Mild Cognitive Impairment

Memory loss is a feature of normal ageing. In a British epidemiological study the prevalence of age associated memory impairment in the 50 years age group was estimated to be 18⋅5 %.¹ About 15–20% of adults aged 80 years and above are known to suffer from dementia, the most common form being Alzheimer’s disease (AD). A transitional stage between normal age associated cognitive impairment and fully developed clinical features of dementia is termed Mild Cognitive Impairment (MCI).² The prevalence of MCI increases with age.² The term MCI was coined in the late 1980s by The New York University Group to identify individuals who were not cognitively normal for age and yet did not have overt dementia.³

The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently the construct of MCI has been proposed to designate this early yet, abnormal state of cognitive functioning. MCI has generated a great deal of research from both the clinical and research perspectives.⁴ Several epidemiological studies have documented accelerated rate of progression to dementia in MCI subjects.

Epidemiology of Mild Cognitive Impairment

Prevalence estimates of MCI vary widely dependent on the population studied and diagnostic criteria applied. It ranges from 3 to 53% and is generally twice that of dementia.^5,6 The National Health and Retirement Study in America found that 22% of adults older than 71 years had cognitive impairment that did not reach the threshold for dementia.⁷ Another US study, The Cardiovascular Cognition study, established that the prevalence rate of MCI increases with age from 19% in younger than 75 years to 29% in those older than 85 years.⁸ Incidence rates of MCI in patients who are older than 75 years are estimated at 1%–1⋅5% annually.

Risk factors for Mild Cognitive Impairment

Higher age, the presence of at least one Apo E ε4 allele and medicated hypertension are independent risk factors for MCI.¹⁰ MCI is also associated with increased levels of glycosylated haemoglobin levels supporting the hypothesis that glucose dysregulation predisposes to MCI.¹¹ The risk of developing cognitive impairment among older adults with impaired fasting glucose and diabetes increases by almost two-fold.¹²

Among older persons without manifest cognitive impairment, a higher level of chronic psychological distress was associated with an increased incidence of MCI. Wilson et al¹³ showed that for each one unit increase on the distress scale the risk of MCI increased by about 2%. This association was slightly stronger in men than women.

Depressive symptoms were also related to the risk of MCI but not after controlling the distress score.¹³ In addition, in a population-based study it was found that men and women have different risk profiles for MCI. Men with MCI were more likely to have higher BMI, diabetes and stroke, whereas, women were more likely to have poor subjective health, to be disabled, socially isolated and to suffer from insomnia.¹⁴

Ethnic minority status (like African-Americans), low education level, cortical atrophy and MRI (Magnetic Resonance Imaging) identified infarcts and the presence of cerebrovascular disease are all associated with increased amnestic type of MCI.⁹ Factors associated with increased risk of MCI are listed in Box 1.

Box 1: Risk factors for developing MCI Genetic: Apo E ε4 allele, family history, increasing age, race Cardiovascular: Diabetes, hypertension, abnormal fasting glucose, abnormal glycosylated haemoglobin, high BMI Cerebrovascular: Stroke, cortical atrophy, strokes and infarcts Psychosocial: Low education level, chronic psychological distress, depression and social isolation Others: Insomnia, anti-cholinergic medication and vitamin

Definition, diagnostic criteria and classification of Mild Cognitive Impairment

The earlier definitions and diagnostic criteria of MCI were predominantly memory focused. Various nomenclatures, like CIND—cognitive impairment not dementia, benign senescent forgetfulness, age-associated memory impairment (AAMI) and age-associated cognitive decline (AACD) were used interchangeably.¹⁵ Since the formation of the International Working Group and the development of consensus on nomenclature and diagnostic criteria, the term Mild Cognitive Impairment is being used universally to represent the clinical condition between normal ageing and dementia in which individuals experience cognitive problems to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable dementia.^4,16

The proposed diagnostic criteria (Box 2) have been validated and operationalised to identify the patients in an at-risk group. It has been demonstrated in a multi-centre clinical trial that successful implementation of operational criteria are possible and MCI can be distinguished from normal ageing and dementia.¹⁷ Despite some agreement in general definitions, MCI is still a heterogeneous clinical syndrome for which no DSM-IV criteria have yet been established. Criteria by Peterson et al (Box 2) are presently the most applied in clinical practice.^18,19,20

