Prevalence and incidence of possible vascular dementia among Mexican older adults: Analysis of the Mexican Health and Aging Study.

INTRODUCTION: Vascular dementia is the second most common cause of dementia. Physical disability and cognitive impairment due to stroke are conditions that considerably affect quality of life. We estimated the prevalence and incidence of possible vascular dementia (PVD) in older adults using data from the Mexican Health and Aging Study (MHAS 2012 and 2015 waves).
METHODS: The MHAS is a representative longitudinal cohort study of Mexican adults aged ≥50 years. Data from 14, 893 participants from the 2012 cohort and 14,154 from the 2015 cohort were analyzed to estimate the prevalence and incidence of PVD. Self-respondents with history of stroke were classified as PVD if scores in two or more cognitive domains in the Cross-Cultural Cognitive Examination were ≥ 1.5 standard deviations below the mean on reference norms and if limitations in ≥ 1 instrumental activities of daily living were present. For proxy respondents with history of stroke, we used a score ≥3.4 on the Informant Questionnaire on Cognitive Decline in the Elderly. Crude and standardized rates of prevalent and incident PVD were estimated.
RESULTS: Prevalence of PVD was 0.6% (95% CI, 0.5-0.8) (0.5 with age and sex- standardization). Rates increased with age reaching 2.0% among those aged 80 and older and decreased with educational attainment. After 3.0 years of follow-up, 87 new cases of PVD represented an overall incident rate of 2.2 (95% CI, 1.7-2.6) per 1,000 person-years (2.0 with age and sex- standardization). Incidence also increased with advancing age reaching an overall rate of 9.4 (95% CI, 6.3-13.6) per 1,000 person-years for participants aged >80 years. Hypertension and depressive symptoms were strong predictors of incident PVD.
CONCLUSION: These data provide new estimates of PVD prevalence and incidence in the Mexican population. We found that PVD incidence increased with age. Males aged 80 years or older showed a greater incidence rate when compared to females, which is comparable to previous estimates from other studies.

Introduction

Vascular Cognitive Impairment (VCI) is the second most common cause of dementia, with 15% of dementia cases [1]. Post-stroke physical disability and cognitive impairment are conditions that considerably affect quality of life. [2]. When compared to Alzheimer’s disease (AD), individuals with vascular dementia (VaD) had a higher level of disability and considerably higher rates of cerebrovascular disease, congestive heart failure, hemiplegia, paraplegia, and myocardial infarction, thus increasing both the complexity and costs of management of the disease [3]. Moreover, patients with VaD have been found to have a higher relative risk of death (RR: 2.7, 95% CI, 1.9–3.9) when compared to AD (RR: 1.4, 95% CI, 1.2–1.7) [4]. Interventions that target potentially modifiable risk factors associated with VCI [5], such as minimizing diabetes, hypertension treatment, and avoiding midlife obesity, among others, have been proposed as a way of reducing dementia in low- and middle-income countries [6].

There has been a significant increase of stroke burden in the world especially in developing countries [7]. In addition, the number of people with dementia in Latin American countries is predicted to increase 4-fold in the next 30–35 years [8]. Globally, VaD prevalence estimates range between 0.9 and 3.3% (95% CI, 2.2–4.5) [9]. In developing countries, these estimates vary from 0.7 (95% CI, 0.1–1.3) to 2.1% (95% CI, 1.6–2.7) in those aged over 55 years [10]. In Mexico, the Fogarty Stroke Cohort Study, which recruited relatively young acute post-stroke patients, found a dementia prevalence of 12% three months after stroke [11].

Epidemiological studies report a VaD incidence stratified by age and gender that ranges from 0.99 (95% CI, 0.96–1.02) [12] to 3.4 (95% CI, 2.1–4.9)/1000 person-years [13]. A meta-analysis reported varying rates of post-stroke dementia that ranged from 7.4% in population-based studies of first-ever stroke in individuals with no previous dementia to 41.3% in hospital-based studies of recurrent stroke in which previous dementia diagnosis was included [5]. A greater age-adjusted incidence rate (per 1000 person-years) for VaD has been found in men (12.2) vs women (9.0), along with an increased relative risk with advancing age (RR: 1.6 (95% IC 1.2–2.0) [14].

VCI frequencies and incidence rates have been reported with great variability possibly because of different settings and designs, as well as some studies’ neuroimaging accessibility [4, 10, 15]. Specific criteria involving the temporal relationship between a vascular event and the onset of cognitive decline is also to be considered when accounting for differences between studies [15]. Still, experts have been making progress in producing guidelines for a more standardized diagnosis [16, 17], where an umbrella of diagnostic possibilities for VaD is considered. Even if the use of magnetic resonance imaging (MRI) is a gold standard requirement for clinical diagnosis, a definition of possible mild or major VCI (VaD) is appropriate when neuroimaging is not available and clinically significant cognitive deficits in at least one cognitive domain with or without functional dependence are present [17].

Epidemiological investigation ought to be a first step in the means of attracting attention to dementia subtypes, especially in Latin America, where limited data for stroke and VaD exists [11, 13]. Therefore, the aim of this study is to determine the prevalence and incidence of PVD in older adults using a national representative panel study in Mexico, the Mexican Health and Aging Study (MHAS 2012–2015 waves).

Materials and methods

Study population

The study population included participants from the MHAS [18], a national representative panel study of Mexican residents aged ≥50 years with four follow-up waves (2003, 2012, 2015, 2018) of the baseline conducted in 2001. The aim and methodological design of the MHAS is published elsewhere [19]. We analyzed data from the third and fourth MHAS waves collected between October 2012 and December 2015. For ethical approval, the MHAS protocols and instruments were reviewed by the Institutional Review Board of the University of Texas Medical Branch, the National Institute of Statistics and Geography (INEGI for its acronym in Spanish) and the National Institute of Public Health (INSP) in Mexico. MHAS data files and documentation are of public use and available at www.mhasweb.org.

