key: cord-0992809-by6efyxi
authors: McGrattan, Andrea M.; Pakpahan, Eduwin; Siervo, Mario; Mohan, Devi; Reidpath, Daniel D.; Prina, Matthew; Allotey, Pascale; Zhu, Yueping; Shulin, Chen; Yates, Jennifer; Paddick, Stella‐Maria; Robinson, Louise; Stephan, Blossom C. M.
title: Risk of conversion from mild cognitive impairment to dementia in low‐ and middle‐income countries: A systematic review and meta‐analysis
date: 2022-03-13
journal: Alzheimers Dement (N Y)
DOI: 10.1002/trc2.12267
sha: 57721816c8b76e7d1d74857a2325247065f8293c
doc_id: 992809
cord_uid: by6efyxi

INTRODUCTION: With no treatment for dementia, there is a need to identify high risk cases to focus preventive strategies, particularly in low‐ and middle‐income countries (LMICs) where the burden of dementia is greatest. We evaluated the risk of conversion from mild cognitive ompairment (MCI) to dementia in LMICs. METHODS: Medline, Embase, PsycINFO, and Scopus were searched from inception until June 30, 2020. The search was restricted to observational studies, conducted in population‐based samples, with at least 1 year follow‐up. There was no restriction on the definition of MCI used as long as it was clearly defined. PROSPERO registration: CRD42019130958. RESULTS: Ten thousand six hundred forty‐seven articles were screened; n = 11 retained. Of the 11 studies, most were conducted in China (n = 7 studies), with only two studies from countries classified as low income. A qualitative analysis of n = 11 studies showed that similar to high‐income countries the conversion rate to dementia from MCI was variable (range 6 [Formula: see text] 0%–44 [Formula: see text] 8%; average follow‐up 3 [Formula: see text] 7 years [standard deviation = 1 [Formula: see text] 2]). A meta‐analysis of studies using Petersen criteria (n = 6 studies), found a pooled conversion rate to Alzheimer's disease (AD) of 23 [Formula: see text] 8% (95% confidence interval = 15 [Formula: see text] 4%–33.4%); approximately one in four people with MCI were at risk of AD in LMICs (over 3 [Formula: see text] 0–5 [Formula: see text] 8 years follow‐up). Risk factors for conversion from MCI to dementia included demographic (e.g., age) and health (e.g., cardio‐metabolic disease) variables. CONCLUSIONS: MCI is associated with high, but variable, conversion to dementia in LMICs and may be influenced by demographic and health factors. There is a notable absence of data from low‐income settings and countries outside of China. This highlights the urgent need for research investment into aging and dementia in LMIC settings. Being able to identify those individuals with cognitive impairment who are at highest risk of dementia in LMICs is necessary for the development of risk reduction strategies that are contextualized to these unique settings.

A meta-analysis of studies using Petersen criteria (n = 6 studies), found a pooled conversion rate to Alzheimer's disease (AD) of 23.8% (95% confidence interval = 15.4%-33.4%); approximately one in four people with MCI were at risk of AD in LMICs (over 3.0-5.8 years follow-up). Risk factors for conversion from MCI to dementia included demographic (e.g., age) and health (e.g., cardio-metabolic disease) variables.

Conclusions: MCI is associated with high, but variable, conversion to dementia in LMICs and may be influenced by demographic and health factors. There is a notable absence of data from low-income settings and countries outside of China. This highlights the urgent need for research investment into aging and dementia in LMIC settings. Being able to identify those individuals with cognitive impairment who are at highest risk of dementia in LMICs is necessary for the development of risk reduction strategies that are contextualized to these unique settings. annually). [5] [6] [7] Although some cases remain stable, others can revert to normal, with studies suggesting reversion ranges of 4% to 15% in clinicbased samples [8] [9] [10] [11] and 29% to 55% in population-based samples. [12] [13] [14] [15] In the absence of a cure for dementia, understanding the likelihood of, and risk factors associated with, conversion to dementia among MCI cases is important to help identify strategies for dementia risk reduction and prevention. 16 The definition of MCI can be a difficult concept to disentangle.

