Metabolic Syndrome: Is It Time to Add the Central Nervous System?
Abstract
:1. Introduction
2. Metabolic Syndrome: Historical Aspects
3. Mild Cognitive Impairment and Metabolic Syndrome: Molecular Basis
3.1. From Metabolic Syndrome to Cognitive Impairment
3.1.1. Role of IR in the Formation of Amyloid-Beta Plaques
3.1.2. Metabolic Syndrome, Insulin Resistance, and Tau Proteins
3.1.3. Metabolic Syndrome, Leptin, Adiponectin, and Cognitive Disorders
3.1.4. Metabolic Syndrome, Microvasculature, and Cognitive Impairment
3.2. Exploring the Inverse Relationship—From Cognitive Impairment to Metabolic Syndrome
3.2.1. Tau Proteins and Deficits in Insulin Signaling
3.2.2. Amyloid β and Insulinemic Alterations
3.2.3. Amyloid β, Tau Protein, and Leptin
4. Mild Cognitive Impairment and Metabolic Syndrome: Epidemiological Basis
4.1. From Metabolic Syndrome to Cognitive Impairment
MS Component | Authors (REF) | Methodology | Results |
---|---|---|---|
High blood pressure | McDonald et al. [109] | Longitudinal cohort study of the association between cognitive function and BP variability in adults ≥65 years. | After 5 years of monitoring, diurnal systolic BP variability was independently associated with a greater decrease in total CAMCOG (CV: 3.205; p = 0.043) and MMSE (CV: 3.985; p = 0.020) scores. |
Haring et al. [111] | Prospective study in 6426 cognitively intact older women of the relationship between hypertension and cognitive impairment. | Hypertension was associated with an increased risk for cognitive decline (HR: 1.20; 95% CI: 1.04–1.39; p = 0.02). | |
Obesity | Sabia et al. [121] | Longitudinal cohort study of the association between BMI and mid-age cognition throughout adult life in 5131 individuals. | Late midlife obesity was associated with lower scores on the MMSE and on memory and executive function scores compared with normal-weight individuals (mean difference (95% CI): −0.99 (−1.78–0.21), −0.82 (−1.57–0.08), and −0.80 (−1.49–0.12), respectively (p < 0.05)). |
Beydoun et al. [122] | Meta-analysis of the association between obesity and major neurocognitive disorder in older adults. | A significant U-shaped association was found between BMI and major neurocognitive disorder (p = 0.034), with an increased risk of disorder (OR (95% CI): 1.42 (0.93–2.18)) and increased incidence of AD (OR (95% CI): 1.80 (1.00–3.29)) in obese individuals. | |
Dyslipidemias | de Frias et al. [124] | Longitudinal cohort study of the association between total cholesterol, triglycerides, and cognitive performance in older adults. | Hypertriglyceridemia was associated with a low score on the verbal memory tests (γ = −2.31; p < 0.05), while hypercholesterolemia was associated with a detrimental effect on facial recognition test score (γ = −2.13; p < 0.05). |
Singh-Manoux et al. [126] | Longitudinal cohort study of the relationship between HDL-c and verbal short-term memory in middle-aged adults. | After 5 years of monitoring, decreased HDL-C was associated with decreased verbal memory (OR = 1.61; 95% CI = 1.19–2.16). | |
DM | Elias et al. [117] | Longitudinal study of the effects of T2DM on cognitive performance of adult individuals. | The amount of time suffering from diabetes was associated with poorer cognitive performance (β = −0.02; p < 0.02). |
Kanaya et al. [137] | Longitudinal cohort study of changes in cognitive performance according to glucose tolerance status in older adults. | After 4 years, women with DM had a 4-fold increased risk of cognitive impairment (OR (95% CI): 4.38 (1.71–11.27); p = 0.02). | |
MS | Atti et al. [147] | Meta-analysis of the relationship between MS and progression to major neurocognitive disorder in individuals with MCI. | Having MS increased the risk of progression from MCI to major neurocognitive disorder (HR (95% CI): 2.69 (1.16–6.27); p < 0.05). |
Pal et al. [146] | Meta-analysis that quantified the relative risk of progression from MCI to major neurocognitive disorder in individuals with MS. | An increased risk of progression was found in individuals with MCI and SM (OR (95% CI): 2.95 (1.23–7.05) p < 0.05). |
