**2.4. Interrelations of clinical-metabolic, neuropsychological features and markers of cognitive impairment in patients with type 1 diabetes mellitus**

When evaluating the results, a negative correlation was found between the fasting glycemia and HbA1c levels with the test parameters responsible for memory and attention (task for


Note: The significance of the differences between the control group and patients with type 1 diabetes mellitus at the level: \* p < 0.001.

**2.3. Characteristics of magnetic resonance imaging of the brain in patients with type** 

**Neuro-specific proteins Type 1 DM (n = 98) Control group (n = 29)**

Myelin basic protein (MBP) (ng/ml) 0.12 ± 0.04\* 0.08 ± 0.033 Glial fibrillary acidic protein (GFAP) (ng/ml) 125.65 ± 66.97\* 62.85 ± 19.66 S100 (ng/ml) 0.13 ± 0.05\* 0.10 ± 0.036

**0.13 ± 0.05\* 0.10 ± 0.036**

Analysis of magnetic resonance imaging of the brain revealed indirect signs of atrophy of the gray matter of the frontal and partly parietal lobes. Thus, in patients with type 1 diabetes mellitus, arachnoid changes (93.1%) and expansion of the convective liquor spaces (72.4%) were significantly more frequent. In the control group, changes in thearachnoid changes were detected in 67% (**Table 3**). **Figure 2** in the coronal projection (mode T2) shows the expansion

Note: The significance of differences between the control group and patients with type 1 diabetes mellitus at the level:

**Table 2.** Characteristic levels of neurospecific proteins in patients with type 1 diabetes mellitus and the control group.

MRI of the brain showed the presence of gliosis sites in 15.5% of cases and lesions of leukoareosis in 18.3% of cases in patients with type 1 diabetes mellitus, whereas in the control group no changes were revealed (**Table 3**). In **Figure 3**, in the axial projection (FLAIR mode) in the white matter of the frontal and parietal lobes, small foci of a dystrophic character are defined. In **Figure 4**, coronal lesions are identified in the coronal projection. According to the classifica-

Perivascular spaces of Virchow-Robin are a morphological and functional structure of the central nervous system; therefore, various versions of their dilatation can be an indirect reflection of changes in the brain substance and indicate atrophy. In the study, expansion of Virchow-Robin spaces occurred in 80.6% of cases in patients with type 1 diabetes mellitus, which was

These changes are shown in **Figure 5**, where in the coronal projection in the thalamus region, nonuniformly expanded Virchow-Robin spaces are determined from both sides. Given the

Thus, according to MRI, the morphological changes in the brain in patients with type 1 diabetes mellitus are represented by arachnoid changes in the liquor cystic, the expansion of the

When evaluating the results, a negative correlation was found between the fasting glycemia and HbA1c levels with the test parameters responsible for memory and attention (task for

**2.4. Interrelations of clinical-metabolic, neuropsychological features and markers of** 

tion proposed by Lui, the severity of leukoareosis is two points.

classification of MacLullich, they are estimated at 2 points.

convective spaces, and the Virchow-Robin spaces of the brain.

**cognitive impairment in patients with type 1 diabetes mellitus**

significantly higher than in the control group, 6.7%, respectively (**Table 3**).

**1 diabetes mellitus and in control group**

of the convective fluidic spaces.

\* p < 0.01.

20 Cognitive Disorders

**Table 3.** Characterization of the magnetic resonance pattern of the brain of patients with type 1 diabetes mellitus in comparison with the control group.

number series and serial subtraction). That is, the higher the levels of carbohydrate metabolism, the worse the memory and attention are (**Table 4**). On the part of other indicators of the MoCA, the connection was not found.

In assignments for attention, a negative correlation was found only with the protein S100 (r = −0.3, p = 0.02, r = −0.3, p = 0.004). We revealed relationship between the decrease in memory functions and the increase in the level was the decrease in memory functions with a simultaneous increase in the level of the studied neurospecific proteins, that is, the presence of a negative correlation with the S100 (r = −0.4, p = 0.001), GFAP (r = −0.4, p = 0.02), and MBP (r = −0.5, p = 0.001) proteins.