Sample selection at baseline and follow-up

Fig 1 shows the flowchart of the baseline sample selection from MHAS 2012 wave. A total of n = 14,893 participants aged 50 or older were included. Individuals who answered the interview directly (self-respondents) represented 91.7% (n = 13,651) of the sample, while 8.3% (n = 1,242) were proxy respondents. Based on self-reported history of stroke, we identified n = 338 (2.2%) individuals with stroke and n = 14,552 (97.8%) without stroke. All individuals were further classified as with dementia or cognitively normal based on diagnostic criteria further described.

Fig 1

Flowchart of sample selection at baseline (MHAS 2012).

Fig 2 shows the flowchart of the sample selection at follow-up from the MHAS 2015. Participants were followed an average of 3 years (SD = 0.61). During follow-up n = 837 (5.9%) individuals died (“decedents”), n = 311 (2.2%) refused to answer (“refusals”), and n = 578 (4.1%) could not be contacted (“lost”). The total follow-up sample comprised n = 12,427 (87.8%) individuals, including n = 202 with a history of stroke at baseline, n = 172 new cases of stroke, and n = 12,053 without stroke. Finally, individuals from each group were classified as with dementia or cognitively normal according to the diagnostic criteria further described.

Fig 2

Flowchart of sample selection at follow-up (MHAS 2015).

Cognitive assessment

For self-respondents, the MHAS assesses cognitive function through a modified version [20] of the Cross-Cultural Cognitive Examination (CCCE) [21], which measures performance in eight cognitive domains—verbal learning, delayed memory, attention, constructional praxis, visual memory, verbal fluency, orientation, and processing speed—and has reference norms by age and education. Imputed data were used on cognitive performance for individuals with missing values using a multivariate, regression-based procedure applied by the MHAS team following the same methodology as the Health and Retirement Study [22]. For respondents interviewed by proxy, the MHAS uses a brief version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) [23]. Proxy interviews are done through an informant, usually a spouse of a close relative when the selected participant is absent or is not healthy enough to complete a direct interview. Self-respondents were classified as having overall dementia if in at least two cognitive domains [24], scores were ≥ 1.5 standard deviations (SD) below the mean based on norms by age and education and also had difficulty performing at least one instrumental activity of daily living (IADL). IADLs included the ability to prepare a meal, go shopping, manage money, or take medications. Pondering the effect of gender on some of the IADLs for the Mexican population (e.g., men do not usually prepare a meal and women do not manage money), individuals that needed help in 1 or more IADL were considered as functionally impaired.

Cognitive performance in those classified as cognitively normal, was no more than one SD below norms in all cognitive domains or ≥1.5 SD below in only one domain, and no IADL limitations were present. For responses collected via proxy-interview, we classified individuals as having overall dementia if IQCODE scores were ≥ 3.4 and < 3.4 for cognitively normal individuals, as recommended [25].

History of stroke

Participants were classified as having a stroke history based on the question: Have you ever been diagnosed with stroke by a doctor? at baseline and follow-up. To correct for possible response bias, we also selected only those individuals who also at least reported one of the following conditions: focal symptoms of stroke (inability to move arms/legs, difficulty speaking/eating, difficulty with sight/vision, difficulty thinking/expressing him/herself), received rehabilitation therapy or took medications for stroke.

Diagnostic categories

For this study, possible vascular dementia (PVD) was defined by the combined presence of history of stroke and dementia. To estimate prevalence, n = 84 cases in the 2012 PVD group were considered. The incident PVD group (n = 75) included n = 44 new cases of stroke with dementia and n = 31 cases with stoke history who were cognitively normal at baseline but met criteria for dementia at follow-up. Sociodemographic and health characteristics were not different between these two groups (S1 Table).

The cognitively normal group was defined following the criteria described above based on cognitive domain scores for self-respondents and IQCODE for proxy respondents. For prevalence and incidence analyses we included cognitively normal individuals without stroke history (2012, n = 13,899 and 2015, n = 11,540, respectively).

Cognitively normal cases with stroke and incident dementia cases without stroke were excluded from the analyses.

Covariates

Sociodemographic characteristics: sex, age as continuous or categorical (50–64, 65–74, ≥ 75), years of education as continuous or categorical (0, 1 to 6, ≥ 7) following the formative periods in the Mexican education system, and (0 to 3, ≥ 4) to classify those in the lowest quartile.

Cardiovascular conditions were self-reported derived from the question: Has a medical doctor diagnosed you with: diabetes, hypertension, heart attack or dyslipidemia? We used each disease categorically (yes-no) and as a continuous variable from the sum of all cardiovascular conditions.

Depressive symptoms: the MHAS includes a modified version of the Center for Epidemiological Studies-Depression (CES-D) with nine items (yes/no). We classified respondents with a score ≥5 as clinically significant depressive symptoms based on a clinical validation study [26].

Global cognition was constructed as the standardized composite score of the CCCE (sum of scores from each domain) for self-respondents and the IQCODE for proxy respondents.

