prognosis

The prognosis of MCI is uncertain. There is great variability in progression rates of MCI to dementia, with studies reporting annual conversion rates from <5%-12-20%.[9] 40-70% of patients with MCI may not progress to dementia for over a decade.[39] About 15-20% of MCI patients will report improved cognition in 1 to 2 years, although this group remains at a higher risk of future cognitive decline.[40]

Risk factors associated with MCI progression include amnestic MCI subtype, older age, stroke, diabetes, and lower educational level.[8] APOE genotype may confer a modest risk of progression to AD.[41] Factors associated with reversion to normal cognition include non-amnestic MCI subtype, younger age, higher baseline cognitive function, and higher educational level.[40] MCI subtype classification can be used to estimate progression risk; however, this model has variable predictive accuracy. Current risk prediction models are limited in presaging the risk of progression to dementia.[9] Future risk prediction models need to account for competing risks, such as cardiovascular disease and cancer, that can cause mortality before the patient develops dementia.[9]

Complications

The most important complication of MCI is progression to dementia. Early diagnosis and treatment of MCI are important because they help patients plan for the future so that emergencies or late-stage complications are avoided. Assessment and treatment of reversible causes can help stabilize or reverse the cognitive changes.[6]