To assess the significance for the diagnosis of proteins, sensitivity and specificity were assessed. It was shown that they are highly specific and have a moderate sensitivity (**Table 5**).

Thus, in patients with type 1 diabetes mellitus and identified cognitive dysfunction, an increase in the content of all neurospecific proteins against hyperglycemia is characteristic. Based on the assessment of specificity and sensitivity, a high level of diagnostic significance of neurospecific proteins is shown, which makes it possible to use them in general medical practice.

When evaluating the effect of carbohydrate metabolism parameters on the change in the results of magnetic resonance imaging of the brain in patients with type 1 diabetes mellitus, positive correlation relationships were recorded. Thus, moderate strengths between the expansion of the cerebrospinal fluid and the level of HbA1c (r = 0.6, p = 0.001) and fasting glycemia (r = 0.5, p = 0.001) were revealed. In addition, connections have also been found with extensions of the Virchow-Robin spaces (r = 0.6, p = 0.001, r = 0.5, p = 0.001) and convective spaces (r = 0.5, p = 0.004, r = 0.3, p = 0.003) with the indices of carbohydrate metabolism. Analysis of the effect of cognitive dysfunction on the results of magnetic resonance imaging of the brain showed the presence of a bond. A correlation was found between memory loss in patients with type 1 diabetes mellitus and the expansion of arachnoid (r = −0.3, p = 0.02) and Virchow-Robin spaces (r = −0.3, p = 0.007). A link was also found between the decrease in attention and atrophy of gray matter in the brain in patients with type 1 diabetes mellitus. Patients with an expansion of arachnoid (r = −0.3, p = 0.007), convective spaces

**Figure 2.** A snapshot of the brain in the coronal projection in T2 mode is determined by the expansion of the convective fluidic spaces (photo by Matveeva, 2015).

**Figure 3.** A snapshot of the brain in the axial projection in the FLAIR mode in the white matter of the frontal and parietal lobes is determined by small foci of increased signal on T2 and FLAIR, without signs of perifocal edema, of a dystrophic nature (photo by Matveeva, 2015).

(r = −0.3, p = 0.007), and Virchow -Robin spaces were worse performing the tasks for attention ("numerical series" and "serial subtraction" by 7) (r = −0.3, p = 0.007). To assess the significance of changes reflected in magnetic resonance imaging of the brain in patients with type 1 diabetes mellitus, sensitivity and specificity were assessed. Morphological signs of gray matter atrophy of the brain, namely, arachnoid changes in the liquor cystic nature, widening of the convective

**Figure 5.** A snapshot of the brain in the coronal projection in the T2 mode in the thalamus region on both sides of unevenly expanded Virchow-Robin spaces is determined (two points according to MacLullich (2003)) (photo by Matveeva, 2015).

**Figure 4.** A snapshot of the brain in the coronal projection in T2 mode in the white matter of the frontal and parietal lobes,; the focus of the leukoareosis is determined by the severity of two points [8] (photo by Matveeva, 2015).

Cognitive Impairment in Patients with Diabetes Mellitus http://dx.doi.org/10.5772/intechopen.74388 23

spaces, and Virchow-Robin spaces, are highly sensitive, but are not specific (**Table 6**).

**Figure 4.** A snapshot of the brain in the coronal projection in T2 mode in the white matter of the frontal and parietal lobes,; the focus of the leukoareosis is determined by the severity of two points [8] (photo by Matveeva, 2015).

**Figure 5.** A snapshot of the brain in the coronal projection in the T2 mode in the thalamus region on both sides of unevenly expanded Virchow-Robin spaces is determined (two points according to MacLullich (2003)) (photo by Matveeva, 2015).

mellitus, sensitivity and specificity were assessed. Morphological signs of gray matter atrophy of the brain, namely, arachnoid changes in the liquor cystic nature, widening of the convective spaces, and Virchow-Robin spaces, are highly sensitive, but are not specific (**Table 6**).