Statistical analysis

To examine differences in covariates between diagnostic groups at baseline and follow-up, t-test for continuous variables and Chi-square test for categorical variables, were used. For estimating prevalence and incidence rates the MHAS sampling weights were used [19]. Prevalence rates of PVD were stratified by sex, age, and education. Estimation of total age- and sex-adjusted rates, using data from the Mexican census 2010 as the standard population, was performed [27]. A binomial logistic regression model was used to analyze the association of sociodemographic factors (sex, age, and education), cardiovascular conditions (hypertension, diabetes, and heart attack) on the likelihood of PVD at baseline. For the estimation of incidence rates of PVD, the total time contributed by all participants (person-years) was calculated as follows: responders who remained cognitively normal at follow-up or were present, but refused to participate contributed 3 years (time between MHAS waves 2012 and 2015); those who were lost at follow-up were assigned a contribution of 1.5 years as the mid-point between baseline and follow-up assessment; time contributed by decedents varied depending on the year of death reported by the next of kin at follow-up; time until onset of vascular dementia was defined as the mid-point between baseline and follow-up. The incidence rate of PVD was defined as the number of new (incident) cases during study follow-up divided by the person-time-at risk. To examine baseline predictors of attrition, logistic regression models for each source of attrition: decedents vs. responders, lost vs. responders, and refusals vs. responders, were used (S2 Table). Inverse probability weights (IPW) were employed to account for death and other sources of attrition as competing risks for VaD in the analyses of risk factors [28]. Weights were based on the inverse probability of being observed at follow-up and thus of being alive and uncensored. The rationale behind these weights is that respondents with similar characteristics at baseline to those missing at follow-up, are up-weighted. The probability of being uncensored at follow-up, for each source of attrition (decedents, lost and refusal) versus those alive (completers), was modeled using a logistic regression adjusting for baseline covariates that had shown to influence attrition: sex, age, education, residence (urban-rural), self-reported diabetes, hypertension, heart attack, and global cognition. Later, the inverse probability weight of survival (1/predicted probability) and the cumulative probability as the product of weights was calculated. Finally, an evaluation of the association between baseline covariates and PVD using IPA-weighted generalized estimating equations (GEE) regression model, was performed. Statistical analyses were using SPSS software for Windows (SPSS Inc., Chicago, IL version 25.0).

Results

Table 1 provides characteristics of the samples at baseline and follow-up stratified by cognitive status. At baseline, participants with PVD had a mean age of 75.5 (SD 9.5) years, 52.4% were female, and the mean educational level was 4.3 years (SD 4.5). We observed that those with PVD (n = 84) were eleven years older than those in the normal diagnostic group. Persons aged 75 years or older comprise one-half of those with PVD. Sex distribution was not different between groups. On average, PVD individuals had 1.4 years of education less than their normal counterparts, with a significantly lower proportion in the 7+ years of education (17.9%). In addition, hypertension (64.3%) and heart attack (20.2%) were the most frequent cardiovascular conditions among PVD individuals (p>.001). Still in the PVD group, diabetes rates were higher (29.8% vs. 22.4%), but not statistically significant (p = 0.105). Excluding stroke, individuals with PVD had on average 1.1 (SD 0.9) vascular conditions compared to 0.7 (SD 0.8) in the cognitively normal group (p < .001). For the analysis of depressive symptoms only self-respondents (n = 28) were included given that proxy participants did not complete the depression scale. The proportion of individuals with significant depressive symptoms in the PVD group (64.3%) was twice as high as their normal counterparts (31.1%). Global cognition scores were significantly lower (-1.3, SD 0.8) in the PVD group compared to normal individuals (0.1, SD 0.9) (p < .001). Regarding the type of interview through which participants completed the MHAS survey, two-thirds of the PVD sample were proxy respondents, compared to 6% of the normal sample (p < .001).

Table 1

Characteristics of the MHAS sample at baseline (2012) and follow-up (2015) by diagnostic group.

	Baseline (MHAS 2012)			Follow-up (MHAS 2015)
Characteristics	Cognitively Normal (n = 13,899)	Possible Vascular Dementia (n = 84)	p-value	Cognitively Normal (n = 11,540)	Possible Vascular Dementia (n = 75)	p-value
	Mean (SD)	Mean (SD)		Mean (SD)	Mean (SD)
	n (%)	n (%)		n (%)	n (%)
Age, Mean (SD)	64.8 (9.5)	75.5 (9.5)	>.001	66.8 (9.2)	75.3 (11.2)	>.001
50–59 years	4583 (33.0)	6 (7.1)	>.001	3014 (26.1)	7 (9.3)	>.001
60–69 years	5221 (37.6)	14 (16.7)	>.001	4359 (37.8)	21 (28.0)	.082
70–79 years	2913 (21.0)	40 (47.6)	>.001	2981 (28.8)	19 (25.3)	.922
80 + years	1182 (8.5)	24 (28.6)	>.001	1186 (10.3)	28 (37.3)	>.001
Sex (female)	7831 (56.3)	44 (52.4)	.466	6551 (56.8)	43 (57.3)	.917
Education, years (SD)	5.7 (4.7)	4.3 (4.5)	>.001	5.7 (4.6)	3.2 (4.4)	>.001
No education	2456 (17.7)	20 (23.8)	.142	1959 (17.0)	26 (34.7)	>.001
1 to 6 years	7167 (51.6)	49 (58.3)	.216	6004 (52.0)	40 (53.3)	.822
7 + years	4276 (30.8)	15 (17.9)	.011	3577 (31.0)	9 (12.0)	>.001
Hypertension	5928 (42.7)	54 (64.3)	>.001	5449 (47.3)	53 (70.7)	>.001
Diabetes	3107 (22.4)	25 (29.8)	.105	2839 (24.6)	25 (33.3)	.082
Heart attack	446 (3.2)	17 (20.2)	>.001	397 (3.4)	13 (17.3)	.>001
Vascular conditions*	0.7 (0.8)	1.1 (0.9)	>.001	0.8 (0.8)	1.2 (0.9)	>.001
Depressive symptoms**	4066 (31.1)	18 (64.3)	>.001	3272 (29.4)	29 (70.7)	>.001
Global cognition	0.1 (0.9)	-1.3 (0.8)	>.001	0.1 (1.0)	-1.2 (0.8)	>.001
Self-respondents	13068 (94)	28 (33.3)	>.001	11122 (96.4)	41 (54.7)	>.001
Proxy respondents	831 (6.0)	56 (66.7)	>.001	418 (3.6)	34 (45.3)	>.001

P-value from t-test for continuous variables and Chi-square for categorical variables. Values in parentheses are weighted percentages derived using the MHAS sampling weights.

MHAS = Mexican Health and Aging Study.

*Vascular conditions = sum of hypertension, diabetes, and heart attack.

**Significant depressive symptoms (≥5) are presented for self-respondents only (2012 n = 13096; 2015 n = 11162), proxy respondents did not complete the depressive symptoms scale based on the study questionnaire.

