DOI: 10.1111/ajag.12913 | Revised: 16 December 2020 | Accepted: 17 December 2020 INVITED ARTICLE Mild cognitive impairment: To diagnose or not to diagnose Kate N. Wang1,2,3 | Amy T. Page2,3,4 | Christopher D. Etherton- eer5 B 1 School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia 2 Pharmacy Department, Alfred Health, Melbourne, Victoria, Australia 3 Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia 4 School of Allied Health, University of Western Australia, Perth, Western Australia, Australia 5 Western Australian Centre for Health and Ageing, School of Medicine, University of Western Australia, Perth, Western Australia, Australia Correspondence Kate N. Wang, School of Health and Biomedical Sciences, RMIT University, Corner of Janefield Dr and Plenty Road, Bundoora, Victoria 3083, Australia. Email: kate.wang@rmit.edu.au Funding information National Health and Medical Research Council, Grant/Award Number: 1156892 Abstract Older people living with mild cognitive impairment (MCI) have a slight but noticeable decline in their cognitive function, though do not meet the diagnostic criteria for dementia. MCI is controversial, with some saying it is a condition that does not require diagnosis, and others stating that it is a genuine clinical syndrome. Many people with MCI will improve, and most will not progress to dementia. Managing co- orbidities and exercising are likely to be the best treatment options. With limited m evidence for effective interventions and uncertainty as to the prognostic value of the condition, the benefit of diagnosing MCI remains unclear. KEYWORDS diagnostics, mild cognitive impairment, older people, treatment 1 | IN T RO D U C T ION Mild cognitive impairment (MCI) is a decline in memory, language, thinking and judgement that is more severe than normal ageing but less so than diagnosed dementia.1 Older people living with MCI have a slight but noticeable decline in their cognitive function, although they do not meet the diagnostic criteria for dementia.2 Performance between 1 and 1.96 standard deviations below the normative mean in neuropsychological tests has been suggested as a criterion for defining MCI.3 The concept of MCI has provided clinicians with an intermediate diagnosis to identify people who may be at increased risk of progressing to dementia or Alzheimer's disease.2 However, one of the most challenging decisions for clinicians working with older persons is determining whether a potential physical or cognitive decline is a part of normal ageing or related to more complex issues such as dementia. Diagnosing MCI is controversial as some claim it is a condition that does not require diagnosis, and overdiagnosis can lead to unnecessary treatment or anxiety.4 Others conceptualise MCI as a genuine clinical syndrome and hope that identifying people with MCI will allow for early intervention to treat the underlying disease processes and prevent or postpone dementia onset.2 Currently, classifying and diagnosing MCI in a reliable manner in clinical practice (as opposed to research settings) may be difficult due to the lack of broadly agreed diagnostic criteria and variable methodologies to diagnose MCI, ranging from clinical judgement alone through to algorithmic scoring tools. 2 | EPIDEM IOLOGY Mild cognitive impairment is strongly associated with increasing age.1 Between 10 and 15% of people with MCI develop dementia each year, in comparison with 1%- % of the 3 1 general older people. A study of 81 people aged 55 years and over with MCI at baseline showed that 18.5% returned to normal cognitive function, 40.7% continued to meet criteria for MCI and 40.7% progressed to dementia after an average Australas J Ageing. 2021;00:1–5. wileyonlinelibrary.com/journal/ajag | © 2021 AJA Inc. 1
2 follow- p period of 2.2 years (Figure 1).5 This shows that u people with MCI have an increased risk of developing dementia in excess of people with normal cognitive function, even among people whose cognition returns to normal in the interim. In Australia, the Sydney Memory and Ageing Study has reported that 40.5% of men have MCIs compared to 33.7% of women.6 The same study also reported that up to 95.5% of participants reported some level of cognitive impairment at baseline.6 It has been suggested that people with amnestic MCI have a higher risk of Alzheimer's dementia, whereas people with non-mnestic MCI have a higher risk of non- lzheimer's a A dementia, due to differences in neuropsychological function and brain structure.7 It has been often debated by clinicians whether diagnosing amnestic or non- mnestic MCI is necesa sary, when less than half of these older persons develop more complex issues such as dementia and Alzheimer's disease. 