Therapeutic Approach | Authors (REF) | Methodology | Results |
---|---|---|---|
Lifestyle changes | Karssemeijer et al. [157] | Meta-analysis of the effect of cognitive and physical exercise intervention in older adults with MCI or major neurocognitive disorder. | A positive effect of the combination of physical–cognitive interventions on global cognitive function was observed (MDS (95% CI) = 0.32 (0.17–0.47); p < 0.05). It was equally beneficial for individuals with MCI (MDS = 0.39 (0.15–0.63); p < 0.05), and for patients with major neurocognitive disorder (MDS = 0.36 (0.12–0.60); p < 0.001). |
Zhang et al. [165] | Meta-analysis of the association between risk of cognitive impairment and intake of fish and PUFAs. | Increased fish consumption was associated with decreased risk of major neurocognitive disorder (RR: 0.95; 95% CI: 0.90–0.99; p = 0.042). A significant curvilinear relationship was observed between PUFA consumption and MCI risk (p nonlinearity < 0.001). | |
Krikorian et al. [164] | Prospective study of the effect of a ketogenic diet in older individuals with MCI. | An improvement in verbal memory performance was observed in patients on a low-carbohydrate diet (p = 0.001). Memory performance was positively correlated with ketone levels (p = 0.04). | |
Antihypertensives | Tzourio et al. [110] | A longitudinal study of the effect of antihypertensive drugs on the risk of cognitive decline in older individuals. | The risk of cognitive impairment was higher in untreated subjects (OR = 6.0 (95% CI: 2.4–15.0)), compared with subjects treated with antihypertensives (OR = 1.3 (95% CI: 0.3–4.9)). |
Guo et al. [168] | Prospective study that evaluated whether the use of antihypertensives affected the appearance and progression of major neurocognitive disorders in older adults. | The risk of major neurocognitive disorder was reduced in subjects receiving antihypertensive treatment and without major neurocognitive disorder at the beginning of the study (RR = 0.7 (95% CI: 0.6–1.0); p = 0.03). | |
Antidiabetics | Ng et al. [170] | Longitudinal study of the protective effect of metformin on the cognitive performance of older adults. | Use of metformin showed an inverse association with cognitive impairment (OR = 0.49 (CI 95%: 0.25–0.95); p < 0.05), and was associated with a low risk of cognitive impairment after 6 years of use (OR = 0.27 (CI 95%: 0.12–0.60); p < 0.05). |
Borzì et al. [171] | Retrospective study of the effect of vildagliptin on cognitive function in older diabetic adults with MCI. | The use of metformin as monotherapy or in combination with vildagliptin was associated with a significant reduction in MMSE score (p < 0.001). | |
Hypolipidemics | Bosch et al. [177] | Clinical trial on the effect of rosuvastatin in reducing cognitive impairment in older adults. | The mean difference in DSST score between rosuvastatin vs. placebo was −0.54 (95% CI: −1.88–0.80); p < 0.05. |
Bettermann et al. [178] | Clinical trial on the impact of statin use on delaying cognitive decline in patients with and without MCI. | Statins were associated with a decreased risk for increased neurocognitive impairment from all causes in patients who did not have MCI at the beginning of the study (HR = 0.79 (95% CI: 0.65–0.96) p = 0.021). In subjects with MCI, these protective effects were not observed. |
4.2. Exploring the Reverse Relationship—From Cognitive Disorder to Metabolic Syndrome
Author (REF) | Methodology | Results |
---|---|---|
Janson et al. [186] | Longitudinal study where prevalence of T2DM in patients with AD was evaluated, along with the association between FPG and aging in these patients. | The prevalence of T2DM (34.6 vs. 18.1%; p < 0.05) and IFG (46.2 vs. 23.8%; p < 0.01) was higher in the AD group vs. the control group. A greater increase was seen in FPG per year in the AD group (0.83 vs. 0.57 mg/dL−1; p < 0.01). |