At follow-up (Table 1), participants with incident PVD (n = 75) showed similar characteristics as the prevalent baseline PVD group. Compared to those cognitively normal, incident PVD adults were on average 8.5 years older, more than half of the group was in the oldest group (≥75years); they were 2.5 years less educated with no education in nearly 35% of the group. Rates of hypertension (70.7% vs.47.3%) and heart attack (17.3% vs. 3.4%) were significantly higher (p < .001). Diabetes was also higher (33.3% vs. 24.6%) in the incident PVD group but the difference did not reach statistical significance (p = 0.082). On average, the incident PVD group had 1.2 (SD 0.9) cardiovascular conditions (excluding stroke) while those cognitively normal had 0.8 (SD 0.8) (p < .001). Considering self-respondents only (n = 67), the proportion of individuals with significant depressive symptoms was significantly higher among incident PVD individuals (70.7%) compared to the normal group (29.4%) (p < .001). On average, global cognition scores were significantly lower (-1.2 SD 0.8) in the incident PVD group compared to normal individuals (0.1 SD 1.0) (p < .001). Finally, the proportion of the incident PVD sample in MHAS represented by a proxy respondent was 45.3% vs. 3.6% compared to the cognitively normal sample (p<0.001)

Table 2 provides prevalence rates of PVD for men and women by age, sex, and education. The total crude prevalence of PVD was 0.6% (95% CI, 0.5–0.8). Prevalence increased with age reaching 2.0% (95% CI, 1.3–2.9) among individuals aged 80 and older, and decreased with higher educational level from 0.8 (95% CI, 0.5–1.2) among those with no schooling, to 0.3% (95% CI, 0.2–0.6) for those with 7 or more years of education. Sex differences were only significant among the youngest group (50 to 59 years) with 6 cases for men and no cases for women. We found an overall age- and sex-adjusted PVD prevalence of 0.5 with no variations between males and females.

Table 2

Prevalence estimates of possible vascular dementia by sex, age, and education from the MHAS (2012).

	Total		Males		Females
	Prevalence estimate	95% CI	Prevalence estimate	95% CI	Prevalence estimate	95% CI
Age, y
50–59	0.1	(0.1–0.3a)	0.3	(0.2–0.7)	0.0	-
60–69	0.3	(0.2–0.5)	0.2	(0.1–0.5)	0.3	(0.1–0.6)
70–79	1.4	(1.0–1.8)	1.4	(0.9–2.2)	1.3	(0.9–2.0)
80+	2.0	(1.3–2.9)	1.6	(0.8–3.0)	2.3	(0.1–4.0)
Education, y
0	0.8	(0.5–1.2)	0.9	(0.5–1.2)	0.7	(0.4–1.3)
1–6	0.7	(0.5–0.9)	0.7	(0.4–1.0)	0.7	(0.5–1.0)
7+	0.3	(0.2–0.6)	0.5	(0.3–0.9)	0.2	(0.1–0.5)
Total crude	0.6	(0.5–0.8)	0.7	(0.5–0.9)	0.6	(0.4–0.8)
Total standardized*	0.5	(0.5–0.5b)	0.5	(0.5–0.6)	0.5	(0.5–0.5c)

MHAS = Mexican Health and Aging Study. CI = confidence interval. Values are weighted percentages (95% CI) derived using the MHAS sampling weights.

*Standardized = age- and sex-standardized to the Mexican population (2010), a: (0.06–0.28), b: (0.50–0.51), c: (0.48–0.50).

Table 3 shows rates of incident PVD by sex and age. A total of 87 new cases comprises 75 observed individuals and 12 estimated cases from the different sources of attrition (decedents = 8, lost = 3, and refuse = 1). Eighty-seven new cases represented an overall 2.2 (95% CI, 1.7–2.6) incidence rate of PVD per 1,000 person-years, the observed 75 cases represented an incidence rate of 1.9 (95% CI, 1.5–2.5). Incidence increased progressively with age, reaching an overall rate of 9.4 (95% CI, 6.3–13.6) per 1,000 person-years for individuals aged >80 years. Total crude incidence rates of PVD were not different between males 2.2 (95% CI, 1.5–2.9) and females 2.2 (95% CI 1.6–2.8). Although, increasing rates of incident vascular dementia with age were slightly higher for females than males between ages 60 to 79 years, at age 80, males showed a significant increase with a rate of 12.3 (95% CI, 7.2–19.7) per 1,000 person-years compared to females who had a rate of 7.0 (95% CI, 3.5–12.4). We found an overall standardized age- and sex-adjusted PVD incidence of 2.0 with no variations between males and females.

Table 3

Incidence rates of possible vascular dementia from the MHAS 2015.

	Total				Males				Females
Age	Person-years at risk	Cases	Incidence rate/1000	95% CI	Person-years at risk	Cases	Incidence rate/1000	95% CI	Person-years at risk	Cases	Incidence rate/1000	95% CI
50–59	13714	9	0.6	(0.3–1.2)	5253	5	0.8	(0.0–1.9)	8461	4	0.5	(0.1–1.2)
60–69	15327	27	1.8	(1.2–2.5)	7097	9	1.3	(0.1–2.4)	8230	18	2.3	(1.4–3.6)
70–79	8260	23	2.7	(1.8–4.2)	3826	8	2.1	(0.1–4.1)	4433	15	3.2	(1.7–5.3)
80+	2964	28	9.4	(6.3–13.6)	1383	17	12.3	(7.2–19.7)	1581	11	7.0	(3.5–12.4)
Total crude	40264	87	2.2	(1.7–2.6)	17559	38	2.2	(1.5–2.9)	22705	49	2.2	(1.6–2.8)
Total standardized*	-	-	2.0	(1.3–2.7)	-	-	2.0	(0.1–3.0)	-	-	2.0	(1.0–2.9)

CI = confidence intervals; MHAS = Mexican Health and Aging Study. Values are weighted percentages (95% CI) derived using the MHAS sampling weights.

*Standardized = age- and sex-standardized to the Mexican population (2010).

