Authors

• Ingrid Prkačin — Medicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska — ORCID: 0000-0002-5830-7131
• Helena Zorko — Medicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska — ORCID: 0000-0002-0418-8536
• Vesna Herceg-Čavrak — Klinika za dječje bolesti Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-1723-1791

Abstract

The progress in disease prevention and health care has prolonged life expectancy, thus increasing the global disease burden. The non-communicable diseases such as arterial hypertension, diabetes mellitus and dementia have been recognized as an inadequately clarified problem in the population all over the world. Senile dementia is an irreversible condition manifested by progressive decline of cognitive functions and considered as one of the leading health problems today. Proper care for this fragile population requires interdisciplinary approach because the pathophysiological events are underlain by hyperinsulinemia and oxidative stress at the whole body level rather than isolated to a single organ.

Keywords

KLJUČNE RIJEČI: mentalno zdravlje, hiperinzulinemija, oksidativni stres, zdravlje srca i bubrega, mental health, hyperinsulinemia, oxidative stress, heart and kidney health

DOI

Full Text

According to the World Health Organization estimates, 35.6 million people in the world suffer from dementia and this figure is expected to triple by the year 2050 (1). Alzheimer’s disease and vascular cognitive disorders are the most common causes of dementia in elderly population (2). There is increasing evidence for Alzheimer’s disease and vascular cognitive disorders to share common pathophysiological mechanisms (3). Although both cerebrovascular disease and Alzheimer’s dementia are frequently present in the elderly who also suffer from obesity, the coexistence of these two conditions may also be quite accidental (4). Alternatively, vascular disease may promote Alzheimer’s dementia and vice versa, resulting in their interplay that enhances their negative effects, whereas cognitive effect depends on the severity of Alzheimer pathology and vascular lesion localization (5). Vascular risk factors include arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, atrial fibrillation and elevated homocysteine level, which all increase the risk of dementia independently of the associated increase in the risk of stroke (6). Furthermore, metabolic syndrome that includes insulin resistance, arterial hypertension and dyslipidemia has been related to a lower cognitive effect (7). Stroke is one of the strongest predictors of the onset of dementia (8). High-grade obesity is implied in most cases of hyperinsulinemia and diabetes (9), which is considered a risk factor for development of dementia (10-15). ## Impact of obesity on development of dementia Elevated body mass index (BMI) in middle age is associated with an increased risk of dementia (16). Abdominal obesity, which is associated with insulin resistance and cardiovascular disease, is a risk factor for Alzheimer’s disease (17). Elevated BMI at the age of 70, 75 and 79 years also is associated with a higher risk of dementia (18). On the other hand, some studies failed to demonstrate an association between increased BMI in advanced age and dementia (19), whereas others found lower BMI to be associated with the development of Alzheimer’s disease (20). The reason for these discrepancies may be the fact that waist circumference is a better indicator of obesity than BMI (21). Aging is characterized by an increased proportion of adipose tissue, mostly without mass gain; therefore, these changes do not lead to BMI increase and the traditional measurements of obesity are less useful in the elderly (21). It has been found that in early old age (65-76 years), there is an U-shaped association of BMI and Alzheimer’s disease, whereas in older age groups (>76 years) higher BMI is associated with a lower risk of Alzheimer’s disease. Also, greater waist circumference is associated with a higher risk of Alzheimer’s dementia in early old age but not in older age groups. Crucial is the association of insulin resistance and vascular endothelial dysfunction for triggering the process of atherosclerosis (22, 23). In the state of insulin resistance, which is a basic pathophysiological factor of the metabolic syndrome and obesity, the synthesis of nitric oxide is decreased and the balance impaired in favor of vasoconstrictory factors and oxidative stress, which is considered the basis of vascular dementia (24). Reduced nitric oxide release leads to increased platelet aggregation and growth factor release in all vascular walls. Besides this, due to the protracted mineralocortical action of glucocorticoids induced by chronic stress, development of obesity and arterial hypertension is associated with further accumulation and deposition of adipose cells in the body and deterioration of insulin resistance, which is related to additional remodeling of target organs, primarily the heart and the kidney. These events require ‘cross-disciplinary’ interventions in this fragile group of patients at an increased risk of morbidity and mortality irrespective of age (25, 26). Temporal lobe atrophy is an early feature of dementia and cognitive decline, and an indicator of neuronal degeneration (27, 28); it was related to elevated BMI values measured 24 years before atrophy measurement by computed tomography (CT) (29) and to a reduced brain volume as determined by magnetic resonance imaging (MRI) in a cross-sectional study including men and women aged 44-60 (30). Individuals with higher BMI values showed a greater rate of brain atrophy progression as assessed by serial MRI (31). In a cross-sectional study, central obesity (waist to hip ratio) was associated with temporal lobe atrophy, also demonstrated by MRI (32). One of the main sequels of obesity is insulin resistance and hyperinsulinemia, which represent a complex interplay of the autonomic nervous system and hormonal system with neuronal mechanisms connecting gastrointestinal system with the central system of energy homeostasis (9). Insulin crosses the blood-brain barrier and enters the central nervous system from periphery, then competing with amyloid β (Aβ) for degradation by the insulin degrading enzyme in the brain, also including the hippocampus (33). Insulin is also produced in the brain, where it exerts a favorable effect on Aβ degradation. Peripheral hyperinsulinemia may inhibit the production of brain insulin, which leads to a reduced Aβ degradation and an increased risk of Alzheimer’s disease (34). A study investigating the effect of rosiglitazone on the reduction of insulin resistance and concentration of peripheral insulin, used in the management of diabetes showed that rosiglitazone might have favorable effects also on reduction of problems related to Alzheimer’s dementia (35). ## Arterial hypertension and Alzheimer’s disease Alzheimer’s disease has been traditionally considered a neurodegenerative condition caused by neuronal dysfunction, consequential to the accumulation of β-amyloid plaques and neurofibrillary tangles formed due to neuronal cytoskeletal abnormalities (36). However, pathologic and experimental evidence suggests that vascular factors including arterial hypertension play a major role in the pathogenesis of Alzheimer’s disease (37). This in particular refers to middle age hypertension, which is considered to contribute to the risk of developing Alzheimer’s disease later in life and to accelerate its progression. Furthermore, brain atrophy, amyloid plaques and neurofibrillary tangles are especially pronounced in the brain of patients with a history of arterial hypertension in their middle age. Hypertension also leads to changes in vascular walls of the brain (heart and kidney), causing hypoperfusion, ischemia and hypoxia, which in turn can trigger pathologic processes of Alzheimer’s disease. Accordingly, elevated arterial pressure induces cerebrovascular lesions that increase the likelihood of developing dementia syndrome in individuals with Alzheimer’s encephalopathy (38). Results of some studies have shown that the hypertension induced lesions and Alzheimer’s dementia can have additive or synergistic effects, and that they in combination cause more severe cognitive disorders than any of the processes alone does (3). In as many as 50 % of cases, dementia is caused by mixed pathology consisting of vascular and neurodegenerative lesions (amyloid plaques and neurofibrillary tangles) (39). Arterial hypertension usually precedes the onset of Alzheimer’s disease and as such may play a role in its progression. On the other hand, arterial pressure decrease that occurs when Alzheimer’s disease has fully developed, probably is related to changes in the central autonomic nucleus that regulates arterial pressure, such as C1 area in the rostral ventrolateral medulla (40). Reduced physical activity, dehydration and malnutrition are associated with developed dementia (38). Although arterial hypertension favors development of amyloid plaques early in the course of the disease, pathologic changes induced by Alzheimer’s disease lead to arterial pressure reduction in later stages, which can cause hypoxemia and ischemia, thus contributing to exacerbation of dementia (41). Considering the growing epidemic of obesity and the association between hyperinsulinemia and diabetes, and between diabetes and an increased risk of Alzheimer’s disease, there is room for novel strategies in the prevention and treatment of these conditions (42). ## Conclusion Insulin resistance and hyperinsulinemia as the main sequels of obesity represent complex interaction of autonomic nervous system and hormonal system with neuronal mechanisms connecting gastrointestinal, cardiovascular and kidney system with the central system of energy homeostasis. Impairment in the system of energy homeostasis due to excessive food intake and/or physical inactivity can be influenced by multifactorial interventions to correct the imbalance.

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