The type 2 diabetes-specific dementia risk score (DSDRS) is associated with frailty, cognitive and functional status amongst Mexican community-dwelling older adults

We performed a cross-sectional study of 257 older adults aged ≥70 years who participated in the Coyoacán Cohort, an observational study conducted in the Coyoacán borough located in Southern Mexico City conducted between 2008 and 2009. Complete methodological details for the design and protocols of this study have been published elsewhere, and questionnaire materials were similar for the full cohort [7, 12]. Briefly, recruited participants were non-institutionalized older adults with residence in Coyoacán who were registered at the comprehensive “Food Support, Medical Care and Free Drugs Program” (FMDP) government program. All participants underwent face-to-face interviews to collect self-reported socio-demographic and health data and a comprehensive geriatric assessment which included physical performance tests, cognitive, nutritional, and medical assessment. Baseline questionnaire data were collected between April–May 2008; clinical evaluation and biological sample collection were carried out between June 2008 and July 2009. In the original cohort, a sample of 1294 participants was calculated to ensure a sample size which could estimate a prevalence of ~ 14% of frailty with α = 0.05 and β = 0.20. Among contacted potential participants, acceptance rate was 86.9% and a total of 1124 participants completed the initial interview, which included individuals with and without T2D. For the present study, we included participants with T2D without previous clinical diagnosis of dementia, defined as self-report of previously diagnosed T2D and/or self-report of taking T2D medications (n = 236). To account for subjects who were not previously diagnosed with T2D, we included subjects with fasting glucose ≥126 mg/dL (n = 21), who had enough information for their dementia-risk stratification using the DSDRS (overall, n = 257).

We evaluated dementia risk using the DSDRS [6]. Self-reported variables included in the score considered duration of T2D from diagnosis in years, self-report of diabetic kidney disease (DKD) and diabetic retinopathy, history of insulin use or oral T2D treatment, previous diagnosis of diabetic foot or peripheral vascular disease, acute myocardial infarction, and stroke. Microvascular complications to estimate DSDRS considered the clustering of DKD, and/or diabetic retinopathy; this definition was also used in linear and logistic regression models. Acute metabolic event was defined as a previous episode of hyperglycemia which required hospitalization or hypoglycemia, defined by self-reported episodes of hyperglycemia or fasting glucose levels < 70 mg/dL as recommended by ADA guidelines. High dementia-risk was defined as an estimated 10-year dementia risk >75th age-specific percentile based on incremental 5-year age categories described by the DSDRS. The selection of this age-specific percentile cut-off was performed to provide fair comparisons of DSDRS to detect age-related phenotypes without a significant influence from age as considered in the DSDRS, whilst still allowing a detection of high-risk individuals within each age group.

We calculated the body mass index using anthropometric evaluation using the formula of weight in kilograms divided by height in m². Blood samples were acquired after a 10–12 h fast to measure fasting glucose (Yellow Springs Instruments Co.); serum lipid concentrations assessed total cholesterol, triglycerides and HDL-C and were measured using colorimetric assays (Unicel DxC 600 Synchron Clinical System Beckman Coulter).

We included 257 subjects with T2D, with a slight female predominance (54.1%), an average age of 78.0 ± 6.2 years and a median of 10 years since T2D diagnosis. Insulin use was observed in 58 subjects (22.6%), 89 subjects had fasting glucose ≤130 mg/dL (34.6%), 89 subjects were categorized as pre-frail (34.6%) and 32 subjects as frail (12.5%). In relation to microvascular complications, 62 subjects referred having a previous diagnosis of diabetic kidney disease (DKD) and 102 referred diabetic retinopathy (39.7%). Furthermore, 88 subjects (34.2%) referred having any degree of diabetic foot disease; acute metabolic events occurred in 19 subjects (7.4%) of whom 7 were categorized ad hypoglycemic events (2.7%) and 12 as hyperglycemic events requiring hospitalization (4.7%, Table 1). The median of the DSDRS was 8.0 (range 6.0–10.0), which corresponds to an estimated 10-year dementia risk of 50% (40.0–63.0%), which was unevenly distributed by sex, without significant differences in sex distribution across dementia risk categories (p = 0.327, Fig. 1). When assessing sex-specific differences in DSDRS components, we identified that female participants had less years of education (6.0 [2.0–11.0], P = 0.003) and higher but non-significant rates of microvascular complications (55.4% vs 43.2%, P = 0.051) and of diabetic foot (39.6% vs. 28.0%, p = 0.051) compared to men but significantly lower rates of acute metabolic events (3.6 vs. 11.9%, p = 0.012).