Table 4 shows the results of the full logistic models predicting incident PVD using GEE with IPA-weights to account for attrition. The first model includes all individuals who participated in the survey through direct and proxy interviews (n = 11,615). We estimated a second model for self-respondents only (n = 11,039) to analyze the association of depressive symptoms in 67 incident cases of PVD. Results showed that being male tended to be associated with a higher risk of PVD, but estimates were only marginally significant (p = 0.081) among self-respondents (OR 1.6, 95% CI, 0.9–2.7). At age 75 years and older individuals had 3.6 greater odds of incident PVD compared to the youngest group (50–64 years). Being in the lowest quartile of the education distribution (0–3 years) increased odds of incident PVD (OR 2.8, 95% CI, 1.5–5.2). The presence of hypertension (OR 2.6, 95% CI, 1.6–4.4), lower global cognition (OR 0.7, 95% CI, 0.5–1.0), and depressive symptoms (OR 2.6, 95% CI, 1.5–4.3) at baseline were associated with increased risk of incident PVD.

Table 4

Generalized estimation equations regression models for predictors of possible vascular dementia using IPA-weights.

	Incident Possible			Incident Possible
	Vascular Dementia*1			Vascular Dementia*2
	Self and Proxy Respondents			Self-Respondents
Baseline predictors	OR	p-value	95% CI	OR	p-value	95% CI
Sex (male)	1.3	.278	(0.8–2.1)	1.6	.081	(0.9–2.7)
Age
• 50–64 (ref)	1			1
• 65–74	1.1	.792	(0.6–2.1)	1.0	.950	(0.5–3.7)
• 75 +	3.6	>.001	(1.9–6.9)	2.7	.005	(1.3–5.3)
Education
• 0 to 3	2.8	>.001	(1.5–5.2)	2.0	.025	(1.1–3.7)
• 4 or more (ref)	1			1
Diabetes	1.6	.084	(0.9–2.5)	1.4	.277	(0.8–2.3)
Heart Attack	1.1	.936	(0.3–3.6)	0.7	.566	(0.2–2.9)
Hypertension	2.6	>.001	(1.6–4.4)	2.3	.003	(1.3–4.0)
Global cognition	0.7	.036	(0.5–1.0)	0.6	.003	(0.4–0.8)
Depressive Symptoms	NA	NA		2.6	>.001	(1.5–4.3)
Observations	11615			11039

*1 Estimates considering all cases of incident possible vascular dementia (PVD, n = 75)

*2 Estimates considering cases of incident PVD with information on depressive symptoms (PVD. n = 67) and excluding proxy respondents who did not complete the depressive symptoms scale based on the proxy study questionnaire. IPA = inverse-probability-of-attrition; OR = odd ratio; CI = confidence interval; MHAS = Mexican Health and Aging Study; OR = odd ratio.

Discussion

The prevalence of PVD in Mexican adults aged 50 years or older in the 2012-MHAS wave was 0.6% (95% CI, 0.5–0.8). A systematic analysis performed by Kalaria et. al [10], reporting VaD prevalence in developing countries, also found low VaD estimates; 0.7% (95 CI, 0.1–1.3) in an analysis of four studies in Taiwan where there is no mention of neuroimaging data and 1.1% (95% CI, 0.2–1.9) in a sub analysis of five rural and urban studies in India, where only two studies [29, 30] made use of brain imaging. In this same systematic analysis, authors reviewed data from 12 centers and concluded that only 26% of cases of dementia fulfilled the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) criteria for VaD [31]. Thus, a higher 2.1% (95% CI; 1.6–2.7) prevalence was found in Venezuela [32] and even a 6% frequency was reported in another study in Israel [33]. The latter used the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria [34] for dementia diagnosis and made VaD diagnosis at hospital discharge after stroke, while the Maracaibo study used the NINDS-AIREN criteria [31] for VaD, included several more neuropsychological cognitive tests, and reported 67% access to neuroimaging data [32].

Age is the main risk factor for any kind of dementia, including cognitive impairment of vascular origin. Based on results from the Maracaibo study in Latin America, Molero et al. [32] also found an increasing pattern of VaD with age, with a frequency of 0.2% (95% CI, 0.1–0.7), 2.0% (95% CI, 1.8–3.3), and 5.2% (95% CI, 3.4–7.8) in adults aged 55–64, 65–74, and 75–84, respectively, which is comparable to our findings. We also found no significant sex variations for PVD prevalence, which is similar to what other Latin-American studies found [11, 32].

In the present study PVD prevalence decreased from 0.8 (95% CI, 0.5–1.2) among individuals with no education, to 0.3% (95% CI, 0.2–0.6) for those with 7 or more years of education. A systematic review reported that the presence of lower educational level increased the risk of VaD 2.5 times (OR 2.5, 95% CI, 1.8–3.4, p < .001) [5]. Similarly, and after adjusting for confounding cardiovascular variables, the Rotterdam Study [35] found that only the least educated (primary education) were at risk for VaD (RR: 2.1, 95% CI, 1.0–4.5). A lack of cognitive reserve, where pre-existing mechanisms allow for neural compensation and favor resilience when coping with the damage caused by vascular pathology, can be a possible explanation in situations where a lower educational level is associated with greater dementia risk [36, 37].

Our rate for PVD incidence [2.2 (95% CI, 1.7–2.6)] was lower than that reported in the Maracaibo study [13], in which a 3.4 (95% CI, 2.2–4.9) per 1000 person-years rate was found. Access to neuroimaging was substantial in this last study, which could again explain the underestimation of VaD cases found in our study, particularly involving subcortical disease, small lacunar brain infarctions, and mixed dementia cases, which are considered as part of the umbrella of diagnostic possibilities for VaD [17]. Another study in the UK [12], which described a lower VaD incidence rate compared to our findings [0.99/1,000 person-years (95% CI, 0.96–1.02)], used an algorithm to identify individuals’ first-time VaD diagnosis based on DSM-IV [34], NINCDS-ADRDA [38] or NINDS-AIREN [31] dementia criteria. Only 15% of participants in this last study complied with diagnosis after neuroimaging. Methodological differences between studies, such as the use of different diagnostic criteria, the inclusion of additional cognitive evaluation tests, and neuroimaging availability, could account for variability in results.