3 | CAU SAL IT Y HY P OT HE S IS/ PAT H O P H YS IOLOGY Hypotheses that have been developed to explain cognitive decline associated with ageing lack consensus. The traditionally accepted theory of Alzheimer's disease process views the accumulation of amyloid- eta peptides as causally related to b the development of cognitive impairment. It is believed that this accumulation starts 15- 0 years before clinical symp2 toms appear and the subsequent progression to Alzheimer's disease.8 However, in the last two decades many trials of therapies targeting amyloid- eta accumulation have failed b to demonstrate improvement in cognitive measures between the treated and placebo groups.8 It has been suggested that the accumulation of amyloid- eta may instead be an adapb tive response to repair losses in neuronal functioning due to Alzheimer's disease.8 However, as the neuronal functions cannot be repaired, amyloid- eta accumulates and eventually b 8 leads to neurotoxicity. Recently, Nelson et al described a new disease entity called the limbic- redominant age- elated TDP- 3 encephap r 4 lopathy (LATE).9 LATE is a common TDP- 3 proteinopathy 4 that is associated with an amnestic dementia syndrome that mimics Alzheimer's disease in autopsy studies.9 These new findings further increase uncertainties about whether the pathology long thought to be the dominant cause of progressive cognitive decline in ageing (amyloid- eta peptide accumulab tion) is as dominant as historically thought. Furthermore, there are multiple reversible causes of cognitive impairment including alcohol and medication-elated r impairments, nutritional deficiencies (eg sodium, vitamin B12 or folate), and depression and thyroid disorders.10 If identified, these conditions can often be corrected, and cognitive impairment can improve. Despite the diagnosis of MCI WANG et al. Impact • Although MCI is a commonly used classification in research and clinical practice, it remains a contested clinical diagnosis. • Some people with MCI progress to develop dementia, while others may return to normal cognitive function. • Exercise shows promise as an effective treatment for MCI. as a prodromal stage of dementia remaining controversial, the assessment for and management of reversible causes of cognitive impairment remain important. There are also several risk factors that have been found to be associated with MCI, and studies have identified associations between MCI and a number of co- orbidities such as m depression, diabetes, obesity, dyslipidaemia, and other cardiovascular risk factors.11 There was also a U- haped assos ciation identified between sleep and developing MCI, with an average of seven hours of sleep a night associated with the lowest risk of developing MCI.12 Some co- orbidities m are more common for people with MCI. For example, an estimated one- third of people with MCI have co- orbid m depression.11 4 | DIAGNOSING M CI The criteria for diagnosing MCI have evolved over time. Currently, MCI is commonly diagnosed based on the combination of patient and clinician's judgement of the clinical symptoms. The original Mayo criteria required a self/ informant report on memory complaint, objective memory impairment (1.5 standard deviations below normal cognition after matching for age and education), essentially preserved cognitive function and preserved independence in functional abilities in people without dementia.2 However, more recent criteria focus on broader cognitive impairment, rather than memory impairment specifically. The diagnosing criteria include self-or informant-eported cognitive r complaints, objective cognitive impairment and preserved independence in functional abilities in people without dementia.2 One limitation of diagnosing MCI based on subjective clinical judgement is variability dependent on the clinicians’ experience and judgement. There is also a lack of consistent cut-off values to define objective cognitive impairment.2 Neuroimaging has been suggested for diagnosing MCI; however, the lack of standard imaging criteria and validation of this method of diagnosing MCI limit its regular
