Mild cognitive impairment

Nerrissa S C Wu 胡瑞枝, Kin-sang Ho 何健生

HK Pract 2009;31:36-40

Summary

As public awareness of dementia increases, more and more people are asking for help and advice on memory problems. Recent research has identified a transitional state between the cognitive changes of normal ageing and Alzheimer's disease (AD), known as Mild Cognitive Impairment (MCI). Patients suffering from MCI progress to clinically probable AD at a considerably accelerated rate, compared with healthy age-matched individuals. Identification of this high risk group for AD would allow early detection of the disease and might even delay progression to dementia, which is an escalating burden to the community. However, there is a heterogeneity of MCI which has posed problems in achieving consensus in its diagnosis, evaluation, treatment and predicting prognosis. There are increasing calls to recognize the pathological nature of MCI, to develop international diagnostic guidelines and to standardize the investigations on prediction of MCI progression to preclinical AD.

摘要

隨著大眾對老年痴呆認識的增加，因為記憶問題就診或尋求幫助的人也越來越多。 近期研究發現在正常老化和亞氏痴呆症之間有一個認知變動的過渡階段，稱為溫和的認知損傷。 溫和的認知損傷患者可能演變成臨床的亞氏痴呆症速度較快。分辨認這個高風險人群， 可以及早察覺並可能延遲形成加重的社區負擔的老年痴呆症。然而溫和的認知損傷缺乏統一性，難以就診斷，評估， 治療和病情預測定義達成共識。需要進一步認識溫和的認知損傷的病理性質，研發國際診斷指南和並加以規範化， 做為預測溫和的認知損傷演變成臨床前期亞氏痴呆症的測試。

Introduction

Our elderly population has been escalating in recent years as a result of improvement in health care and medical treatment. With an ageing population, memory impairment is a symptom commonly encountered in primary care settings. Recent research has identified a transitional state between the cognitive changes of normal ageing and dementia, known as Mild Cognitive Impairment (MCI). This condition refers to patients who have experienced memory loss to a greater extent than one would expect for their age, yet they do not meet the clinical criteria for dementia.¹ Clinical studies by Petersen and colleagues² on elderly individuals with memory impairment revealed a rapid rate of conversion to Alzheimer's disease (AD), reaching as high as 12% per year, which is reasonably rapid compared with 1% to 2% per year in the normal elderly population.

Recognition of MCI offers possibilities for early diagnosis and probably potential treatment with the aim of delaying the onset of dementia or even preventing the disease.³ However, there has been some confusion concerning its definition and classification. This is mainly due to its aetiological heterogeneity,⁴ which limits the development of specific diagnostic criteria, specific therapeutic approaches and the prediction of clinical progression.

Diagnostic criteria

MCI is a clinical diagnosis. While there have been different diagnostic criteria for this clinical condition, a recent set of diagnostic criteria was suggested by the European Consortium on Alzheimer's Disease Working Group on MCI,⁵ viz:

1. Cognitive complaints coming from the patient or their families (not normal for age).
2. The reporting of a relative decline in cognitive functioning during the past year by a patient or informant.
3. Cognitive disorders as evidenced by clinical evaluation (either impairment in memory or in another cognitive domain).
4. Absence of major repercussion on basic daily activities (however, complex day-to-day activities may be slightly affected).
5. Absence of dementia.

These criteria stress the importance of clinical evaluation, family interview together with neuropsychological evaluation to detect mild cognitive impairment. It no longer focuses on just the memory domain alone. There are also syndrome subtypes which may be recognized at an early stage. These include amnestic MCI, non-amnestic MCI and multiple-domain MCI.

Prevalence

Research on the prevalence of MCI has produced inconsistent data mainly because of the different criteria to diagnose the condition, sampling composition, assessment procedures and neuropsychological measurements. According to a local study by Lam et al, the overall prevalence of MCI for persons aged 70 years or above was 8.5%.⁶ So far no consistent relationship to MCI could be drawn regarding age, gender and education.

Clinical presentation

MCI may have the following clinical types of presentation:

a) Amnestic MCI, which is the most common type and is usually preclinical, involving memory impairment alone while other cognitive functions remain intact. The memory complaints may be subjective or initiated by informant. The impaired memory function is adjusted for age and education. There is preserved general cognitive function, with intact basic activities of daily living and no evidence of dementia by DSM IV.⁷ The most common memory complaint seen in amnestic MCI patients is loss of recent memory such as forgetting where things are placed, being unable to recall names of close friends, recent conversation, appointments and events. It is noted that although these MCI patients appear to be independent and normal in their usual activities of daily living, they have subtle impairment in doing more complex tasks such as job performance, handling finance, engaging in hobbies and interest (e.g. stock market, horse gambling, working on the computer) and social interaction.

b) Multiple domain MCI: in this type, there are impairment of more than one cognitive domain, e.g. memory, language, executive function or visuospatial skills.

c) Single non-memory domain MCI: single domain outside of memory is impaired e.g. language, executive function or visuospatial skills.

