Discussion

The aim of the present study was to investigate the neurocognitive state of diabetic patients, specifically through the study of processing speed and executive functioning, and taking into consideration several associated variables. To be precise, we studied the incidence of clinical factors linked to DM as well as the patients’ sociodemographic variables.

First, in the range of clinical signs pertaining to vascular pathologies, our study revealed significant results. Most notable are the findings between cardiopathy and the MMSE and TMT-B tests. As we know, the former test offers dementia screening, while the latter is noted for its sensitivity in detecting early processes thereof (Shindo et al., Reference Shindo, Terada, Sato, Ikeda, Nagao, Oshima and Uchitomi2013); therefore, based on our data, we can hypothesize a possible relationship between the DM patient suffering from cardiopathy and a risk of cognitive impairment. Moreover, our results reveal the relationship between cardiopathy and signs of established cognitive impairment (or dementia), based on its relationship to MMSE results, regardless of age (Joosten et al., Reference Joosten, van Eersel, Gansevoort, Bilo, Slaets and Izaks2013). This data would be consistent with postulating the existence of possible signs of vascular dementia as an etiopathogenesis that accounts for such cognitive impairment. And with good reason: Despite the fact that DM and its accompanying clinical factors are associated with the risk of other types of neurodegenerative disorders (e.g. Alzheimer’s; Arvanitakis, Wilson, Bienias, Evans, & Bennet, Reference Arvanitakis, Wilson, Bienias, Evans and Bennet2004), a large percentage of prospective studies point out its particular connection with risk for vascular dementia (Acee, Reference Acee2012). This link seems to stem from the association between diabetes and the metabolic and hemodynamic disorders that cause macro and microvascular damage, altering blood flow to the brain and vascular reactivity. This postulated consistency between our results and the possible existence of cerebrovascular disease would also be reinforced by the cognitive parameters that we have collected, given that vascular dementia is especially characterized by attentional and executive alterations (Graham, Emery, & Hodges, Reference Graham, Emery and Hodges2005). This data calls for further comparative studies that use protocols addressing other cognitive functions, thereby supplying further empirical arguments to help clarify this question.

Hypercholesterolemia showed an inverse relationship to ability to resist interference. On one hand, this clinical sign goes further into the cardiovascular point mentioned above, since hypercholesterolemia is one of the most important risk factors within this spectrum of vascular pathology (Cai et al., Reference Cai, Li, Zhang, Mo, Mai and Zhou2013). This finding is consistent with the important function of lipids within the nervous system, something that research has testified to for years (Beisiegel & Spector, Reference Beisiegel and Spector2001). We know that about 20% of total body cholesterol is found in the brain, specifically in the neurogliocyte membranes, which provide structural and metabolic support to the neurons. But the study of a relationship between lipids and the nervous system was triggered by the discovery of a connection between isoform *4 of apolipoprotein (Apo) E and Alzheimer’s disease (Jarvik et al., Reference Jarvik, Wijsman, Kukull, Schellenberg, Yu and Larson1995). Inquiring further into its neurodegenerative potential, several studies have associated hypercholesterolemia with a dementia diagnosis (Hughes et al., Reference Hughes, Lopez, Evans, Kamboh, Williamson, Klunk and Kuller2014); it has even been described as a predictive risk factor of mild cognitive impairment as well as Alzheimer’s disease, regardless of other genetic or associated comorbid factors (Toro et al., Reference Toro, Degen, Pierer, Gustafson, Schröder and Schönknecht2014).

Next, we did not find statistically significant results between cognitive performance and high blood pressure, even though the figures tend towards decline. According to previous studies, high blood pressure would be associated with general cognitive impairment (Obisesan et al., Reference Obisesan, Obisesan, Martins, Alamgir, Bond, Maxwell and Gillum2008), which at more advanced ages becomes more notorious in alterations in attention, processing speed and executive function (Reitz, Tang, Manly, Mayeux, & Luchsinger, Reference Reitz, Tang, Manly, Mayeux and Luchsinger2007). On the other hand, as a recent study shows, it seems that this tendency toward cognitive decline and dementia does not appear necessarily, but only in those subjects with a certain propensity toward dementia already (Wysocki et al., Reference Wysocki, Luo, Schmeidler, Dahlman, Lesser, Grossman and Beeri2012).

