**2. Pilot study: identification of cognitive impairment markers (neurospecific proteins, magnetic resonance tomography) in patients with type 1 diabetes mellitus**

complications from the central nervous system, manifested by morphological and functional disorders. The reflection of brain neuroplasticity is the dynamics of cognitive impairment.

According to the latest revision of the international guidelines for the diagnosis of mental disorders, cognitive disorders include a decrease in one or more higher cerebral functions, in comparison with the premorbid level, that provide the processes of perception, preservation, transformation, and transmission of information. The presence of cognitive impairments has an extremely negative effect on the quality of life of the patient and their immediate family and complicates the treatment of concomitant diseases and the conduct of rehabilitation activities. Therefore, timely diagnostics and the earliest possible initiation of therapy for exist-

**Figure 1** shows that the effect of dysglycemia in the debut of type 1 diabetes mellitus, especially in childhood, leads to a statistically more significant pronounced cognitive impairment,

To date, it is urgent to search for a quick, simple, and well-tried method for diagnosing cognitive impairment, taking into account the minimum costs. One of the promising methods that can be considered is the identification of neurospecific proteins, which are signals of brain damage [2–4]. To diagnose central nervous system diseases, magnetic resonance methods of brain examination are used as additional techniques for detecting morphological changes [5, 6].

**Figure 1.** The trajectory of disorders from the brain's magnetic resonance imaging data in patients with type 1 diabetes mellitus is associated with loss of brain volume (blue line, evolution of brain volumes with age in the general population, and red line, estimated trajectories for type 1 diabetes mellitus (A), and brain atrophy is a loss of neuron communication (B)) [1].

ing cognitive disorders are very important.

16 Cognitive Disorders

as well as structural changes in the brain over time [1].

The study of cognitive dysfunction in patients with type 1 DM was carried out at the clinical bases of the Departments of Endocrinology and Diabetology, Neurology and Neurosurgery of the Siberian State Medical University, and the plan and the study were in full compliance with the principles of Good Clinical Practice (GCP) and Helsinki Declaration (including amendments).

The study included 116 patients with type 1 diabetes mellitus at the age of 22.4 ± 4.6 years, 58 men and 58 women, and the duration of the disease was 6.6 ± 3.9 years. The control group consisted of 29 healthy people, aged 22.4 ± 4.8 years, 14 men and 15 women, without acute and chronic diseases. Inclusion criteria are patients with type 1 diabetes mellitus at the age of 16–30 and signed informed consent of the patient to participate in the study.

Exclusion criteria are hypoglycemic and ketoacidotic coma for 1 year prior to study; presence of hematological, oncological, and serious infectious diseases; condition after severe craniocerebral injuries and surgeries; participation in other clinical trials in the last 30 days; and now refusal to sign an informed consent of the patient to participate in the study.

To detect violations of carbohydrate metabolism, glucose was determined by the glucose oxidase method on the biochemical analyzer "Hitachi 912" (Hoffmann-La Roche Ltd./Roche Diagnostics GmbH, Germany). HbA1c content was analyxed in capillary blood - by liquid chromatography method on DS5 Glycomat analyzer (Drew Scientific, the Netherlands).

With the biochemical methods of research, the content of neurospecific proteins in plasma was determined. To analyze the quantitative content of the S100 protein (S100A1B + S100BB), a kit was used (FujirebioS100 EIA, BioC himMak, Russia). GFAP was determined by enzyme immunoassay using a standard protocol using a reagent kit from the manufacturer (BioVendor Laboratory Medicine, Inc., Germany). The myelin basic protein (MBP) level was studied using the "DSL-10-58,200" kit (BioChimMak, Russia). The complex of mandatory diagnostic methods included magnetic resonance imaging of the brain on the Harmony 1.0 T apparatus (Siemens, Germany) by MDCS-Tomsk Ltd., which was carried out according to the standard procedure in the axial, sagittal, and coronal projections using T2 (TR (time of repetition) 4932 ms, TE (Echotime) 90 ms) and T1 (TR 280 ms, TE 6.1 ms) and using programs with free water signal suppression fluid-attenuated inversion recovery (FLAIR; TR 8000 ms, TE 105 ms, TI (time in version) 2200 ms). Evaluation of gliosis foci of brain substance was carried out according to the size and quantity in the frontal (subcortical, paraventricular), temporal (white matter, hippocampal area), parietal (subcortical, paraventricular), and occipital (subcortical, paraventricular) areas. Taking into account the classification of F. Fazekas, in the modification of NN Yakhno, a quantitative gradation of focal changes in the white matter was carried out [7]. The severity of leukoareosis was assessed in scores proposed by Liu et al. [8]. For the quantitative evaluation of the expansion of perivascular spaces, the estimated scale of MacLullich [9] was used.

