Mild Cognitive Impairment: An Overview

Abstract

Heterogeneity of symptoms within and among mild cognitive impairment (MCI) individuals often makes it challenging to document cases clinically. Number of diagnostic criteria have been proposed in recent decades. MOCA and MMSE are two tests useful for the assessment of MCI, besides the neuroimaging studies with MRI and PET scan, have provided promising results in the early diagnosis of MCI. Lifestyle changes and cognitive training have been found to be more effective in the treatment of individuals with MCI.

1. Introduction

1.1 Cognitive decline in aging

Changes in brain morphology resulting from normal aging have been documented in neuroimaging studies. The results show that there are alterations in white matter integrity, white matter hyper-intensities, and reduced hippocampal volumes [1, 2, 3].

Cognitive decline is a common phenomenon associated with normal aging and is getting a lot of attention among clinicians. Some of the earlier labels such as “benign senescent forgetfulness,” [4] “age-associated memory impairment” (AAMI) [5], “age-associated cognitive decline” (AACD) [6], and “age-related cognitive decline” [7] are frequently used to describe the deterioration in cognition.

The decline in cognitive performance with aging is due to several cognitive processes, including a reduction in processing speed, working memory capacity, and loss of sensory input. This thereby results in deficits in encoding, storing, and retrieving information, but cognitive capability remains unaffected [8, 9]. The problems are mainly noted while retrieving information from the long-term and short-term memory store, where the retrieval of information is slower in the former, and the amount of information that can be stored decreases in the latter [9].

During the aging process, the onset of dementia has been widely reported. Recently, the label “mild cognitive impairment (MCI)” has been used to signify the intermediate condition between dementia and normal aging [10]. Cases presenting with the following signs and symptoms such as (i) informant-corroborated history of memory symptoms, (ii) impairment in memory when measured objectively (usually <1.5 standard deviations on a verbal memory test), (iii) spared general cognition, (iv) activities of daily living (ADL) well preserved, and (v) no dementia are recommended to use this label [11]. Recent criteria proposed include the following cognitive domains for diagnosing MCI, and four subgroups made are of (1) only memory deficit; (2) memory deficit along with deficits in other cognitive domains; (3) deficit in the non-memory domain; and (4) non-memory domain deficit along with deficits in other cognitive domains [12, 13]. Evidence suggests that cognitive decline in MCI has no adverse effects on the activities of daily living in contrast to dementia, and this is consistent with the definition of “mild neurocognitive decline”(NCD) from DSM-V [14]. Cognitive decline was studied in individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and normal cognition for 11 years, and it was concluded that the cognitive capacity in the normal group declined at a slower extent than in the MCI group and that of the MCI group declined at slower extent than the group with Alzheimer’s disease [15]. Studies report that all cases diagnosed as MCI do not progress to dementia [12, 13].

There is substantial evidence that neuropathological alterations occur several years before the clinical manifestation of Alzheimer’s disease (AD) [16, 17] and that subtle cognitive abnormalities persist up to 9 years before a dementia diagnosis [18].

As a result of these findings, researchers have coined the term moderate cognitive impairment (MCI), which was coined by Flicker, Ferris, and Reisberg [19]. MCI is defined by Petersen and colleagues [16] as a transitional, preclinical state characterized by intermediate symptomatology between cognitive changes associated with healthy aging and the more pathological alterations associated with Alzheimer’s disease [20].

Memory complaints (confirmed by an informant), objective evidence of memory impairment (for age and education level), generally intact overall cognitive function, essentially preserved activities of daily living, and the absence of dementia are all clinical criteria for diagnosing MCI, according to the American Academy of Neurology [21]. Separate subgroups of MCI have been found more recently [12] based on the element of cognition that is most impacted. Memory loss is the most significant symptom of amnestic MCI (a-MCI). In longitudinal studies, this kind of MCI is the most frequent and is most likely to be related to conversion to AD.