Box 2: Criteria for identification of MCI, given by the Working Group of the European Consortium on Alzheimer’s disease.19 Diagnostic criteria for Mild Cognitive Impairment: Cognitive complaints by the patient, family or both Report by the subject or family of a decline in cognitive or functional performance relative to previous abilities Cognitive disorder evident by clinical evaluation, impairment in memory or other cognitive domain Cognitive impairment without any repercussions on daily life even if the subject reports difficulties concerning complex daily activities No dementia

Classification of Mild Cognitive Impairment

The main cognitive domain often impaired in MCI is memory (amnestic domain). However, cognitive domains other than memory, like executive functions, language etc can also be affected. Depending on the nature and extent of cognitive domains impaired, four clinical subtypes of MCI have been identified.

Amnestic MCI is the most studied of all subtypes and is frequently a prodrome to AD.²¹ Non amnestic type of MCI is as frequent as the amnestic MCI. MCI single domain is more frequent than MCI involving multiple domains.²²

Box 3 provides information, that should help distinguish MCI from normal ageing and early dementia, which are the most commonly encountered differentials in clinical practice.

Box 3: Differential diagnosis of MCI Diagnostic criteria for Mild Cognitive Impairment Age associated cognitive impairment Early dementia Depression with cognitive impairment Delirium Organic causes: Metabolic abnormalities–glucose and electrolyte imbalance Endocrine problems–hypothyroidism CNS infections–post encephalitis syndrome Vitamin deficiency–B12 and Folate deficiency Post concussion syndrome

Treatment

Pharmacological interventions

Cholinesterase inhibitors

Cholinesterase inhibitors have been tried in MCI because of the effect these medications show in AD. Two large trials^23,24 of donepezil did not report any significant difference between the treatment and placebo group in progression to AD. Effect of rivastigmine on progression to AD was studied by Feldman H et al²⁵ in a double blind randomised controlled trial. Though there was a small numerical advantage in slowing the progression, this did not reach significance. Clearly there were no benefits on global, functional, neuropsychiatric outcomes and in quality of life measures.

Trials by Dekosky et al²⁶ and Winblad et al²⁷ found no significant treatment effect of galantamine in terms of symptomatic improvement or delay in the rate of progression to AD. In the light of current research there is insufficient evidence to suggest the use of cholinesterase inhibitors in MCI and so cannot be recommended. One hypothesis against using cholinesterase inhibitors is that there are reports of up regulation of cholinergic receptors in MCI.

Vitamin E

Vitamin E functions as a scavenger for different free radicals and works as an antioxidant. In a large randomised controlled trial,²⁴ over a three-year period, there were no significant differences in the probability of progression to AD between the vitamin E and placebo group. A few differences in cognitive functions from baseline were found.

Dopaminergic agonists

The ageing brain is accompanied by a reduction in central dopaminergic receptors, which correlate with general cognitive performance. In one very small RCT,²⁸ piribedil, a dopamine agonist, was studied for treatment of MCI and it showed improvement in global cognitive functions after three months. This finding has not been replicated again.

Acetylcarnitine [ALC]

Acetylcarnitine is described as agonist on mitochondrial function, neuronal growth factor and has antioxidant effects. A metanalysis of 21 double blind placebo-controlled trials by Montgomery et al in 2003 found a significant advantage for ALC compared to placebo in improving global cognitive and memory scores. ALC was well tolerated without any major side effects. However, the studies involved a heterogeneous population and included studies over a 20-year period of time during which the concept and treatment for MCI has changed significantly. It is difficult to draw meaningful conclusions from this study.

Anti-inflammatory agents

The outcomes of the trials investigating the benefit of NSAIDs (indomethacin²⁹ and diclofenac30) and COX-2 inhibitors (rofecoxib or celecoxib) failed to show any effect of treatment or the progression to AD.31,32

Melatonin

Two small sized retrospective studies have shown that melatonin can improve sleep, mood and memory³³ and performance in neuropsychological tests.³⁴ The neurobiological effect of melatonin apart from the sleep–wake cycle is yet to be proved convincingly.