We observed negative adjusted and unadjusted linear associations between DSDRS and MMSE, IST, SF-36 PCS, SF-36 MCS and MNA. We also observed a positive and significant linear associations between DSDRS and CDT, Katz, Lawton and the frailty score (Table 2). We did not observe a significant correlation between DSDRS, fasting glucose, triglycerides, HDL-C, total cholesterol or BMI. Using step-wise linear regression analyses we identified that frailty (β = 0.400, 95%CI 0.080–0.719), MMSE (β = − 0.153 95%CI -0.255 - -0.050) and MNA scores (β = − 0.160 95%CI -0.283 - -0.037) explained 26.8% of the variability in DSDRS, adjusted for sex, years of schooling and years since T2D diagnosis (R² = 0.268, p < 0.001). Furthermore, we observed significantly higher DSDRS among frail participants compared with non-frail subjects and in subjects with disability (Fig. 2).

Subjects with high 10-year dementia risk had less years of education, lower MNA, SF-36 PCS, SF-36 MCS, MMSE, IST, Katz and Lawton-Brody scores, higher frailty and GDS scores, and years of T2D exposure in comparison to DSDRS <75th age-specific percentile (Table 1). As expected, subjects with high 10-year dementia risk were also more likely to be frail, at risk of malnutrition (50.0% vs. 20.0%, p < 0.001), with disability (ADL 29.8% vs. 12.4%, p = 0.002; IADL 22.0% vs. 7.1%, p = 0.001) and a trend towards low cognitive performance (20.0% vs. 8.8%, p = 0.057). When evaluating the role of the DSDRS score to identify frailty and disability we observed highest area under the curve (AUC) for detection of ADL disability (AUC 0.803 95%CI 0.715–0.892; sensitivity 85.7%, specificity 61.3%), IADL disability (AUC 0.733 95%CI 0.629–0.838; sensitivity 62.0%, specificity 75.7%), low cognitive performance (AUC 0.704 95%CI 0.582–0.826; sensitivity 83.3%, specificity 54.3%), and frailty (AUC 0.700 95%CI 0.601–0.799; sensitivity 71.9%, specificity 69.1%). Using logistic regression, high-estimated 10-year dementia risk was associated to ADL and IADL disability, frailty and risk of malnutrition, adjusted for sex, years of schooling and years since T2D diagnosis. In multivariable logistic regression analyses, frailty and risk of malnutrition were associated with high-estimated 10-year dementia risk, adjusted for sex, years of schooling and years since T2D diagnosis (R² = 0.294, χ² =8.682, p = 0.370, Table 3).

In the case of the frailty score, age, microvascular complications, diabetic foot, stroke and depression explain the observed associations. Older age, microvascular complications and cardiovascular disease were associated with Lawton scores whilst older age, microvascular complications and were associated with lower Katz scores. For MMSE we observed significant associations with age, schooling, depression and microvascular complications, whilst for MNA scores, we observed associations with diabetic foot disease, cardiovascular disease, stroke and depression. Finally, lower SF-36 PC scores were associated with microvascular disease, cardiovascular disease and depression (Supplementary Material).

Older adults with T2D are at an increased risk of frailty; furthermore, interactions between frailty and hypoglycemia during T2D treatment have been reported to increase dementia-risk. This is significant, since patients with increasing number of macro and microvascular complications might be assessed as requiring more intensive glycemic control which, in subjects with impaired functional status and frailty might increase dementia risk [19]. The role of frailty in increasing morbidity and impacting QoL in patients with T2D has previously been shown and has led to recommendations against intensive glycemic control in this population [20, 21]; in addition, frailty is related to vascular damage and might contribute to increased risk of vascular dementia in T2D [22]. DSDRS might prove useful to identify patients with impaired functional status, multiple comorbidities, and frailty, who might benefit from less intensive T2D treatment and might require treatment adjustments [21]. In our study, we did not assess hypoglycemic episodes or hypoglycemia risk, but the interaction between frailty and hypoglycemia in relation to DSDRS and its impact on dementia risk should be evaluated in future studies.