(r = −0.3, p = 0.007), and Virchow -Robin spaces were worse performing the tasks for attention ("numerical series" and "serial subtraction" by 7) (r = −0.3, p = 0.007). To assess the significance of changes reflected in magnetic resonance imaging of the brain in patients with type 1 diabetes

**Figure 3.** A snapshot of the brain in the axial projection in the FLAIR mode in the white matter of the frontal and parietal lobes is determined by small foci of increased signal on T2 and FLAIR, without signs of perifocal edema, of a dystrophic

**Figure 2.** A snapshot of the brain in the coronal projection in T2 mode is determined by the expansion of the convective

fluidic spaces (photo by Matveeva, 2015).

22 Cognitive Disorders

nature (photo by Matveeva, 2015).


**Table 4.** Interrelation of the parameters of the MoCA test with HbA1c and fasting glycemia.

Thus, the obtained data showed the relationship of gray matter atrophy of the brain magnetic resonance imaging in patients with type 1 diabetes mellitus with chronic hyperglycemia and cognitive impairment. In addition, nonspecificity of the revealed changes was revealed in patients with type 1 diabetes mellitus in comparison with the control group.

type 1 diabetes have not been found [13]. Comparison of MBP with HbA1c and fasting glucose showed a positive correlation. Most likely, fluctuations in glycemia caused damage to the oligodendrocytes of the brain with the release of more MBP. In the literature, such data were not found. A third, but no less important, protein was the GFAP marker for astrocyte damage. In our study, a positive correlation was found between the parameters of carbohydrate metabolism and the level of GFAP, which indicates the effect of hyperglycemia on the mechanisms of apoptosis of astrocytes. The results obtained are confirmed by the studies of F.E. Saravia and coauthors; they showed the effect of hyperglycemia on higher amounts of GFAP during the manifestation of type 1 diabetes mellitus, when uncompensated hyperglycemia is observed,

Cognitive Impairment in Patients with Diabetes Mellitus http://dx.doi.org/10.5772/intechopen.74388 25

**Table 5.** Characteristics of specificity and sensitivity of neurospecific proteins as markers of cognitive dysfunction.

**NSP Value Sensitivity (%) Specificity (%)**

MBP ng/ml 0.1025 45.7 81 GFAP ng/ml 0.106 41.3 76.2 S100 ng/ml 65.15 58.7 95.2

As an additional method for evaluating cognitive dysfunction, magnetic resonance imaging of the brain was proposed; this was performed according to a standard procedure, that is, as screening without additional functional options. As a result of the study, signs of cerebral atrophy were found, namely, arachnoid changes in the liquor cystic and expansion of the convective fluidic spaces, which correlates with the data of the special literature [15]. The data obtained during the study confirm the presence of indirect signs of cerebral atrophy in patients with type 1 diabetes mellitus of a nonspecific type. In addition, the literature addresses the duration of type 1 diabetes mellitus and the possible weighting of morphological changes. In our study, the association with age and duration of the disease was not revealed. However, Trofimova et al. found that the degree of severity of structural changes in the brain substance is associated with the progression of type 1 diabetes mellitus and with an increase in the age of the patients [16]. In the study, an evaluation of the influence of glycemia on the morphological structure of the brain showed the relationship of hyperglycemia with the expansion of fluidic spaces, convective spaces, and Virchow-Robin spaces. In the literature, cases of atrophy of the gray matter of the brain, which was detected predominantly in the frontal lobes and central areas of the parietal lobes [17], is described, both in acute cases of ketoacidosis and prolonged increase in HbA1c. In addition to the relationship with the parameters of carbohydrate metabolism, the analysis revealed the relationship of cognitive impairments to brain atrophy, which was also noted in the publications of Hoogma [18]. In our study, there was a correlation of memory loss in patients with type 1 diabetes mellitus with an expansion of arachnoid and Virchow-Robin spaces (r = −0.3, p = 0.007). Also, a connection was found between poor performances of tasks for attention (numerical series and serial subtraction by 7) by patients with the expansion of arachnoid, convective spaces, and

that is, hyperglycemia has the greatest impact on brain damage [14].