Trans cranial magnetic stimulation (rTMS)

In a small scale study³⁵ rTMS induced transient improvement in associative memory in patients with MCI, but this has not been replicated in any further large scale RCTs. The potential effect of rTMS to recruit compensatory networks during the memory encoding process was postulated to improve and influence cognitive functions in MCI.

Box 4: Differentiation between MCI, dementia and age related cognitive impairment
	Cognitive impairment	Instrumental functions	Daily functioning	Neurophysiological testing
MCI	Mild	Preserved and may have mild impairment of complex instrumental activities	Normal	Scores slightly below the percentile expected for age but above those of dementia
Early dementia	Global and progressive cognitive impairment	Impaired	Affected	Scores within the range of dementia
Age associated cognitive impairment (normal ageing)	Mild	Preserved	Unaffected	Scores within the normal percentile for age

Nonpharmacological methods

Cognitive training interventions

Rapp et al³⁶ compared memory intervention (memory enhancement treatment), which included 6 weekly sessions [one general education and five sessions of memory skills teaching that included education about memory loss, relaxation training, memory skills training, cognitive restructuring for memory related beliefs] against no treatment and found no significant difference between the groups at six months but an improvement in word list recall.

Gunther et al, 2003,³⁷ tested a computer assisted cognitive training programme in which the author reported positive results on episodic and working memory after 14 sessions that persisted five months after the completion of training. This study did not include a control group. Two studies published the efficacy of a computerised intervention programme in MCI38-39 which involved exercise covering a broad range of capabilities including memory, perception, attention, language and the group which had cognitive training and cholinesterases together improved on the memory test scores and problem-solving tasks.

Belleville et al, 2006,⁴⁰ studied multi factorial cognitive intervention on 21 participants with MCI, with eight subjects as control group. The intervention included teaching on episodic memory encoding strategies, semantic knowledge, retraining in executive control, cognitive speed and visual imagery. The study reported significant benefits in objective measures like episodic memory, subjective memory measures and general well being.

The role of different cognitive training methods appears to have some positive effects in subjective memory complaints, episodic memory, and general wellbeing, but yet to be convincingly replicated in large studies. Additional trials are needed to prove the efficacy of these interventions alone or in combination with medication management.

Physical exercise

There have been studies suggesting that physical activity has on neuroprotective effect on later life cognition. Colcombe and Kramer et al⁴¹ did a metanalysis of fitness training effect on cognitive function of non demented older adults and found a positive influence on cognition including executive control processes. Ishizaki et al⁴² did a prospective study of psychosocial intervention in the form of attendance at a day centre set up once a week for six months for very mild AD and found improvement in MMSE scores and digit span in the intervention group. So far, the effects of aerobic exercise on progression to AD have been inconclusive but still some centres do advise 30–45 minutes aerobic exercise three times a week in MCI.

Future prospects

New targets for treatment for MCI would be on agents, that modify the disease process such as tau or Aβ and also antagonising indirect toxic mechanism on neurons. Future trials would involve gamma secretase inhibitors, active or passive immunisation which favour Aβ peptide clearance and Aβ aggregation inhibitors to modify/delay the progression of MCI to AD.

Conclusion

MCI is a heterogeneous disorder that can be reliably diagnosed using standardised criteria. The exact aetiology of this disorder is yet to be proven convincingly. Various treatment modalities have been tried over number of years without much benefit in slowing down or preventing progression to dementia. Current management should focus on some lifestyle modifications, treating vascular risk factors, psycho-education and regular follow up assessments. Disease modifying treatment for MCI would much depend upon the progress in dementia research and further trials to prove efficacy and cost effectiveness in MCI.

Conflict of interest: none declared

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Authors

• Ashok Krishnamoorthy, Specialist Registrar in Psychiatry, Sir Douglas Crawford Unit, Mossley Hill Hospital, Park Avenue, Liverpool. Email: [email protected]
• Dr Archana Jauhari, ST5 in Psychiatry, Deeside CMHT, Aston House, Deeside Community Hospital, Plough Lane, Aston, Deeside, Flintshire
• Dr M Krishna, Consultant in Old Age Psychiatry, Honorary Lecturer, University of Chester, Deeside CMHTE, Aston House, Deeside, Flintshire