One of the most widely applied set of criteria, in clinical and research practice, are those defined by Petersen et al., describing patients with subjective memory loss verified by neuropsychological testing, with no significant impairment in other cognitive domains, no functional impairments, and no dementia. 17 Other similar criteria have also been developed and applied including, for example, from the International Working Group, 18 National Institute on Aging-Alzheimer's Association (NIA-AA), 19 

This systematic review and meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Appendix A.1 in supporting information). 27 The study protocol was registered on the PROSPERO database (registration number CRD42019130958). 

Two reviewers independently assessed potentially relevant articles for eligibility (AMM and EP). The decision to include or exclude studies was hierarchical and initially made based on the study title and abstract to eliminate obviously irrelevant studies (see Figure 1 ). When a study's title/abstract could not be rejected with certainty, the full text of the article was obtained for evaluation. Discrepancies between reviewers were resolved by a third reviewer (BCMS). Next, full-text articles were searched. In addition, the reference lists of all included articles were checked for any potentially missing papers. to dementia in population-or community-based studies from low and middle-income countries (LMICs).

The search strategy included terms that encompassed "dementia," "mild cognitive impairment," "incidence," and "conversion. population-based data, to determine the best strategies for identifying those individuals at highest dementia risk to inform the development of dementia risk reduction plans in these settings.

A standardized form was used to extract data from the included studies for assessment of study quality and evidence synthesis. 

Quality assessment was guided by the Newcastle-Ottawa Scale for cohort studies. 33 Risk of bias was assessed on three main categories:

selection, comparability, and outcome. The maximum possible score was 8; three stars for selection, two stars for comparability, and two stars for outcome. Two authors (AMM and EP) independently assessed risk of bias, with any disagreement resolved by discussion with a third assessor if required.

For each study, we report the proportion of MCI cases that converted to dementia for each definition of MCI separately. This was calculated as the ratio of those who converted to dementia over the total sample size. We also report on the key risk factors significantly associated with an increased risk of dementia.

Details of all risk factors assessed are in Table S2 in supporting information.

Where there were multiple studies using the same criteria to diagnosis MCI and dementia, a meta-analysis was undertaken. This was only possible for studies that diagnosed MCI using Petersen-type criteria with an outcome of AD (n = 6 studies). The analysis was run in Stata using the Metaprop command to compute the meta-analysis of pooled proportions. This allows computation of 95% confidence intervals (95% CI) using the score statistic and the exact binomial method and incorporates the Freeman-Tukey double arcsine transformation of proportions to compute the weighted pooled estimate for normality assumptions. The program also allows the within-study variability to be modeled using the binomial distribution. 34 Given large differences in the design and sampling across studies, the random effects model was computed. Heterogeneity was assessed using the I 2 statistic.

From the electronic search, the titles and abstracts of 8977 publications were screened, and the full texts of 87 articles reviewed. The screening and study selection process is illustrated in the PRISMA flow diagram ( Figure 1 ). Nine articles met the eligibility criteria. The most common reasons for exclusion were that the study was not from a LMIC, the sample was not population-based, and the study did not report incident dementia. A second search conducted in June 2020

identified a further 1670 articles, from which two studies were eligible for inclusion. Thus, 11 articles are included in this review.

Of the 11 studies, most were conducted in China (n = 7 studies), [35] [36] [37] [38] [39] [40] [41] followed by Brazil (n = 2 studies), 42, 43 Nigeria (n = 1 study 44 ), 44 and Tanzania (n = 1 study). 45 Only one study was nationally representative using census data from Rio Grande do Sul, Brazil. 42 year). At follow-up, MCI sample size ranged from n = 21 42 to n = 638, 35 with a mean of n = 298 (SD = 238).