Figure 1 depicts current perspectives on the shift from healthy cognitive aging to amnestic MCI and Alzheimer’s disease. Single non-memory domain MCI (sd-MCI) is another subtype of MCI that is characterized by significant abnormalities in linguistic skills, executive function, or visuospatial function [12]. Finally, multiple domain MCI (MD-MCI) is characterized by the involvement of multiple cognitive domains and can occur with or without memory problems (MD-MCI + a). According to epidemiologic research, persons diagnosed with MCI are substantially more likely to develop AD or dementia within 5 years than those without MCI. In one study, 56% of amnestic MCI individuals and 50% of non-amnestic MCI participants transitioned to Alzheimer’s disease or dementia within 4 years [22].

Figure 1.

Current perspectives on the shift from healthy cognitive aging to amnestic MCI and Alzheimer’s disease.

Table 1 summarizes the four widely recognized subtypes of MCI. Generally, a case of MCI is classified in one of the following four subtypes as per four essential characteristics, (1) Complaints of cognitive problems; (2) Memory impairment; (3) Impaired or spared functional ability, and (4) Presence or absence of dementia. Within MCI, amnestic versus non-amnestic MCI is classified based on memory impairment. Suppose an individual is objectively confirmed to have memory-related issues. In that case, it is classified within amnestic types, and if s/he has issues related to other domains of cognition rather than memory, then it is confirmed to be non-amnestic. Further, if a single aspect of cognitive function is affected, it is termed a single domain, and if two or more elements are involved, it is confirmed to be multiple domains.

Subtypes	Characteristics
Amnestic MCI (Single Domain)	Subjective or proxy cognitive complaint Objective memory impairment Relatively intact functional ability Not demented
Amnestic MCI (Multiple Domain)	Subjective or proxy cognitive complaint Objective impairment in memory and at least one other cognitive domain Relatively intact functional ability Not demented
Non-Amnestic MCI (Single Domain)	Subjective or proxy cognitive complaint Objective impairment in one non-memory domain Relatively intact functional ability Not demented
Non-Amnestic MCI (Multiple Domain)	Personal or proxy cognitive complaint Objective impairment in two or more non-memory domains Relatively Intact functional ability Not demented

Table 1.

Four widely recognized subtypes of mild cognitive impairment (MCI).

1.2 MCI—signs and symptoms

There are three main types of trajectories seen in cognitive decline, which are (1) Stable pattern, observed for the impaired language skills; (2) Gradual pattern, noted for immediate recall, inhibition, and visuospatial skills; (3) Stable period followed by accelerated decline pattern, seen in delayed recall, visuospatial memory, and working memory skill [23]. It has been reported that episodic and working memory are the domains that are affected to a greater extent among MCI individuals and present with the fastest decline in those individuals who progress to other groups like dementia. These studies have consistently found that memory deficits are the major deficits reported by individuals with MCI or their caregivers [24].

Individuals with MCI exhibit a wide range of difficulties in multiple areas of cognitive functioning, such as attention, memory (primary and secondary), visuospatial ability, and language and executive functioning [6]. MCI has been considered a “syndrome” due to the presence of a cluster of symptoms centered around major neuropsychological manifestations, such as (i) complaints of noticeable cognitive decline, (ii) memory deficit observable on tests, and (iii) spared activities of daily living except mild deficit in instrumental activities of daily living [25, 26]. Evidence suggests individual with MCI usually presents with the complaint of a certain decline in normal cognitive functioning. Evidence shows that mood variations are a good predictor of MCI [26, 27, 28]. An important diagnostic variable is the presence of preserved activities of daily living. However, it is observed that the instrumental activities of daily living are much more affected than the ADLs [26]. For example, an auto-driver with MCI might face more difficulty executing his skill/or job effectively.