An increasing VaD incidence with age of 0.8 (95% CI, 0.2–2.3), 3.8 (95% CI, 1.9–6.9), and 8.9 (95% CI, 4.1–16.9)/1,000 person-years, in adults 55–64, 64–74, and 75–84 years of age, respectively, was described by Maestre et.al [13]. These findings are comparable to our study, given that incidence rates reached an overall 9.4 per 1,000 person-years in individuals aged >80 years. We also observed that males aged 80 years or older, showed greater incidence rates when compared to females [12.3 (95% CI, 7.2–19.7) vs 7.0 (95% CI, 3.5–12.4) per 1,000 person-years], which is also consistent with what other studies have shown [12, 14, 39].

The presence of depressive symptoms (OR = 2.6, 95% CI, 1.5–4.3) and hypertension (OR = 2.6, 95% CI, 1.6–4.4) at baseline were associated with an increased risk of incident PVD. It has been proposed that late life-depression is a risk factor for VaD as it is for AD [1]. A metanalysis [40] reported a 2.5 (95% CI, 1.8–3.6) and 1.7 (95% CI, 1.4–1.9) greater risk for VaD and AD, respectively, associated with late-life depression. Moreover, poorer health and a higher burden of cardiovascular and cerebrovascular disease have also been associated to depression in older age [41, 42]. Barnes, et.al., in a retrospective cohort study found that chronic depression during the life course may be associated with an increased risk of dementia, particularly VaD [43]. Vascular abnormalities, specifically white matter changes and small vessel disease possibly playing a contributing role for dementia development, have been observed on brain imaging of depressed patients [44]. Other studies have found similar results concerning high blood pressure and VaD, with an OR of 2.0 (95% CI, 1.3–2.9) in the Hisayama study [14] and 1.2 (95% CI, 1.1–1.3) in a report by Imfeld et.al [12]. Hypertension is a major risk factor for stroke, thus linking it to VCI [7]. Recent reports have found that high blood pressure throughout midlife, increases the risk of dementia alone, even without stroke [6].

We acknowledge several limitations. First, information was obtained through a survey, with results that can only be applied to the Mexican population. Due to the nature of the survey’s IADLs evaluation, a clear differentiation between disability due to stroke complications or because of cognitive impairment alone, is not allowed. Second, as in most epidemiological surveys, neuroimaging studies were not systematically performed in the MHAS. The exclusion of new dementia cases without a history of stroke but with small vessel disease or silent lacunar strokes that can be identified through neuroimaging, could have also played an important role in the underestimation of VaD cases. Third, the cognitive evaluation test used in the MHAS, although proper in a cross-cultural context, could have also contributed to an underestimation of cases, since its use does not allow a clear identification of subcortical cognitive domains. Lastly, two-thirds of the sample included in the PVD group were diagnosed using answers of proxy respondents, which may also have made PVD criterion less sensitive for detecting new cases.

One of the strengths of our study is that it is the first study that shows PVD incidence rates in a large sample of Mexican residents. It is a longitudinal, representative, study that includes adults 50 years or older and shows an overview of important sociodemographic risk factors that mirror the health situation faced in developing countries, where educational policies, health behaviors, and health care practices might be different from that in high-income countries. Additionally, common cardiovascular risk factors are present predominantly in Latin America, highlighting the need for prevention strategies [45].

Conclusions

These data provide new estimates of PVD prevalence and incidence in the Mexican population. Males aged 80 years or older showed a greater incidence rate when compared to females, which is comparable to the mean of previous incidence estimates from other studies. Vascular dementia prevention strategies should focus on potentially modifiable risk factors.

General characteristics of incident possible vascular dementia by time of stroke register.

S1 Table provides general characteristics of individuals with incident possible vascular dementia comparing those who reported history of stroke in 2012 and 2015. Results show no significant differences in sociodemographic, cardiovascular conditions, depressive symptoms (≥5), and global cognition among groups.

(PDF)

Click here for additional data file.

Logistic regression models predicting attrition at follow-up.

S2 Table shows the results of the full logistic regression models for each source of attrition compared to responders. Being male, older age, having history of diabetes and heart attack and lower global cognition were predictors of mortality. Attrition due to lost was associated with lower age, higher education, living in urban areas, having history of stroke, lower hypertension, and lower global cognition. Refusals were predicted by lower age, higher education, and lower rates of hypertension.

(PDF)

Click here for additional data file.

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

3 Mar 2021

PONE-D-20-39225

Prevalence and incidence of possible vascular dementia among older Mexican adults: analysis of the Mexican Health and Aging Study

PLOS ONE

Dear Dr. Aguilar-Navarro,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 17 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Claudia K. Suemoto

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript subject stands out a great health concern since dementia population will increase in the next years in Latin America. The topic is interesting and here I present some suggestions for the authors to make the manuscript more suitable and complete for publication:

1. Introduction

Cardiovascular diseases, including stroke, are the leading cause of death globally. Its consequences bring a significant burden to its carriers and we can identify post-stroke cognitive impairment as being one of the greatest onuses, as it affects labor independence and quality of life. As dementia is the 5th cause of mortality in the world, the authors should bring information about dementia and vascular dementia mortality rates and burden to the health system (costs, for example). This might increase the relevance of recognizing the prevalence and incidence of vascular cognitive impairment, so interventions are targeted to potentially modifiable risk factors associated with VCI.

Still in the introduction, pg 11, line 81, I would quote that “a meta-analysis reported rates of post-stroke dementia that ranged from 7.4% […] to 41.3% […]”.

2. Methods

The methods and study design are appropriate for the questions and claims of this study. When reading the section “Cognitive assessment”, I suggest the authors to cite the reference for the criterion of overall dementia for self-respondents (pg 7, line 134).