3 WANG et al. F I G U R E 1 Flow chart showing prognosis after mild cognitive impairment (MCI) diagnosis (adapted from Alexopoulos et al) use in a clinical setting. Magnetic resonance imaging (MRI) has also been used to diagnose MCI. Using the MRI, people with MCI had a reduced volume of the hippocampus, the amygdala and the entorhinal cortex compared to people with normal cognition.7 There are also several screening tools that have been used to identify MCI. The Montreal Cognitive Assessment (MoCA) and the Mini- ental State Examination (MMSE) M are both examples of such cognitive screening tools. Both tools aim to identify cognitive decline through a series of examinations such as orientation, learning new words, and recalling and naming items.13 A meta- nalysis comparing the a two screening tools found that the optimal cut- ff score of o 24/25 for identifying MCI in older people aged 60 or above using the MoCA produced 80% sensitivity and 81% specificity compared to 66% sensitivity and 73% specificity using an MMSE cut- ff score of 27/28.13 However, demographic o factors such as age, sex and education levels are strong predictors of the MoCA score and need to be considered when identifying MCI.13 Hence, the cognitive screening tools should be considered in combination with the patient's clinical symptoms. Currently, diagnosing MCI remains controversial. While some health-are professionals believe diagnosis MCI can c identify patients at higher risks of developing dementia, the current lack of a standardised approach could lead to negative clinical outcomes such as overtreatment or anxiety,4 which could lead to further worsening of cognition.14 Implementing standardised methods to diagnose MCI may be a more effective approach to ensure that MCI is diagnosed consistently and help clinicians to identify at- isk patients. r 5 | T R E AT ME N T O P T ION S 5.1 | Cognitive and social interventions There is currently no evidence to show that interventions addressing loneliness are effective in improving MCI. Activities that stimulate cognitive activity such as computerised cognitive training have been suggested to be beneficial for maintaining or improving cognitive function in a older people.15 A 2017 meta- nalysis found that computerised cognitive training interventions had moderate effects in improving global cognition, attention, memory and learning.15 The authors suggested that although there was limited follow- p duration, there seemed to be a rapid reversion to u baseline after the intervention ceased, suggesting that the invention could be effective in improving symptoms associated with MCI.15 5.2 | Physical interventions Exercise often makes a marked difference in improving health conditions by maintaining functional capacity and slowing disease progression. Exercise has been found to be effective in improving many aspects of cognitive function in people with MCI.16 A recent meta- nalysis found that mind- a body exercises such as yoga and tai- hi have a significant c effect on improving attention, short-erm memory, execut tive function, visual-patial/executive function and global s cognitive function, but not cognitive processing speed.16 In addition, aerobic exercises were also found to improve cognitive function in people with MCI.17 Improvement in other co- orbidities may result in an overall improvement m in quality of life and health outcomes for people with cognitive symptoms. Sleep disorder or sleep disturbance has been found to be associated with developing MCI.12 Although there is currently no evidence to suggest that altering sleep patterns affects prognosis, improving sleep may be a potential strategy to reduce risks of MCI among people with sleep disorders. 5.3 | Nutritional interventions There is some emerging evidence, which shows that nutritional supplements may be able to improve cognitive function in people with cognitive decline, although not specific to MCI. Souvenaid® is a nutritional supplement drink that contains eicosapentaenoic acid, docosahexaenoic acid, phospholipids, choline, uridine monophosphate, vitamin E, vitamin C, selenium, vitamin B12, vitamin B6 and folic acid.18 It has been suggested that Souvenaid® may improve memory in people with Alzheimer's disease.18 However, Souvenaid® has not been found to slow the progression from early to moderate or severe Alzheimer's disease. Combinations of vitamin B groups such as folic acid, vitamin B6 and vitamin B12 have been shown to reduce the rate of brain atrophy on MRI scans.19 However, a recent Cochrane review found very minimal differences in memory and thinking skills between the vitamin B combinations and placebo.20 Given the studies did not report on whether participants developed dementia, it remains unclear whether vitamin B supplementation will