Regarding the diagnosis of MCI, there is a considerable amount of debate going on. Previous literature has reported that the condition of MCI is characterized solely by memory impairment. Further studies, however, supported that MCI could be an impairment in the non-memory domain alone or a condition with multiple cognitive components (executive function, memory, language, etc.) being affected simultaneously [10, 12]. Research suggests that MCI generally develops into an Alzheimer’s disease (AD) type of dementia. However, contradictory studies also support that MCI is reversible or could develop into non-AD type dementia [10, 29]. Therefore, to bring uniformity to the diagnosis of MCI, the international working group on MCI has given modified criteria for diagnosis, suggesting any cognitive impairment that fails to meet the diagnostic criteria of dementia is categorized as MCI [10].

2. MCI assessment

According to Petersen et al. [30], the clinician can use the progression criteria as per the description provided in the flowchart for an easy understanding of the procedure used for making a diagnosis for MCI. The same is depicted in Figure 2 [31]. The clinician is thus faced with the challenge of evaluating this symptom, given that the patient appears with a cognitive concern. It is vital to obtain a patient’s history and confirm it with someone who is familiar with the patient. It is critical that the patient, the patient’s informant, or the physician expresses some level of cognitive concern. The cognitive concern is important since it reflects a change in the person’s performance. MCI is not meant to reflect a person’s low cognitive function for the rest of their life; rather, it is meant to show a shift in this specific person’s cognitive function. As a result, the clinical history is vital in the absence of formal longitudinal cognitive data on an individual. The clinician should emphasize the types of cognitive changes the patient has experienced. If the primary concern is memory loss, the clinician should focus on recent forgetfulness occurrences (approximately in the last 6 months to a year). In cases of forgetfulness involving current events, appointments, visits by friends, or conversations, the physician should be particularly interested. If the patient begins to repeat themself, this indicates that impairments are emerging. Again, the clinician should evaluate for changes in that person’s memory or cognitive performance [32].

Figure 2.

Flowchart for clinical evaluation and diagnosis of cases with MCI.

The clinician should investigate the extent of the cognitive impairment. The question is whether the issue is solely about memory or does it also involve other cognitive areas like attention and concentration. Patients frequently identify cognitive alterations in the memory domain when, in reality, they may be referring to attention or language issues. It is essential to define the breadth of the cognitive shift. The clinician will need to conduct a mental status examination and explore the various cognitive domains at this time. If schedule allows, a mental status assessment using an instrument like the Montreal Cognitive Assessment (MoCA) or the Short Test of Mental Status can be useful, but the clinician should be aware that these screening instruments are insufficient to make the diagnosis; however, they can be useful in isolating domains of impairment and advising the clinician on additional assessments like neuroimaging and for amyloid imaging (MRI, PET scan, etc.,) and a CSF study [33, 34]. Neuropsychological testing can be beneficial if the key question with the patient is how to differentiate between the patient’s symptoms and the changes in cognitive function that occur with normal aging. The neuropsychologist can examine whether the level of cognitive function is acceptable for the patient’s age, gender, and education by describing the profile of cognitive function. If the clinician does not have access to this information, they must make the best assessment of function possible.

Test materials such as the Montreal Cognitive Assessment (MoCA) [34] and the Mini-Mental State Examination (MMSE) [35] are typically used to assess patients with cognitive impairment. According to Nasreddine et al. [34], the sensitivity of MMSE to detect MCI was only 18%, whereas the sensitivity of MoCA to detect MCI was 90% [34, 36]. The specificity of both tests was reported to be good. The poor sensitivity for the MMSE to see conditions of MCI was attributed to the poor scoring, and any score greater than 26 was considered normal, within which the scores of persons with MCI are just above average [37]. Hence, it can be concluded that the condition of MCI can be detected successfully using the MoCA.

Both MMSE and MoCA are primarily used for screening, and the time of administration required is 5–10 min. Subtle differences exist between the two. Longer delayed recall time and fewer trial learning stimuli are present in MoCA, giving more challenges to the patient. Executive and complex language abilities (abstraction) are not assessed in MMSE but in MoCA. This increases the complexity of the tasks of MoCA when compared to MMSE. Studies report that the attention tasks in MoCA, such as the digit span, sustained attention, and the serial 7 calculation task helped to discriminate between AD versus the normal and MCI group as all the three tasks were affected in the AD group but were preserved in MCI group. AD and MCI groups also demonstrated impairment in sentence repetition, and delayed recall was found to be the most impaired task in the MCI group [34].