Virchow-Robin spaces (r = −0.3, p = 0.007).

#### **2.5. Comparison of the results and literature data**

As methods for finding markers of cognitive impairments, neurophysiological and biochemical methods with certain limitations are described in the literature. We conducted a comprehensive study that included as a neuropsychological technique a screening MoCA test, an evaluation of neurospecific proteins, and a magnetic resonance imaging data in patients with type 1 diabetes mellitus. In our study, screening for cognitive dysfunction with the MoCA test showed a decrease in only memory function and attention in patients with type 1 diabetes mellitus, while other functions were not impaired. Analysis of the relationship of cognitive dysfunction with sex, age, and duration of the disease did not reveal these. The results confirm the meta-analysis conducted in 2007 by Brands and Bissels, where it was shown that there were moderate cognitive impairments that did not manifest themselves in daily life, but influenced the professional sphere, where high concentration, attention, and memory are required [1]. The question of the metabolic component as the cause of the development of cognitive dysfunction for a long time was debatable. The data obtained in this study on cognitive dysfunction allowed a mathematical analysis of the effect of carbohydrate metabolism on it and the effect of hyperglycemia on the development of cognitive dysfunction in patients with type 1 diabetes mellitus. In patients with type 1 diabetes mellitus, Russian scientists also noted a decrease in memory function, which worsened with chronic hyperglycemia [11]. In the endocrine community, a large-scale study on the control and complications of diabetes (DCCT/EDIC) is considered authoritative [12], which confirmed the absence of the effect of hypoglycemia on the development of cognitive dysfunction. The analysis of additional markers of cognitive dysfunction was carried out with the help of biochemical methods, which made it possible to evaluate neurospecific proteins. In patients with type 1 diabetes mellitus, S100, GFAP, and MBP proteins were elevated, which may indicate microscopic brain damage. One of the proteins studied was S100; as a result, it was found that patients with unsatisfactory control of carbohydrate metabolism had higher levels of S100 protein. So, a positive correlation of S100 protein with the HbA1c level and fasting glycemia was found, which can prove the role of chronic hyperglycemia in the dysmetabolic processes of the brain. A study of this protein in patients with type 1 diabetes mellitus was also conducted by Strachan (2000) [13], but significant changes in groups with


**Table 5.** Characteristics of specificity and sensitivity of neurospecific proteins as markers of cognitive dysfunction.

Thus, the obtained data showed the relationship of gray matter atrophy of the brain magnetic resonance imaging in patients with type 1 diabetes mellitus with chronic hyperglycemia and cognitive impairment. In addition, nonspecificity of the revealed changes was revealed in

**S100 MBP GFAP**

HbA1с r = −0.69; p = 0.01 r = −0.30; p = 0.01 r = −0.35; p = 0.04 Fast glucose r = −0.45; p = 0.02 r = −0.36; p = 0.01 r = −0.31; p = 0.01

p < 0.05.