4 WANG et al. have any meaningful clinical effect.20 Similarly, there is limited evidence that vitamin E in MCI alters either functional outcomes or prognosis.11,20 CONFLICTS OF INTEREST Christopher Etherton-eer is a Australasian Journal on B Ageing Editorial Board member. The other authors have no conflict of interest to declare. 5.4 | Controlling co-morbidities ORCID Kate N. Wang https://orcid.org/0000-0001-5208-1090 Christopher D. Etherton- eer https://orcid. B org/0000-0001-5148-0188 Effectively managing co- orbidities appears to be the most m practical approach to managing people with MCI. The management of co- orbidities is postulated to have cognitive m benefits and reduce or slow the progression to dementia.11 Therefore, it may be more important to determine common co- orbid conditions where people with MCI are at a greater m risk of progressing to dementia and Alzheimer's disease and only diagnosing and treating this group of people. An Australian study found that people with history of smoking had almost two times higher odds of developing MCI, and people taking depression medications over three times higher odds.14 Strategies to target these lifestyle factors are thus included as part of the approach to maintaining cognitive health.14 The pragmatic approach of controlling co- morbidities may not only improve cognition but also general well- eing and quality of life. b 6 | CO NC LU S ION S MCI is a contentious diagnosis with some clinicians doubting whether it is clinically relevant to identify the condition. While there is currently minimal research on consumer's perspective in making a MCI diagnosis, emerging research shows that under- iagnosis may be strategic in reducing unnecessary d or non- eneficial treatment.4 From patient's perspective, diagb nosing MCI can lead to outcomes such as anxiety or polypharmacy, in particular among people who already take multiple medications, have anxiety or multiple morbidities. Many of the interventions discussed in this paper, such as promoting physical and social activity, improving sleep and good nutrition, are low- ost and low-isk interventions, and anyone c r with subjective cognitive complaints, regardless of diagnosis, would benefit from this advice. There are currently no interventions that have been reliably demonstrated to alter the clinical outcomes and rate of progression for people with MCI, although exercise appears promising. With limited evidence for effective interventions and uncertainty as to the prognostic value of the condition, the benefit of diagnosing MCI remains unclear. Future studies should focus on developing a standardised method of MCI diagnosis that identifies people with MCI who are at high risk of developing dementia. ACKNOWLEDGEMENTS AP is supported by a NHMRC Early Career Fellowship (1156892). R E F E R E NC E S 1. Mild cognitive impairment (MCI). Mayo Foundation for Medical Education and Research. 2020. Available from: https://www. mayoclinic.org/diseases-conditions/mild-cognitive-impairment/ symptoms-causes/syc-20354578. Accessed 17/10/20. 2. Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L. Mild cognitive impairment: a concept in evolution. J Intern Med. 2014;275:214-228. 3. Jak AJ, Bondi MW, Delano- ood L, et al. Quantification of five W neuropsychological approaches to defining mild cognitive impairment. Am J Geriatr Psychiatry. 2009;17:368-375. 4. Page A, Etherton- eer C. Undiagnosing to prevent overprescribB ing. Maturitas. 2019;123:67-72. 5. Alexopoulos P, Grimmer T, Perneczky R, Domes G, Kurz A. Progression to dementia in clinical subtypes of mild cognitive impairment. Dement Geriatr Cogn Disord. 2006;22:27-34. 6. Ageing Centre for Healthy Brain Ageing. Sydney Memory and Ageing Study. School of Psychiatry: University of New South Wales; 2020. https://cheba.unsw.edu.au/research-projects/sydney- memory-and-ageing-study. Accessed 18/10/20. 7. Csukly G, Sirály E, Fodor Z, et al. The differentiation of amnestic type MCI from the non- mnestic types by structural MRI. Front a Aging Neurosci. 2016;8:52. 8. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid- - argeting therapies for Alzheimer disease. Nat βt Rev Neurol. 2019;15:73-88. 9. Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic- predominant age- elated TDP- 3 encephalopathy (LATE): consenr 4 sus working group report. 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