With reference to the functional performance, a patient with MCI should suggest that the patient’s daily function is mostly retained. However, the history of being assessed for any cognitive decline. For example, the patient may be inefficient at particular tasks and take longer to do them, but he or she will eventually be able to complete them without assistance. This form of evaluation satisfies the criteria retained for cognitive function requirements. This can be a very subjective judgment. Therefore, having a trustworthy informant on hand can help. However, if the individual continues to operate daily, such as driving, paying bills, and filing taxes, and appears normal to the casual observer, a function is often kept. Finally, the patient does not meet the criteria for dementia based on all of these factors. The person’s cognitive deficits are not severe enough to interfere with daily activities. As a result, an essential condition for dementia is not met.

The clinician should then decide whether the patient has had a change in cognition, whether there is objective evidence of this, whether a function is generally intact, and whether or not the patient meets dementia criteria. Suppose MCI is considered to be a valid diagnosis. In that case, the clinician must then assess whether memory is a significant element of the cognitive impairment and if so, the amnestic MCI arms would be appropriate. The non-amnestic arm of the diagnosis, on the other hand, would apply if the person is experiencing cognitive loss, but their memory is generally intact.

Following the determination mentioned above of the clinical syndrome, the clinician must then discover the cause or etiology of the syndrome. Figure 2 depicts potential explanations for various clinical symptoms with degenerative, vascular, psychiatric, or medical etiologies and can aid in determining the next steps in the diagnostic process. A degenerative disease is a plausible possibility if the onset of the disorder has been slow and gradual. A vascular contribution must also be evaluated if the patient has a history of vascular risk factors and has had cerebral ischemia episodes. Furthermore, some mental diseases, such as major depression or generalized anxiety disorder, might have cognitive components. As a result, cognition may be compromised in the early stages of these disorders. Other medical conditions, such as uncompensated heart failure, poorly controlled diabetes mellitus, or chronic obstructive pulmonary disease, must always be considered factors of cognitive impairment by the clinician. Some of these medical comorbidities are curable, and their drugs may also lead to clinical syndrome [32].

2.1 MCI pathogenesis and outcomes

An amyloid-b deposition is linked to dementia caused by decades of proteinopathy, such as Alzheimer’s disease caused due to extraneuronal neuritic plaques and intracellularly neurofibrillary tangles. They are characterized as tauopathy for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, and synucleinopathy for Lewy body dementia and Parkinson’s disease dementia. However, there are also significant aspects in the pathophysiology of dementia that can be modified, including a sedentary lifestyle, low nutritional status, social or environmental influences, and hereditary factors [38].

MCI can be caused by a variety of factors, including systemic disorders. Differential outcomes are caused by neurological diseases, drugs, and psychological disorders [39]. There are just a handful of possible outcomes of MCI—stabilization, progression, or reversion to normal aging. There is a unique presentation of metabolic disorders in older persons. Basic investigations are recommended, and when clinically necessary, neuroimaging is used. Reversible reasons are uncommon, with most cases occurring in surgical and depressive patients [32, 40, 41, 42].

If the clinician considers a degenerative condition the most likely cause, then the clinical symptoms can help identify an underlying diagnosis. If the patient has a typical amnestic condition with MCI and is in the right age range, Alzheimer’s disease (AD) is a possible diagnosis. However, suppose the patient is having trouble with attention, concentration, and visuospatial difficulties. In that case, a form of dementia with Lewy body should be considered. If the person has behavioral changes, inappropriate behavior, apathy, lack of insight, and impaired attention and concentration, frontotemporal lobar degeneration should be considered. In fact, Alzheimer’s disease, the most frequent degenerative disease of old age, can manifest itself in unusual ways involving attention, focus, and language [12, 32].