When analyzing the possible influence of clinical and comorbid factors, we found a significant, inverse relationship between Body Mass Index (BMI) and cognitive performance, specifically as an alteration in sustained attention and processing speed. This finding agrees with other studies that allude to low global cognitive performance (Jeong, Nam, Son, Son, & Cho, Reference Jeong, Nam, Son, Son and Cho2005), and specifically executive performance (Gunstad et al., Reference Gunstad, Paul, Cohen, Tate, Spitznagel and Gordon2007). Moreover, obesity has been suggested as an independent risk factor for developing dementia, and that BMI follows an inverted U pattern in relation to risk for dementia (Beydoun, Beydoun, & Wang, Reference Beydoun, Beydoun and Wang2008). Obesity during middle age (40–45 years) has been shown to have a substantial connection with increased risk of dementia 30 years later. Thus, persons with a BMI indicating obesity (30 or more), had a 75% greater possibility of developing dementia as compared to those who had a normal BMI (18.5 to 24.9; Whitmer, Gunderson, Barrett-Connor, Quesenberry, & Yaffe, Reference Whitmer, Gunderson, Barrett-Connor, Quesenberry and Yaffe2005). Elsewhere, BMI has been related to a reduction in total volume of the brain (Ward, Carlsson, Trivedi, Sager, & Johnson, Reference Ward, Carlsson, Trivedi, Sager and Johnson2005), especially with a decrease in frontal lobe areas (Pannacciulli et al., Reference Pannacciulli, Del Parigi, Che, Le, Reiman and Tataranni2006); a correlation has been described between this index and low levels of N-acetyl-aspartate and choline, mainly in gray and white matter of the frontal lobe (Gazdzinski, Kornak, Weine, & Meyerhoff, Reference Gazdzinski, Kornak, Weine and Meyerhoff2008). The negative effect of obesity on the brain and on cognition can be explained through a number of etiopathogenetic mechanisms; for the purposes of our study, we would highlight resistance to insulin and oxidative stress, as well as inflammatory processes and vascular alterations (Freeman, Haley-Zitlin, Rosenberger, & Granholm, Reference Freeman, Haley-Zitlin, Rosenberger and Granholm2014). Furthermore, in a particularly large cohort study, a greater risk for neurodegeneration was found in connection with visceral fat, more than with subcutaneous fat. Visceral fat seems to be metabolically more active, being associated with substantial production of adipocytokines, and more importantly in our view, to greater insulin insensitivity (Whitmer et al., Reference Whitmer, Gustafson, Barrett-Connor, Haan, Gunderson and Yaffe2008).

Based on the results of our study, we find a difference in cognitive performance according to the type of diabetes and its treatment, specifically in regard to sustained attention and processing speed. This data point is consistent with results from a prior study, where a greater tendency toward dementia was seen in the insulin-dependent patients (Ryan & Geckle, Reference Ryan and Geckle2000). More specifically, given that hypertension comorbidity is the only factor that differentiates our Type 1 DM sample from the Type 2 sample, percentage wise, this result could be interpreted in the terms posed by Reitz et al. (Reference Reitz, Tang, Manly, Mayeux and Luchsinger2007), who attributes attention and processing speed disorders to hypertension. However, this distinction between types of diabetes is not observed on most tests, where similar results are found for patients treated with insulin and patients on oral hypoglycemics. Similarly, years of treatment for diabetes (a variable that possibly overlaps with diabetes type, due to the early appearance of type 1 or insulin-dependent diabetes) was not found to be a factor that impacts performance. These results emphasize the importance of the actual condition that is shared by both types of diabetics, regardless of the therapeutic (especially the pharmacological) treatment. Not surprisingly, experimental models developed with type 1 and type 2 DM showed clearly evident negative repercussions from both hyperglycemia and hypoglycemia, as well as the neurological anomalies present in both subtypes, substantiated in negative impact on hippocampal neurogenesis, alterations in dendritic remodeling and increased apoptosis (Ho et al., Reference Ho, Sommers and Lucki2013).