Most studies diagnosed MCI using Petersen criteria 17,28,46,47 (n = 5 studies). 35, 36, 38, 40, 41 Other criteria included the Clinical Dementia Rating scale (CDR 0.5; 48 n = 1 study), 43 Dubois 2004 criteria 49 (n = 1 study), 42 the criteria from the DSM-IV 31 (n = 2 studies), 37,39 and the International Working Group on MCI criteria 18 (n = 1 study). 45 Only 1 study 44 used the Cognitive Impairment No Dementia (CIND) classification. 50 This paper 44 reports that of the n = 87 CIND participants, n = 74 were classed as having "medically unexplained memory loss" (MUML) described as comparable to MCI using Petersen criteria. 51 For this review, the total sample of n = 87 CIND participants

were included. Table 1 shows a description of the MCI diagnostic criteria used across the different studies. The majority of studies classified participants as MCI (n = 9 studies), [35] [36] [37] [38] [40] [41] [42] [43] 45 while others subtyped MCI into amnestic MCI (aMCI; n = 2 studies), 39 

Most studies (n = 7 studies) 35 (n = 8 studies), [35] [36] [37] [38] [39] [40] 42, 45 or vascular dementia (VaD; n = 2 studies). 36, 45 One study 44 mentioned using International Classification of Diseases (ICD)-10 criteria from the World Health Organization. 53

Rates of conversion from MCI to dementia ranged from 6.0% 39 CIND (n = 1 study), 44 and CDR (n = 1 study) 43 Table S2 .

Full details of the risk of bias assessment can be found in Table S3 in supporting information. The included studies averaged 7.3 stars out of 10 (range [5] [6] [7] [8] . Eight studies (out of 11) scored the maximum of eight stars.

Six studies were included in the meta-analysis; n = 4 from China 35, 36, 38, 40 and n = 1 each from Tanzania 45 and Brazil. 42 Across the six studies, MCI sample size ranged from n = 21 42 to n = 837 35 and age from > 55 years 35, 36 to > 70 years. 45 Figure 2 is a significant research gap particularly considering the high burden of cognitive impairment and dementia in low-income country settings. 25 Of the studies included in this review, there was also variability in terms of outcome measure (all-cause dementia vs. AD vs. VaD), length of follow-up, sample size, and diagnostic criteria for MCI. In addition, the examination of MCI conversion to other dementia subtypes was limited as only AD and VaD were investigated. Therefore, there is an urgent need for future studies to attempt to standardize the methodology used to allow for better cross-study comparisons, aiming for studies to be population representative and generalizable.

Studies from HICs estimate annual conversion from MCI (irrespective of MCI definition used) to dementia at approximately 3% to 10% in community settings and 10% to 15% in clinical settings. 5, [16] [17] [18] 54 Similar to findings from HCIs, conversion rates were found to be variable across the different LMICs sites ranging from 6.0% to 44.8%. Rates of conversion to dementia were generally higher for those definitions that capture broader impairment (e.g., range of conversion for all-MCI, CIND, and CDR: range 16.8% to 44.8% over 2.0-5.8 years follow-up) compared to more restricted definitions of single domain MCI (e.g., aMCI range 6.0% to 6.9% over an average of 3.5 years follow-up). [55] [56] [57] [58] [59] [60] [61] Given the high reported prevalence of MCI in LMIC settings 4 in addition to the high dementia conversion rates reported here, the development of strategies to prevent or delay dementia progression in those individuals with cognitive impairment could have a significant impact on the burden of disease associated with mental health conditions in these settings.

Similar to findings from HICs, non-modifiable risk factors for progression to dementia from MCI included age [62] [63] [64] [65] and APOE ε4 allele status. 51, 66, 67 Regarding sex, while being female has been found to be associated with increased risk of prevalent MCI, 4 and has been associated with higher risk of progression to dementia in HICs, 68 only 2 studies 38,44 out of 10 that investigated sex effects found that being female was a risk factor for conversion from MCI to dementia.