Bae et al. [181] | Cross-sectional study of the prevalence of MS by type of MCI in 3312 older adults and differences related to sex. | The prevalence of MS was higher in participants with naMCI (men: p = 0.030; women: p = 0.040) and the risk of MS was higher in men (OR = 2.45; 95% CI: 1.13–5.32) than in women (OR = 1.94; 95% CI: 1.12–3.39) compared with participants with normal cognition. |
Altschul et al. [187] | Longitudinal cohort study of the association between cognitive function, HbA1c, and other variables in early and late life in 1091 adults. | High cognitive function at age 11 predicted low HbA1c levels at age 70 (p < 0.001). Additionally, high cognitive function at age 70 was associated with a smaller increase in HbA1c levels between age 70 and 79 (p < 0.001). |
Peng et al. [188]. | Study comparing 1063 newly T2DM diagnosed individuals with 1063 control individuals for an association between plasma concentrations of Aβ40 and Aβ42 with risk of T2DM. | The risk of T2DM was higher in individuals with the highest concentrations of Aβ40 and Aβ42 (OR = 2.96 (95% CI: 2.06–4.25)) compared with subjects with the lowest concentrations of Aβ. |
Peng et al. [188]. | Prospective study of the association between plasma concentrations of Aβ40 and Aβ42 with risk of T2DM. | A higher risk of T2DM was found in individuals with concentrations greater than that of Aβ (OR = 3.79 (95% CI: 1.81–7.94)) for Aβ40 and (OR = 2.88 (95% CI: 1.44–5.75)) for Aβ42. |
Author (REF) | Treatment | Methodology | Results |
---|---|---|---|
Ettcheto et al. [190] | Memantine | Preclinical study of the effects of MEM on learning and memory impairment in rats with familial AD and HFD-induced insulin resistance. | MEM prevented body weight increase in HFD-fed mice with APP/PS1 (p < 0.001). Hepatic IR protein levels showed a significant increase in APP/PS1 MEM mice compared to nontreated controls (p < 0.05), improving insulin function in the liver. |
Zhang et al. [194] | Anti- Aβ Immunotherapy | Preclinical study of the effects of intraperitoneal injections of anti-Aβ antibodies in APP/PS1 rats on glucose metabolism. | After 9 months of treatment, neutralization of Aβ reduced fasting blood glucose level (p < 0.001), improved insulin sensitivity (p < 0.05), and inhibited hepatic JAK2/STAT3/SOCS1 signaling (p < 0.05) in APP/PS1 AD model rats. |
Wessels et al. [193] | Lanabecestat | RCT that assessed whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. | Even though treatment with lanabecestat did not slow cognitive decline, patients who completed week 104 had a mean (SD) weight loss of 0 (4.7) kg for placebo, −0.8 (4.6) kg for patients treated with 20 mg lanabecestat, and −1.9 (5.2) kg for those treated with 50 mg. |
Ahmed et al. [191] | MemantinePiracetam | Clinical study of the effect of piracetam and memantine on diabetes mellitus. | A significant decrease in all diabetic markers (FPG, HbA1c%, and insulin levels) in the diabetic and Alzheimer’s patients was observed after treatment with memantine or piracetam compared to diabetic and Alzheimer’s patients with symptomatic treatment (p < 0.05). |
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Rojas, M.; Chávez-Castillo, M.; Pirela, D.; Parra, H.; Nava, M.; Chacín, M.; Angarita, L.; Añez, R.; Salazar, J.; Ortiz, R.; et al. Metabolic Syndrome: Is It Time to Add the Central Nervous System? Nutrients 2021, 13, 2254. https://doi.org/10.3390/nu13072254
Rojas M, Chávez-Castillo M, Pirela D, Parra H, Nava M, Chacín M, Angarita L, Añez R, Salazar J, Ortiz R, et al. Metabolic Syndrome: Is It Time to Add the Central Nervous System? Nutrients. 2021; 13(7):2254. https://doi.org/10.3390/nu13072254
Chicago/Turabian StyleRojas, Milagros, Mervin Chávez-Castillo, Daniela Pirela, Heliana Parra, Manuel Nava, Maricarmen Chacín, Lissé Angarita, Roberto Añez, Juan Salazar, Rina Ortiz, and et al. 2021. "Metabolic Syndrome: Is It Time to Add the Central Nervous System?" Nutrients 13, no. 7: 2254. https://doi.org/10.3390/nu13072254