Regarding possible influence detected from sociodemographic variables, we observed a gender difference. In our study, women present poorer cognitive performance than men on the TMT-A test, which, as we noted earlier, is able to detect nascent processes of dementia. The data have not yet established a supposed tendency toward dementia in diabetics according to gender, as there are studies that show greater risk in men (Mejía-Arango & Zúñiga-Gil, Reference Mejía-Arango and Zúñiga-Gil2011) or a lack of gender difference (Ott et al., Reference Ott, Stolk, van Harskamp, Po, Hofman and Breteler1999), while other research studies would justify a greater impact of DM on women, based on sociological, educational, economic, psychological and behavioral factors, in countries with similar socioeconomic characteristics to the context of the present study (Dasgupta, Khan, & Ross, Reference Dasgupta, Khan and Ross2010; De Melo, de Sa, & Gucciardi, Reference De Melo, de Sa and Gucciardi2013).

As could be expected from a long tradition of neurological studies (Haninen et al., Reference Haninen, Koivisto, Reinikainen, Vanhanen, Helkala, Soininen and Riekkinen1996), we obtained a direct relationship between greater age and greater deficiency on cognitive tests, in our case dealing exclusively with a sample of diabetic patients. For this investigation, this functional impairment is more justifiable due to the predominance of executive functions and processing speed in our assessment protocol, these cognitive abilities being especially susceptible to the passing of years (Ardila & Rosselli, Reference Ardila and Rosselli2007). Specifically, the executive decline noted here seems to be reinforced, from the neuroanatomical perspective, by the so-called “frontal lobe theory of aging” (West, Reference West1996), as this specific region is significantly involved in such functions (Gioia, Isquith, Guy, & Kenworthy, Reference Gioia, Isquith, Guy and Kenworthy2000). This fact is clearly visible in the results from Letter-Number Sequencing, as well as in the Stroop interference scores, since these place greater demands on executive functioning. Although a tendency toward functional decline was found on the MMSE, it did not reach levels of statistical significance, the sensitivity of this test being more oriented to the appearance of dementia. This fact seems to be justified since age in itself is not a cause of dementia; the impairment is produced where aging acts in conjunction with another pathology, such as cardiopathy or diabetes (Ravona-Springer et al., Reference Ravona-Springer, Luo, Schmeidler, Wysocki, Lesser, Rapp and Beeri2011). Our data confirms precisely this assumption, since the clinical factors discussed (e.g. cardiopathy) do not appear here as isolated entities, but as comorbid pathology with diabetes, given that our study sample is entirely composed of diabetic patients.

Regarding influence from the patients’ academic level (measured as years of schooling), we can observe a significant direct correlation with attention span. This could suggest a possible beneficial effect, and prompts us to inquire further into a positive influence from education that mitigates the risk of dementia in diabetic patients. This result is consistent with prior studies that address DM as one metabolic pathology (Mejía-Arango & Zúñiga-Gil, Reference Mejía-Arango and Zúñiga-Gil2011); elsewhere, studies from other spheres also confirm this benefit in different types of neurodegenerative pathology. All this has given academic or cultural education a high-value status within the concept of “cognitive reserve” (Andel, Vigen, Mack, Clark, & Gatz, Reference Andel, Vigen, Mack, Clark and Gatz2006). This has been explained through neural mechanisms that generate a cognitive brain remnant, whether through neurobiological events (brain size, number of neurons, synaptic density and abundance of interconnections), or through other phenomena such as using cognitive resources from preexisting processing or compensatory cognitive resources, triggering activation of new neural networks. In this manner, adequate cognitive stimulation (Nithianantharaiah & Hannan, Reference Nithianantharaiah and Hannan2011) seems to be behind this neural remnant that would equip a person with the ability to minimize the effects of age-related neurological disorders, as well as any damage from brain pathology, offering protection against the clinical development of the symptoms or signs typical of neurocognitive disease and dementia (Fratiglioni & Wang, Reference Fratiglioni and Wang2007). From another perspective, one cannot overlook the effect of education in providing more information, and therefore, better and healthier lifestyle habits, which are especially important in relation to pathologies like DM (Trujillo & Fleisher, Reference Trujillo and Fleisher2013).