Research evidence, predominantly from HICs, suggests a putative link between sex and/or educational attainment and cognition. [69] [70] [71] [72] However, methodological weaknesses and potential of reverse causality within these studies adds limitations to their interpretation and warrants longitudinal studies with longer follow-up. 71 Furthermore, key modifiable risk factors were also similar to those reported in HIC settings, including poor cardiometabolic health, the presence of vascular risk factors, and poor neuro-psychiatric health such as the presence of depression. 23, 62, 73 Targeting these factors could be an early strategy for not only preventing MCI, but also reducing the burden of dementia. Research evidence suggests that up to 40% of dementia cases may be preventable through targeting 12 modifiable risk factors, 74 many of which can be influenced by diet and lifestyle practices. 75, 76 Emerging evidence also indicates that non-pharmacological interventions such as cognitive training may reduce dementia risk. 77 There is an urgent need for research investment into robust, population-representative studies focused on risk of cognitive impairment and dementia in LMICs using harmonized methodology. 78 This is necessary to make it possible to campaign for prioritization of funding toward cognitive screening and risk reduction. This would also allow investment in better education and development of infrastructure in these settings to improve knowledge of diagnosis and risk factor management, but also facilitate the implementation of more population representative, robust studies, particularly in countries of low income. Care. 

This systematic review was registered via Prospero; PROSPERO registration number: CRD42019130958. A copy of the systematic review protocol is available on request and can be provided by the corresponding author. Requests for access to the data reported in this article will be considered by the corresponding author.

Mild cognitive impairment: a concept in evolution

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

The Prevalence of mild cognitive impairment in China: a systematic review

Prevalence and risk of mild cognitive impairment in low and middle-income countries: a systematic review

Progression of mild cognitive impairment to dementia in clinic-vs community-based cohorts

Rate of progression of mild cognitive impairment to dementia -meta-analysis of 41 robust inception cohort studies

Medical Research Council Cognitive Function and Ageing Study. Two-year progression from mild cognitive impairment to dementia: to what extent do different definitions agree?

Stability and predictability of the classification of mild cognitive impairment as assessed by episodic memory test performance over time

Twoyear outcome of MCI subtypes and aetiologies in the Goteborg MCI study

Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study

Are subjective cognitive complaints a risk factor for dementia?

Incidence and outcome of mild cognitive impairment in a population-based prospective cohort

Mild cognitive impairment, amnestic type: an epidemiologic study

Outcomes of mild cognitive impairment by definition: a population study

Variations in case definition affect prevalence but not outcomes of mild cognitive impairment

Is MCI really just early dementia? A systematic review of conversion studies

Mild cognitive impairment: clinical characterization and outcome

Mild cognitive impairmentbeyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment

The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

American Psychiatric Association. Diagnostic and statistical manual of mental disorders

Different subpopulations of mild cognitive impairment are identified by using Petersen's or DSM-5 criteria

Evolution and future directions for the concept of mild cognitive impairment

Dementia prevention, intervention, and care

Risk factors for the progression of mild cognitive impairment to dementia

The global impact of dementia. An analysis of prevalence, incidence, cost and trends. London: Alzheimer's Disease International

Dementia in low-income and middle-income countries: different realities mandate tailored solutions

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review)

Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer's Disease

Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

DSM-IV: diagnostic and statistical manual of mental disorders

Vascular dementia: Diagnostic criteria for research studies: Report of the NINDS-AIREN International Workshop

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis

Metaprop: a Stata command to perform meta-analysis of binomial data

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease

Progression of mild cognitive impairment to Alzheimer's or vascular dementia versus normative aging among elderly Chinese

Incidence rate of mild cognitive impairment and the conversion rates into dementia or Alzheimer disease among elderly people: a population-based cohort study