Screening for mild and moderate cognitive impairment was performed using the MoCA test, which assesses various cognitive functions: visual–spatial perception (the test of drawing a clock and a cube); executive functions (task of creating an alternating path and testing the ability to abstract thinking); attention, concentration, and operational memory (serial subtraction by 7 and playback of the digital series in forward and reverse order); and speech (naming animals, repetition of two syntactically complex sentences) and the specificity of the method is 90% [10]. Statistical processing of the obtained data was carried out using the application software package R Systems International.

Characteristics of the carbohydrate metabolism parameters showed a difference in the parameters between the main group and the control group. The average level of HbA1c in patients with type 1 diabetes mellitus was 8.8 ± 1.8%, and the average level of fasting glycemia was 11.5 ± 5.0 mmol/l. This indicated an unsatisfactory metabolic control. In addition, differences in the parameters of carbohydrate metabolism were revealed taking into account gender characteristics, so women had better values of fasting and HbA1c glycemia than men.

In the control group, healthy volunteers complained of asthenic syndrome (37.9%), manifestations of which were fatigue (13.3%), dizziness (6.7%), and headache (16.9%). Patients with type 1 diabetes mellitus also had these complaints but in a more pronounced form. The next in frequency recorded cephalic syndrome, occurring in 25.9% of patients. Among the localizations, the most frequent areas were occipital (60%) and temporal (2.6%) areas, with the same frequency; headache was diffuse and was found in the frontal region. The most common cause of headache was overexertion due to stress. In addition, complaints were found from the peripheral nervous system on paresthesia (37.9%), pain (22.4%), numbness (12.1%), and convulsions in the lower extremities (6.9%). Often, patients with type 1 diabetes mellitus complained of memory loss. This was manifested by the difficulty in concentrating, remembering new information, and solving short-term problems. The objective status of patients was characterized by autonomic symptoms, manifested as anxiety. Neurological symptoms of the examined patients were mainly represented by disorders of the autonomic nervous system, namely, distal and diffuse hyperhidrosis (in 43.1% of patients) and persistent red spilled dermographism (in 22.4% of patients) in the face, neck, and décolleté area. The manifestations of lesions of the peripheral nervous system were in the form of diabetic polyneuropathy. Sensory disorders were noted from the lower extremities in 62% of cases and the upper ones in 27.5%. A clinical study of random movements in the limbs with an evaluation of the tone revealed a hypotonia of the upper limbs in 51.7% and lower in 34.5% of cases.

five words and repeating them after subsequent tasks in about 5 minutes. Patients with type 1 diabetes mellitus had difficulty in reproducing words, were confused, and invented new words. At the same time, this task was performed unsatisfactorily by both men and women. The attention function was evaluated using two tasks. The first task is a numerical series, that is, a repetition of the numbers mentioned. With this task men were worse than women. The

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

p < 0.001, m is the median, and SD is the standard deviation.

**Table 1.** Characteristics of the MoCA test parameters in patients with type 1 diabetes mellitus and control group.

**Parameters Type 1 DM (n = 98) Control group (n = 29)**

Cognitive Impairment in Patients with Diabetes Mellitus http://dx.doi.org/10.5772/intechopen.74388 19

Alternating Trail Making 3.0 ± 0.4 3.0 ± 0.1 Alternating path (drawing) 3.0 ± 0.8 3.0 ± 0.1 Cube (drawing) 3.0\* ± 1.3 5.0 ± 0.2 Clock (drawing) 2.0\* ± 0.6 2.0 ± 0.1 Naming 1.0 ± 0.9 1.0 ± 0.1 Memory 2.0\* ± 0.8 3.0 ± 0.1 Number series 2.0 ± 0.4 1.8 ± 0.4 Concentration 1.0 ± 0.8 0.8 ± 0.3 Serial subtraction by 7 2.0 ± 0.4 2.0 ± 0.1 Repeat suggestions 6.0 ± 0.2 6.0 ± 0.1 Fluency of speech 25.0\* ± 0.8 30\* ± 0.4 Abstraction 3.0 ± 0.4 3.0 ± 0.1 Orientation 3.0 ± 0.8 3.0 ± 0.1 Sum of points 3.0\* ± 1.3 5.0 ± 0.2

**2.2. Analysis of parameters of neurospecific proteins in patients with type 1 diabetes** 

As a result of the analysis, a significant increase in all studied proteins was revealed in patients with type 1 diabetes mellitus, S100, MBP, and GFAP, compared to the control group

The levels of neurospecific proteins, depending on the duration of the disease, had fluctuations. So, the S100 protein was higher in patients with a short duration of the disease (1–4 years) and the smallest with duration of the disease for more than 15 years. While MBP had an equally stable level in patients with different durations of type 1 diabetes mellitus. The fluctuations in the level of GFAP were also insignificant and tended to decrease with increasing duration of the disease. According to our study, in women, the level of GFAP was

second task is the serial subtraction by 7, which was given equally hard.

significantly lower than in men (U = 643.0, z = −2.4, p < 0.05).

**mellitus**

(p < 0.001) (**Table 2**).

parameters of MoCA test: \*