Regarding IADLs impairment, some cultural influences may affect the interpretation of this matter. One to consider is the effect of gender on IADLs for the Latin population (some men do not usually prepare a meal and some women may not manage money) – was that considered? Still in IADLs impairment, it can happen due to stroke complications (focal symptoms), as difficult to move arms/legs (so the patient will have difficult in cooking, for example). Was it possible to separate IADL disability due to cognitive impairment and not due to stroke complications? If these two points could not be considered, the authors should cite them as limitations.

Still in the method section, as this study involved human participants, it is important to include ethical approval, as the name of the institutional review board or ethics committee that approved the research. The MHAS protocols and instruments were approved by the Institutional Review Board of the University of Texas Medical Branch, the National Institute of Statistics and Geography (INEGI for its acronym in Spanish) and the National Institute of Public Health (INSP) in Mexico (In pg 5, line 101) – is this the ethical approval? This information needs to be more specific.

3. Figures, tables and results

The figures and tables are clearly presented and correctly labeled. I suggest that, throughout the text, the results can be cited with only one decimal place, as an example on pg 22 line 294: “At age 75 years and older individuals had 3.6 greater odds of incident PVD…” and line 295: “Being in the lowest quartile of the education distribution increased in 2.8 the odds of incident PVD”.

4. Conclusions

The overall rate of PVD incidence found was lower of that reported in other studies and authors pointed out that methodological differences between studies could account for variability in results. The authors should mention which differences there are that could explain this variability, with references (e.g. use of different PVD criteria and cognition scales?).

In the limitation section of the discussion, the fact two thirds of the PVD population were diagnosed by proxy respondents may have made the criterion for detecting PVD less sensitive, so the authors should mention that. Second, the exclusion of new cases of dementia without history of stroke is also a limitation and must be explained through the manuscript, such as patients with cerebral small vessel disease without typical stroke history and evolving with dementia.

I suggest the authors make a careful analysis of grammatical and spelling errors, as: Pg 17, line 316 – “found an increasing pattern”, Pg 18, line 332: “hypothesis where pre-existing mechanisms” and Pg 18, line 340: methodological.

Reviewer #2: The study by Yeverino-Castro et al. reported the prevalence and incidence of vascular dementia in the MHAS.

The manuscript is well-written and the findings are consistent with other studies performed previously.

I have only 2 major comments:

1. was the weights of MHAS that are needed to have prevalence and incidence rates representative of the Mexican population used?

2. In the Discussion, the authors need to discuss how using a criteria attached to the presence of stroke influence the prevalence and incidence of vascular dementia. They need to make clearer that the findings probably understimante the rates of VaD in this study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

14 May 2021

April 8, 2021

Claudia K. Suemoto

Academic Editor

PLOS ONE Journal

We would like to thank the editor for his helpful suggestions. We also thank the reviewers for their generous comments on the manuscript. We have addressed all the suggestions in our current version which we allow ourselves to review and edit with the direction of your comments.

In this letter, our responses are written in purple. We have included a marked-up copy (pdf) of the manuscript where changes are highlighted in yellow.

In response to Journal’s additional requirements:

1. Please review your reference list to ensure that it is complete and correct.

- Thank you for identifying this. We have corrected 2 references [22 and 28] that had a broken e-link.

2. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

- Thank you for identifying the problem. We have corrected the Title page to accommodate PLOS ONE, Title, Autor, Affiliations formatting guidelines. We included a full and short title (page 1, lines 1-3) and used symbols to indicate author contributions and included the corresponding author’s e-mail address (page 1, line 14 and 15).

- We added an author, José A. Ávila Funes (page 1, line 5), who was not included in the initial submission. We acknowledge our error but want to correct it, as this author meets criteria for authorship, and must be included.

- We removed the key word section in the abstract (originally on page 3, line 51 and 52).

- We also corrected figure citations according to guidelines (page 6, line 114 and 121).

3. We note that you have included the phrase “data not shown” in your manuscript.

- We have removed this sentence originally located on pg. 11, lines 228-230 of the unrevised manuscript. The data was not a core part of the research being presented in our study.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found.

- We have added, in the manuscript’s methodology section (page 6, lines 109 and 110) as well as in the revised cover letter, an e-link to access the MHAS data and documentation, which are of public use and available at www.mhasweb.org. If specific data is required, please let us know, so we can share the requested information.

In response to Reviewer #1 comments:

5. Introduction: (…the authors should bring information about dementia and vascular dementia mortality rates and burden to the health system (costs, for example).

- Thank you for your recommendation. To increase the relevance of recognizing vascular cognitive impairment we have updated the first paragraph with information on dementia’s mortality and cost of care (page 4, lines 61-66).

6. Still in the introduction, pg 11, line 81, I would quote that “a meta-analysis reported rates of post-stroke dementia that ranged from 7.4% […] to 41.3% […]”.

- We have made this correction, page 4, line 79.

7. Methods: When reading the section “Cognitive assessment”, I suggest the authors to cite the reference for the criterion of overall dementia for self-respondents (pg 7, line 134).

- We appreciate that you have found this. We have added the missing reference (page 7, line 142).

8. Methods: The effect of gender on IADLs for the Latin population (some men do not usually prepare a meal and some women may not manage money) – was that considered?

- We are very thankful that you have noticed this. We have added a comment about the effect on gender in the Mexican population on page 7, lines 145-147).

9. Methods: Was it possible to separate IADL disability due to cognitive impairment and not due to stroke complications?

- We appreciate your comment. We have included this issue on the limitations section of the study (page 20, lines 380-382).

10. Methods: (In pg 5, line 101) – is this the ethical approval? This information needs to be more specific.

- As correctly noted in page 6 line 106, the Institutions mentioned are responsible for ethical approval of the MHAS protocol.

11. Figures, tables, and results. I suggest that, throughout the text, the results can be cited with only one decimal place. “At age 75 years and older individuals had 3.6 greater odds of incident PVD…” and line 295: “Being in the lowest quartile of the education distribution increased in 2.8 the odds of incident PVD”.

- We are thankful for your suggestion. Decimals on page 16, line 296 and 297, have been modified, as well as all decimals in figures, tables, and results throughout the manuscript.