**Table 4.** Interrelation of the parameters of the MoCA test with HbA1c and fasting glycemia.

As methods for finding markers of cognitive impairments, neurophysiological and biochemical methods with certain limitations are described in the literature. We conducted a comprehensive study that included as a neuropsychological technique a screening MoCA test, an evaluation of neurospecific proteins, and a magnetic resonance imaging data in patients with type 1 diabetes mellitus. In our study, screening for cognitive dysfunction with the MoCA test showed a decrease in only memory function and attention in patients with type 1 diabetes mellitus, while other functions were not impaired. Analysis of the relationship of cognitive dysfunction with sex, age, and duration of the disease did not reveal these. The results confirm the meta-analysis conducted in 2007 by Brands and Bissels, where it was shown that there were moderate cognitive impairments that did not manifest themselves in daily life, but influenced the professional sphere, where high concentration, attention, and memory are required [1]. The question of the metabolic component as the cause of the development of cognitive dysfunction for a long time was debatable. The data obtained in this study on cognitive dysfunction allowed a mathematical analysis of the effect of carbohydrate metabolism on it and the effect of hyperglycemia on the development of cognitive dysfunction in patients with type 1 diabetes mellitus. In patients with type 1 diabetes mellitus, Russian scientists also noted a decrease in memory function, which worsened with chronic hyperglycemia [11]. In the endocrine community, a large-scale study on the control and complications of diabetes (DCCT/EDIC) is considered authoritative [12], which confirmed the absence of the effect of hypoglycemia on the development of cognitive dysfunction. The analysis of additional markers of cognitive dysfunction was carried out with the help of biochemical methods, which made it possible to evaluate neurospecific proteins. In patients with type 1 diabetes mellitus, S100, GFAP, and MBP proteins were elevated, which may indicate microscopic brain damage. One of the proteins studied was S100; as a result, it was found that patients with unsatisfactory control of carbohydrate metabolism had higher levels of S100 protein. So, a positive correlation of S100 protein with the HbA1c level and fasting glycemia was found, which can prove the role of chronic hyperglycemia in the dysmetabolic processes of the brain. A study of this protein in patients with type 1 diabetes mellitus was also conducted by Strachan (2000) [13], but significant changes in groups with

patients with type 1 diabetes mellitus in comparison with the control group.

**2.5. Comparison of the results and literature data**

Note: The significance of the correlation: \*

24 Cognitive Disorders

type 1 diabetes have not been found [13]. Comparison of MBP with HbA1c and fasting glucose showed a positive correlation. Most likely, fluctuations in glycemia caused damage to the oligodendrocytes of the brain with the release of more MBP. In the literature, such data were not found. A third, but no less important, protein was the GFAP marker for astrocyte damage. In our study, a positive correlation was found between the parameters of carbohydrate metabolism and the level of GFAP, which indicates the effect of hyperglycemia on the mechanisms of apoptosis of astrocytes. The results obtained are confirmed by the studies of F.E. Saravia and coauthors; they showed the effect of hyperglycemia on higher amounts of GFAP during the manifestation of type 1 diabetes mellitus, when uncompensated hyperglycemia is observed, that is, hyperglycemia has the greatest impact on brain damage [14].

As an additional method for evaluating cognitive dysfunction, magnetic resonance imaging of the brain was proposed; this was performed according to a standard procedure, that is, as screening without additional functional options. As a result of the study, signs of cerebral atrophy were found, namely, arachnoid changes in the liquor cystic and expansion of the convective fluidic spaces, which correlates with the data of the special literature [15]. The data obtained during the study confirm the presence of indirect signs of cerebral atrophy in patients with type 1 diabetes mellitus of a nonspecific type. In addition, the literature addresses the duration of type 1 diabetes mellitus and the possible weighting of morphological changes. In our study, the association with age and duration of the disease was not revealed. However, Trofimova et al. found that the degree of severity of structural changes in the brain substance is associated with the progression of type 1 diabetes mellitus and with an increase in the age of the patients [16]. In the study, an evaluation of the influence of glycemia on the morphological structure of the brain showed the relationship of hyperglycemia with the expansion of fluidic spaces, convective spaces, and Virchow-Robin spaces. In the literature, cases of atrophy of the gray matter of the brain, which was detected predominantly in the frontal lobes and central areas of the parietal lobes [17], is described, both in acute cases of ketoacidosis and prolonged increase in HbA1c. In addition to the relationship with the parameters of carbohydrate metabolism, the analysis revealed the relationship of cognitive impairments to brain atrophy, which was also noted in the publications of Hoogma [18]. In our study, there was a correlation of memory loss in patients with type 1 diabetes mellitus with an expansion of arachnoid and Virchow-Robin spaces (r = −0.3, p = 0.007). Also, a connection was found between poor performances of tasks for attention (numerical series and serial subtraction by 7) by patients with the expansion of arachnoid, convective spaces, and Virchow-Robin spaces (r = −0.3, p = 0.007).


**Table 6.** Characteristics of specificity and sensitivity of signs of magnetic resonance imaging.