The clinician may be able to make a fair assumption about the nature of the condition based on the history and examination. Additional testing, such as an MRI scan, fluorodeoxyglucose positron emission tomography (FDG-PET) or positron emission tomography (PET) for amyloid imaging, and a CSF study, may be considered at this time. These additional tests may aid in determining the underlying cause of the clinical symptoms. While the US Food and Drug Administration (FDA) has not yet approved any pharmaceutical therapy for MCI caused by Alzheimer’s disease, lifestyle changes and cognitive and behavioral therapies may be beneficial. Counseling patients about their expectations is also crucial. Medical comorbidities, such as sleep disorders like sleep apnea, should be investigated, as previously stated because some have curative components [12, 30, 32, 43].

3. MCI treatments

The FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan have not approved any pharmacological treatments for MCI. There have been numerous randomized control trials in the MCI spectrum, but none has been successful in slowing the progression of MCI to AD dementia [44, 45, 46, 47]. The Alzheimer’s Disease Cooperative Study tested donepezil with high-dose vitamin E in amnestic MCI as one of the earliest trials [32]. This study found that donepezil could delay the rate of advancement in all patients with amnestic MCI for the first year of the trial and perhaps for up to 2 years in those with amnestic MCI. They were positive for the APOE4 isoform. However, because the study was only supposed to last 36 months, no treatments were shown to be helpful at that point, and the trial was deemed a failure. Other studies employing cholinesterase inhibitors, which have been used to treat Alzheimer’s disease dementia, have also failed [32, 44, 45].

Only a few research looked at the effects of over-the-counter (OTC) intervention on clinical MCI caused to Alzheimer’s disease, according to a systematic review [37]. There are no studies that compare placebo to omega-3 fatty acids, soy, folic acid, B vitamin (folic acid plus B12), B vitamin (folic acid plus B6, B12), vitamin D plus calcium, vitamin E, vitamin C, or b-carotene in terms of MCI prevention. There was insufficient evidence to conclude the benefits of Ginkgo biloba, and a clinical trial found that multivitamins had no effect. In general, there is little evidence that OTC vitamins protect the brain [48].

There is research with reference to changes in lifestyle and non-pharmacologic therapy like aerobic exercise may be useful in slowing the progression of MCI to Dementia [49]. However, a 2010 state-of-the-science report from the National Institutes of Health (NIH) found no effective therapies for dementia progression [32]. However, recent evidence suggests that lifestyle adjustments may have some efficacy, which needs further investigation.

There was insufficient data to conclude the effect of a multi-component physical intervention that included flexibility, strength, balance, endurance, and aerobic training. No studies compared attention control to aerobic training, strength training, physical activity plus diet, physical activity plus protein supplement, or physical activity, diet, and cognitive training [37]. Even though single-component physical activity programs had negative results, a multidomain intervention appeared to improve cognitive function in older people with normal cognition. It is advised that clinicians encourage their patients to participate in clinical practice because the advantages can help avoid or manage other chronic conditions [50].

With reference to cognitive training, according to a systematic review, there is no clinical research on the protective impact of cognitive training in persons with normal cognitive function from developing MCI [37, 48]. Training in specific domains, such as reasoning, executive function/attention/processing speed, and memory, improved cognitive performance in the trained domains. As a result, there is inadequate evidence of cognitive training in people with the normal cognitive ability to prevent or delay cognitive decline [48].

4. Conclusion

In clinical practice and research, MCI has become an important topic. MCI established boundaries for this intermediate stage, focusing on earlier detection of incipient forms of cognitive impairments. Several randomized controlled studies for the MCI subtype caused by Alzheimer’s disease are currently underway, and doctors should be aware of these research prospects for their patients. The cognitive abnormalities may be reversible once treatable etiologies of MCI (such as those caused by psychiatric illnesses, drugs, or medical comorbidities) are recognized. The development of biomarkers should give clinicians new tools for detecting and possibly treating MCI.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the book chapter.

Funding

There is no funding by any agency for the manuscript.