The course and outcome of MCI

Longitudinal studies with repeated assessment over a long period of time in large community samples are needed if we would want to know the course and outcome of MCI.² However, in the meantime, data on the rate of conversion to dementia reported in the literature varies greatly.

The Mayo Alzheimer's Disease Research Center, Rochester, Minn, has been observing a group of these subjects for more than 10 years. Data showed that the conversion rate of individuals with MCI to dementia was 10-15% on a yearly basis, which was significantly higher than the 1-2% per year of healthy control subjects. It also demonstrated a conversion rate to AD of up to 80% during approximately 6 years.^3,10

The question of which subjects with MCI might be more likely to progress at an accelerated rate and represent a clinically meaningful subgroup is still awaiting an answer. Some researchers and investigators have identified various risk factors for MCI converting to dementia, including family history, older age, fewer years of education, Apo E e-4, lower pre-morbid IQ, and results of neuropsychiatric tests showing deficit in verbal episodic memory and delay recall. However, findings in some other studies were inconsistent. Detailed comparison of the predictive value of physiological, socio-economical and neuropsychological measurements is necessary to determine which combination of tests and measurements are of greatest diagnostic and prognostic use.²

Heterogeneity

The heterogeneous aetiologies of MCI is reflected by the fact that some MCI patients progress to AD and others remain stable or even recover from the disease when they are followed up over time. Each of the clinical subtypes could have different and multiple aetiologies which include degenerative, vascular, metabolic, traumatic and psychiatric causes. Examples of such clinical conditions in late life include stroke, hypothyroidism, normal pressure hydrocephalus, depression or mood disorders. As a result, individuals who present clinically with MCI symptoms may not share the same fate ultimately. Some may progress to AD, some remain stable while others may progress to other disorders11 like vascular dementia, frontal-temporal dementia or Lewis Body dementia. Therefore once the syndromes of MCI and the subtypes are recognized, the underlying aetiopathogenic factors should be determined.

Assessment

Both cognitive and functional abilities need to be assessed in the evaluation of MCI. Although there are controversies on how MCI can be best assessed in general, both clinical evaluation and various rating scales are commonly used in clinical practice. Neuropsychological tests and neuroimaging may be used in selected cases. Other tests are currently mainly for research purposes.

a) Clinical evaluation

At the primary care level, family physicians should pay attention to subjective cognitive complaints and take a structured history to verify any subtle cognitive deterioration and impairment in functional activities. This should be coupled with a thorough clinical examination to determine aetiological factors and to exclude possible treatable causes of cognitive impairment such as anaemia, hypothyroidism, depression, medication used and vitamin deficiencies (e.g. B12 and folate). MCI patients may show mild difficulties in areas of thinking such as naming objects or people and solving problems or planning complex tasks. Careful questioning may reveal some difficulties with complex daily activities and visuospatial abilities. A detailed history from an informant is usually necessary. MMSE may be used to test for clinical dementia. Patients should be referred to secondary care if any persistent, deteriorating cognitive impairment or clinical dementia is suspected.

b) Rating scale

There are several useful rating scales available for characterizing subjects along a continuum from normal ageing through various stages of dementia.¹¹

Clinical Dementia Rating (CDR)^12,13 is a popular scale used to classify subjects along a continuum from normal ageing (CDR 0) to severe AD (CDR 3). The clinician uses this scale to interview the patient and family, assigns a severity score to each of six CDR subcategories (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal hygiene). Standard scoring rules are then applied. MCI patients would have a score of 0.5 with or without evidence of mild functional decline. Details on the application of this tool and the training needed can be found in the following website:http://alzheimer.wustl.edu/cdr/PDFs/downloadselectionpage.htm.

Global Deterioration Scale (GDS)¹⁴ stages subjects from GDS 1 (normal) to GDS 7 (severe dementia), while those with MCI would correspond to a GDS of 2 or 3. However, the amnestic form of MCI does not map to a specific stage of this rating scale, thereby justifying a separate terminology.

c)Neuropsychological tests

A wide range of cognitive functions including memory, attention, language, visuospatial skill, perceptual speed and executive functioning can be used for assessment. The clinical psychologist and psychiatrist may use more sophisticated tests such as verbal list learning and memory, nonverbal memory, orientation (items from the Mini-Mental State Examination), verbal reasoning, nonverbal reasoning, naming, letter fluency, category fluency (animals, food and clothing), repetition, auditory comprehension, visuoconstruction (drawing test) and visuoperceptual skills (matching figures). The subtlety of any change may be ascertained by repeating the evaluation one year later.

Prospective studies on people with amnestic MCI have shown that episodic memory, semantic memory, attention processing and mental speed can consistently predict which patients will develop dementia. Similarly, in a retrospective study of people with MCI who developed AD, verbal and visual memory, associative learning, vocabulary, executive function and other verbal tests of general intelligence were impaired at baseline.⁸ One has to understand that the performance of these tests isaffected by many factors, including education, age, cultural background and illnesses other than AD. These neuropsychological tests in combination with clinical judgement, if interpreted properly, can provide useful and valuable information for screening and diagnosis of MCI.

d) Neuroimaging

Brain imaging has an important role in identifying specific and treatable causes of cognitive decline e.g. subdural haematoma, brain tumour, and predicting probability of development of dementia.