Multi-state Markov model in outcome of mild cognitive impairments among community elderly residents in Mainland China

A threeyear follow-up study on the transfer of mild cognitive impairment to Alzheimer's disease among the elderly in Taiyuan city

Neuropsychiatric symptoms and risk factors in mild cognitive impairment: a cohort investigation of elderly patients

Progression and predictors of mild cognitive impairment in Chinese elderly: a prospective follow-up in the Shanghai Aging Study

Estimation of the risk of conversion of mild cognitive impairment of Alzheimer type to Alzheimer's disease in a south Brazilian population-based elderly cohort: the PALA study

Clinical Dementia Rating independently predicted conversion to dementia in a cohort of urban elderly in Brazil

Cognitive impairment in community-dwelling older Nigerians: clinical correlates and stability of diagnosis

Mild cognitive impairment in rural Tanzania: prevalence, profile, and outcomes at 4-year follow-up

Mild cognitive impairment as a clinical entity and treatment target

Aging, memory, and mild cognitive impairment

A new clinical scale for the staging of dementia

Amnestic MCI or prodromal Alzheimer's disease?

Working Party of the International Psychogeriatric Association in collaboration with the World Health Organization

Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals

Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria

The international classification of WHO diseases (ICD-10) and its application in neurology (ICD-10 NA)

Rate of conversion from prodromal Alzheimer's disease to Alzheimer's dementia: a systematic review of the literature

The risk of incident mild cognitive impairment and progression to dementia considering mild cognitive impairment subtypes. Dement Geriatr Cogn Dis Extra

Mild cognitive impairment: long-term course of four clinical subtypes

The validity of amnestic MCI and non-amnestic MCI at age 75 in the prediction of Alzheimer's dementia and vascular dementia

Subtype of mild cognitive impairment and progression to dementia and death

Predicting conversion to dementia in a memory clinic: a standard clinical approach compared with an empirically defined clustering method (latent profile analysis) for mild cognitive impairment subtyping

Twoyear outcome of MCI subtypes and aetiologies in the Göteborg MCI study

Neuropsychological measures predict decline to Alzheimer's dementia from mild cognitive impairment

Vascular risk factors, incidence of MCI, and rates of progression to dementia

The incidence of dementia: a meta-analysis

Frequency and course of mild cognitive impairment in a multiethnic community

Annual rate and predictors of conversion to dementia in subjects presenting mild cognitive impairment criteria defined according to a population-based study

The role of APOE-4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging

Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease

Marked gender differences in progression of mild cognitive impairment over 8 years

The association between educational level and dementia in rural Tanzania

The gender gap in education and late-life cognition: evidence from multiple countries and birth cohorts

Sex differences in dementia: on the potentially mediating effects of educational attainment and experiences of psychological distress

Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies

Rates and risk factors for progression to incident dementia vary by age in a population cohort

Dementia prevention, intervention, and care: 2020 report of the LancetCommission

Yannakoulia M. Nutrition and prevention of cognitive impairment

Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. WHO

Speed of processing training results in lower risk of dementia

How can population-based studies best be utilized to reduce the global impact of dementia? Recommendations for researchers, funders, and policymakers

Cohort profile: the 10/66 study

Harmonized cognitive assessment protocol (HCAP): study protocol summary

Current concepts in mild cognitive impairment

The clinical dementia rating (CDR)

Mild cognitive impairment1 -a review of prevalence, incidence and outcome according to current approaches

The prevalence of mild cognitive impairment about elderly population in China: a meta-analysis

Classification and epidemiology of MCI

Age-stratified prevalence of mild cognitive impairment and dementia in European Populations: a systematic review

Mild cognitive impairment: disparity of incidence and prevalence estimates

The prevalence and progression of mild cognitive impairment among clinic and community populations: a systematic review and meta-analysis

Risk of conversion from mild cognitive impairment (MCI) to dementia in low-and middle-income countries (LMICs): A systematic review and meta-analysis