Microvascular complications, particularly diabetic retinopathy, are evaluated by DSDRS to discriminate subjects with increased dementia risk who might also have disability, impaired QoL and functional status [23]. Diabetic retinopathy and neuropathy cause severe sensory impairments in older patients with T2D; furthermore, T2D has been associated to increased risk of bilateral sensorineural hearing loss in addition to established microvascular damage, which might contribute to further sensory loss [24, 25]. Sensory impairments, particularly in eyesight, hearing, and neuropathy have been associated with increased dementia risk and favor the development of disability and increased mortality; in addition, end-organ microvascular damage in T2D increases risk of falls and impairment of functional status [26, 27]. The role of microvascular damage in the pathophysiology of dementia in diabetes has also been studied, but the evidence of this association is inconsistent and neurological changes have been observed in individuals with T2D without end-organ microvascular damage [28]. Thus, DSDRS might identify individuals at high risk of disability in IADL and ADL due in part to sensory impairment by recognizing a population with increased dementia risk in whom rehabilitation would be beneficial [29]. The role of depression, macro and microvascular factors and obesity in promoting disability in individuals with T2D has also been reported, and its evaluation by the score contributes to the identification of individuals with ADL and IADL disability [30].

Older adults with T2D present lower performance on cognitive evaluations, particularly when affected by micro and macrovascular complications [31]. Cognitive evaluations of individuals with T2D have demonstrated impaired domains in information processing speed, visuospatial functions, attention, executive functioning abstract reasoning [32]; furthermore, individuals with T2D present a higher rate of cognitive decline, directly dependent with glycemic control. Individuals with T2D and cognitive impairment also experience a higher rate of conversion to dementia, with earlier disease onset and increased disease progression in relation to T2D duration and microvascular complications, as has been shown in previous studies [33, 34]. The lower cognitive performance observed in individuals with increased DSDRS in our study might be attributable to the consideration of microvascular damage, age and glycemic control, which underlie associations with impaired cognition in T2D in most prospective studies. Furthermore, the impact of frailty and disability on cognition, both of which increase dementia risk, must also be considered [35, 36]. Since individuals with T2D are a population with high susceptibility to impaired cognition, our demonstration of lower cognitive performance when screening subjects using the DSDRS provides evidence for its utility in a cross-sectional setting. Future longitudinal studies should shed light on the role of DSDRS for prediction of cognitive impairment conversion to dementia in individuals with T2D.

Our study had some strengths and limitations. First, we performed a wide range of evaluations, which allowed a thorough assessment of cognition, QoL, disability, and frailty in a sample of community-dwelling individuals with T2D in which most of these predictors had previously been validated. We also demonstrated that the DSDRS identifies subjects who could be considered for short-term interventions to improve function and ameliorate the negative effects of disability, frailty and T2D related complications. Furthermore, this is the first study in which DSDRS is used besides its original evaluation, demonstrating its utility in different populations and settings. Validation of DSDRS for functional and frailty status as demonstrated in this study allows to characterize the phenotype observed for subjects with high-estimated dementia risk score and extend the applications of DSDRS; nevertheless, prospective validation studies are required to both externally validate the score in different populations and replicate the observed associations for DSDRS in this study.

Amongst the limitations to be acknowledged is its cross-sectional setting, which limits the ability to establish causal relationships and the self-report of comorbidities and T2D complications, which might underestimate the true impact of the associations. The modified frailty definition which uses self-reported measures instead of physical evaluations has previously been applied in other studies involving the Coyoacán Cohort study; furthermore, epidemiological studies in other settings with self-reported data have been conducted and yielded reproducible results [17, 37]. Recent studies have compared the performance of frailty definitions which substitute physical based for self-reported based measures, identifying adequate diagnostic performance for self-reported definitions and adequate concordance with physical based definitions [38, 39]. Given this evidence, we propose that this operational definition should adequately capture the variability of the frailty phenotype in our subjects. Since the evaluated sample was representative of the community and previous reports have shown an increased rate of undiagnosed T2D in our population [1], some cases of T2D with fasting glucose < 126 mg/dL could have been excluded, thus limiting information of such cases. In addition, since no specific dementia information was available for diagnosis in the Coyoacán Cohort study there exists a possibility for undiagnosed cases of dementia not identified by cognitive assessment, thus modifying the strength of these associations. Our results however are in accordance with recent findings which show that DSDRS might be useful to detect cognitive impairment in indivudals with T2D [40]. Moreover, cognitive assessment did not include more extensive measures of executive function, which are highly sensitive to T2D-related cognitive changes and remain to be explored in future studies.