Longitudinal studies have shown that decreased entorhinal cortex and hippocampal volume can predict development of AD in MCI patients. Whole-brain, hippocampal and entorhinal-cortex atrophy assessed by MRI were found more common among patients with amnestic MCI who went on to convert to AD compared to non-converters.¹ However, these findings are not specific enough for the diagnosis of MCI.

The rate of hippocampal atrophy for control subjects and for patients who convert to MCI or from MCI to AD are comparable, suggesting that MCI may be a transitional stage before developing AD.¹⁵

e) Functional imaging

There is evidence that deficits in regional cerebral blood flow as measured by SPECT and regional cerebral glucose metabolism as measured by FDG-PET can predict the future development of AD in patients with MCI.¹

f) Neuropathology

As reported in a few longitudinal studies, most patients with amnestic MCI demonstrated neurofibrillary pathological changes in the median temporal lobe which could possibly contribute to the memory development while others were found to have non-AD pathological conditions. However, it is obvious that neuropathology cannot be used as a bedside diagnostic tool for MCI.

g) Biomarkers

There are few studies investigating the presence of biomarkers in MCI. Certain CSF markers including total tau, phospho tau and 42 amino acid form of B-amyloid may help in differentiating early and incipient AD from normal ageing.

Longitudinal studies¹⁶ have demonstrated that nearly all the MCI patients who convert to AD have a high CSF tau values, whereas in non-progressive MCI, tau levels remain low. This implies that biomarkers might be a useful tool in predicting the prognosis and assessing the usefulness of treatment interventions. However, acceptance by the patient of the need for an invasive procedure (lumbar puncture) and the lack of normative data on changes of these CSF markers with age pose another problem in its application.

h) Genetics

There are no major genes known to be involved in MCI. As different genes could underlie the different aetiologies of MCI, it seems MCI is a genetically complex condition. A few studies have suggested that the APO e4 allele is associated with a greater likelihood of MCI progressing to dementia, but more studies are needed to determine if genetics is a risk factor of MCI.⁹

Treatment

At the primary care level, it is important to provide education on healthy lifestyle, encourage the elderly to engage in cognitive leisure activities (e.g. mah-jong, reading, playing musical instrument and dancing) after excluding treatable causes of cognitive dysfunction. Family physicians should aim at optimizing the treatment of vascular risk factors such as hypertension, diabetes mellitus and hyperlipidaemia, which are also risk factors for AD in the management of MCI. They should also provide appropriate counselling and give continual support for the family.

So far there is a lack of good evidence on the long-term efficacy of pharmacological treatments. Currently, there are ongoing MCI clinical trials focusing on subjects with amnestic MCI. The endpoints for these trials are improvement of symptoms, slowing down the rate of progression and delaying a clinical milestone. The agents used in these studies¹¹ include cholinesterase inhibitors, anti-oxidants, anti-inflammatory agents, glutamine receptor modulators and gingko biloba.

While these trials are underway, treatments should not be prescribed based on current speculations until confirmations from well-designed clinical trials are available.

Ethical issues

The concept of MCI raises some ethical issues. Labeling patients as suffering from MCI will result in both psychological and psychosocial consequences. It is questionable whether the benefits of establishing the entity of MCI outweigh the risks to these patients. Investigators and clinicians must develop sufficient data to verify that MCI is a valid pathological condition. Clinicians should also realize that making an accurate diagnosis is the key element in the practice of medicine for the patient's best interest.¹¹ Counselling should be offered on the expectations of this condition.

Conclusion

MCI, the borderline state between normal ageing and dementia, has received increasing attention because of its increased risk of developing AD. Accurate identification of MCI might enable early therapeutic interventions to palliate substantially, if not reverse, the significant emotional and economic costs of the illness. When encountering patients with memory complaints, primary care physicians should not reassure patients lightly as normal ageing. It is important to compare the patient's condition with elders of the same age. Further clinical evaluation and use of rating scales may be employed. Awareness of this pre-dementia condition can prompt the patient to have regular surveillance and an early initiation of treatment whenevidence of dementia is present.

At present, it is reasonable to test for MCI in patients with memory complaint, but it is not appropriate to screen asymptomatic individuals until proven treatment and benefits are demonstrated.

WTo facilitate research, guidelines on assessment and diagnosis of MCI require standardization before they can be adopted into clinical practice. A combination of clinical evaluation, neuropsychological tests, structural and functional imaging and measurement of biomarkers would certainly provide useful information towards the refinement of the concept and treatment of MCI in the future.

Key messages

1. It is important to differentiate between normal and pathological ageing.
2. MCI is a clinical syndrome in which there is a mild impairment or relative decline of cognitive function and yet no major repercussions on daily activities.
3. Once the syndrome of MCI is recognized, the subtypes of MCI and their aetiopathogenic subtypes should be determined.
4. While there is no approved pharmacotherapies for MCI, counselling and advice on life style modification should be given.