- For decimals with minor numeric intervals (e.g., 0.48 – 0.50) we chose to include the exact 2 decimal digit at the corresponding table’s footnote (page 14, 272, 273) and at one citation (page 4, line 78).

12. Conclusions. The authors should mention which differences there are that could explain this variability, with references (e.g., use of different PVD criteria and cognition scales?).

- We have made this distinction by explaining, in the Introduction (page 5, lines 84-93) section of the Manuscript, how methodological differences between studies, such as the use of different diagnostic criteria, the inclusion of additional cognitive evaluation tests, and studies’ neuroimaging availability, could account for variability in results.

13. Conclusions. In the limitation section of the discussion, the fact two thirds of the PVD population were diagnosed by proxy respondents may have made the criterion for detecting PVD less sensitive, so the authors should mention that.

- We have included a statement regarding this issue on page 20, lines 388-390.

14. Conclusions. Second, the exclusion of new cases of dementia without history of stroke is also a limitation and must be explained through the manuscript, such as patients with cerebral small vessel disease without typical stroke history and evolving with dementia.

- We have learned a lot from your comments and are deeply grateful for your them. We have added a statement about this issue in the limitations section (page 20, lines 383-386) of our study.

15. I suggest the authors make a careful analysis of grammatical and spelling errors, as: Pg 17, line 316 – “found an increasing pattern”, Pg 18, line 332: “hypothesis where pre-existing mechanisms” and Pg 18, line 340: methodological.

- We are very thankful for noticing this. A careful grammatical and spelling analysis has been made and errors have been corrected (page 18, line 330 and 340).

In response to Reviewer #2 comments:

16. Were the weights of MHAS that are needed to have prevalence and incidence rates representative of the Mexican population used?

- The 2001 baseline survey of the MHAS includes a nationally representative sample of individuals born prior to 1951, that is the population aged 50 or older as of 2001. The sample for the MHAS baseline was selected from residents of both rural and urban areas and distributed in all 32 states of the country in urban and rural areas. A new sample of adults born between 1952-1962 was added in 2012. This information is explained elsewhere, and we added the reference for this on page 6 line 104 and 105.

17. In the Discussion, the authors need to discuss how using a criterion attached to the presence of stroke influence the prevalence and incidence of vascular dementia. They need to make clearer that the findings probably underestimate the rates of VaD in this study.

- We agree and are thankful for your comments. We believe we have addressed this issue in the Discussion section (page 19, lines 346-349) of our study, as well as in page 20 lines 382-390.

We believe the manuscript is now suitable por publication in PLOS ONE.

Thank you for your consideration.

Sincerely.

Corresponding Author

Submitted filename: Response to reviewers.docx

Click here for additional data file.

7 Jun 2021

PONE-D-20-39225R1

Prevalence and incidence of possible vascular dementia among Mexican older adults: analysis of the Mexican Health and Aging Study

PLOS ONE

Dear Dr. Aguilar-Navarro,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 22 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Claudia K. Suemoto

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: In my previous review, I have requested information on the use of sampling weigths.

However, the authors did not answer this comment.

They provided information about the sample procedure.

In epidemioloic sutdies, we cannot evaluate the whole population, so we sample some individuals.

To make the sample representative of the population, we can weight the analyses by the sampling weigths.

This is a common procedure in studies that aim to measure prevalence and incidence rates.

Please, provide information if you used the weights.

If you have not used them, recalculate your analyses.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Claudia Kimie Suemoto

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

8 Jun 2021

Dear:

Academic Editor

PLOS ONE Journal

We would like to thank academic editor for her helpful suggestions. We also thank the reviewers for their generous comments on the manuscript. We have addressed all the suggestions in our current version which we reviewed and edited accordingly.

In this letter, our responses are written in purple. We have included a marked-up copy of the manuscript where changes are highlighted in yellow.

In response to Journal’s additional requirements:

1. Please review your reference list to ensure that it is complete and correct.

- Thank you for identifying this. We have corrected a misplaced reference (#17 instead of #15) in page 5, line 94.

- We also noted a misplaced reference on page 6 line 110-111. The web address where information can be downloaded is www.mhas.org. The aim and methodological design of the MHAS is indeed published elsewhere, and reference 19 (https://doi.org/10.1093/ije/dyu263) is correctly placed at page 6 line 106.

- We added a previously misplaced reference (#45) at page 21 line 399 (previously referenced as #40)

- We also removed any bold formatting we used for references.

In response to reviewer #2:

1. In my previous review, I have requested information on the use of sampling weights. However, the authors did not answer this comment. They provided information about the sample procedure. In epidemiologic studies, we cannot evaluate the whole population, so we sample some individuals. To make the sample representative of the population, we can weight the analyses by the sampling weights. This is a common procedure in studies that aim to measure prevalence and incidence rates. Please, provide information if you used the weights. If you have not used them, recalculate your analyses.

- We are very thankful of your comment. Yes, we used MHAS sampling weights. We now added a sentence at the statistical analysis section (page 10, line 192-193) including the reference to the paper that explains the MHAS sampling weights. We also added this information to each of the tables where weighted data is presented; Table 1 (page 13, line 244-245), Table 2 (page 15, line 274-275), Table 3 (page 16, lines 292-293), and Supporting information table 1 (S1_table).

We believe the manuscript is now suitable por publication in PLOS ONE.

Thank you for your consideration.

Sincerely.

Corresponding Author

Sara G. Aguilar Navarro

On behalf of all authors.

Submitted filename: Response to reviewers2.docx

Click here for additional data file.

15 Jun 2021

Prevalence and incidence of possible vascular dementia among Mexican older adults: analysis of the Mexican Health and Aging Study

PONE-D-20-39225R2

Dear Dr. Aguilar-Navarro,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Claudia K. Suemoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

29 Jun 2021

PONE-D-20-39225R2

Prevalence and incidence of possible vascular dementia among Mexican older adults: analysis of the Mexican Health and Aging Study

Dear Dr. Aguilar-Navarro:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Claudia K. Suemoto

Academic Editor

PLOS ONE