Next, our study showed aerobic physical exercise as the most important guideline for neuroprotection, evident from its direct relationship to all the cognitive processes that were analyzed. This data point corroborates the benefit found in many preceding studies that focus on whether the practice of physical exercise has any positive impact on cognition (Smith et al., Reference Smith, Blumenthal, Hoffman, Cooper, Strauman, Welsh-Bohmer and Sherwood2010), and more specifically, within the aging process of persons with or without cognitive impairment (for a review, Franco-Martín, Parra-Vidales, González-Palau, Bernate-Navarro, & Solis, Reference Franco-Martín, Parra-Vidales, González-Palau, Bernate-Navarro and Solis2013). In another review that deals only with diabetic pathology, the advantages of establishing physical exercise guidelines are reaffirmed, and the importance of physical exercise is emphasized not only from a preventive perspective but also directly in a therapeutic role (Sanz, Gautier, & Hanaire, Reference Sanz, Gautier and Hanaire2010,). Moreover, an empirical study using a population over age 57 ratified the positive effective produced by aerobic exercise on prediabetic or Type 2 DM subjects (Baker et al., Reference Baker, Frank, Foster-Schubert, Green, Wilkinson, McTiernan and Craft2010). In our study, the benefit increases in proportion to frequency of practice, consistently with other studies that testify to this phenomenon (Subirats-Bayego, Subirats-Vila, & Soteras-Martínez, Reference Subirats-Bayego, Subirats-Vila and Soteras-Martínez2012). This beneficial effect of exercise seems to be based on biomolecular mechanisms and underlying neural mechanisms. Specifically, the effects of exercise and its benefits come about through changes in the neuroplasticity of the hippocampus (which also impacts APOE ε4), through production of brain-derived neurotrophic factor (BDNF), regulation of brain levels of β amyloid, and interaction with the Klotho gene (aging suppressor) through fibroblast growth factor and type 1 insulin-like growth factor (IGF-1); these in turn can lead to several neurovascular structures being affected, along with glial cells such as astrocytes and microglia (Foster, Rosenblatt, & Kuljiš, Reference Foster, Rosenblatt and Kuljiš2011). All this would justify the neural and cognitive benefits that result from physical exercise in patients with diabetic pathology.

Based on our analysis that focuses on certain cognitive functions, we propose future research that incorporates a global neuropsychological protocol, in order to detect possible differences as a function of specific cognitive processes, and thereby construct better hypothetical profiles of cognitive decline in diabetics. In any case, our emphasis on executive functions and processing speed contributes valuable information toward a more adequate understanding of the risk of dementia and receding quality of life in diabetic patients, since we analyzed cognitive processes with unique importance in more sophisticated, global mental functioning – processes that are the most susceptible to the aging process and are highlighted in numerous studies as the most affected functions. On the other hand, our correlation-based study would be well complemented by other experimental and longitudinal studies. Nonetheless, our design met our fundamental objective, allowing inferences to be drawn based on the effect of factors associated with diabetes and present in the de facto diabetic population. Thus, any appearance of clinical variables–cardiopathy, high blood pressure, obesity, etc.— constituted comorbidity, just as the sociodemographic variables could be analyzed with respect to a homogenous sample of diabetes sufferers. In any case, we consider it advantageous for the sample to be expanded in further studies, so as to optimize its statistical goodness and the consequential inferential consistency. We also see benefit from future studies of different drugs that are prescribed for diabetic patients, taking into account their specific mechanisms of action as well as the long-term effect as measured by the time they have been administered. On the other hand, in order to carry out a more exhaustive analysis of each participant, it would be helpful to know their personal parameters of fasting blood glucose and glycosylated hemoglobin levels. Furthermore, this cognitive-related data should be contrasted to biomolecular and neuroimaging results, in order to more accurately define the associated genetic and anatomic-functional structure, and thereby draw the appropriate implications for neurological clinical practice. In this regard, we consider it vital to inquire into the mechanisms that are linked to both cognitive stimulation and to aerobic physical exercise, in order to obtain a stronger empirical foundation that reinforces its therapeutic role.

Our results have analyzed clinical and demographic variables that are found in diabetic patients, inquiring into their functionality as risk factors or beneficial elements with respect to cognitive impairment and/or dementia. Our objective was to contribute more data to enhance our understanding of and neurological intervention in an ever-growing sector of the population, expanding due to greater longevity as well as to the introduction and establishment of unhealthy lifestyle habits. More adequate control of the factors involved in the neurology of this disease would result in more effective healthcare, and more importantly, enhance the quality of life of these particular patients.