Когнитивни и поведенчески нарушения при пациенти с множествена склероза
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Дата
2018-11-26
Автори
Кунчев/Kunchev, Тодор Ангелов/Todor Angelov
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Издател
Резюме
ЦЕЛ И ЗАДАЧИ *****
Целта на настоящата работа е да се установи профила на когнитивните нарушения в кохорта български пациенти с множествена склероза в зависимост от продължителността на заболяването им и тези данни да бъдат корелирани с ключови показатели от образните изследвания на централната нервна система, както и с биомаркери в цереброспиналната течност и серума на болните –амиолид-бета и тау протеини в ликвор и ApoE генотипна характеристика. ***
За осъществяване на целта са поставени следните ЗАДАЧИ: ***
1. Разработване и усвояване на специализиран невропсихологичен инструментаиум за определяне на когнитивен профилспоред известните му особеностипри множествена склероза;
2. Събиране на кохорта от пациенти с множествена склероза;
3. Детайлно клинично фенотипизиране на пациентите чрез клинични, невропсихологични, невроизобразяващи и лабораторни методи;
4. Провеждане на невропсихологични изследвания при пациентите чрез използване на установената невропсихологична батерия и сравняване на получените резултати с тези на здрави контроли, съответстващи по възраст и образователен ценз на изследваните лица;
5. Провеждане на невроизобразяващи изследвания в групата пациенти с множествена склероза;
6. Провеждане на лумбална пункция при пациенти с множествена склероза, изразили в писмен вид информирано съгласиеза провеждане на манипулациятаи изследване на цереброспиналната течност за количествено определяне на амилоид-бета и тау протеини;
7. Вземане на периферна кръв и изолиране на ДНК при пациенти с множествена склероза, изразили в писмен вид информирано съгласие за провеждане на генетични изследвания, ApoE генотипизиране на пациентите и сравняване на получените резултати с тези на здрави контроли, изразили съгласието си за участие под същата форма;
8. Сравняване на резултатите от невропсихологичните изследвания при пациентите с множествена склероза в зависимост от продължителността на заболяването им;
9. Изследване на корелациите между невропсихологичните резултати на пациентите с множествена склероза и ключови показатели от невроизобразяващите изследвания, отразяващи тежестта на невровъзпалителната и невродегенеративна (глобална и регионална) компонента на заболяването ;
10. Изследване на корелациите между невропсихологичните резултати на пациентите с множествена склероза и получените резултати от количественото определяне на ликворните биомаркери;
11. Сравняване на резултатите от невропсихологичните изследвания при пациентите с множествена склероза в зависимост от ApoE генотипа им. ***** SUMMARY
Multiple sclerosis is a chronic progressive autoimmune disease of the central nervous system characterized by the presence of inflammatory plaques of demyelination in the brain and spinal cord. Among the many unanswered questions regarding multiplesclerosis is the pathogenesis of cognitive dysfunction observed in this disease. Its high frequency, its presence in all the disease courses and its significant impact in a certain percent of the cases turn this aspect of multiple sclerosis into one of its most debilitating features which greatly worsens patients’ quality of life.Depression and fatigue, on the other hand, show great inter-patient variability and conflicting data on the connection between them and with the degree of physical disability and disease duration. Current neuroimaging methods have changed the classic notion that cognitionin multiple sclerosis is a function only of the number and size of demyelinatinglesions -brain atrophy and cortical pathology have proved their significance in the genesis of cognitive dysfunction.In the meantime, research continues on trying to find a reliable biomarker of the disease which would individually indicate disease progression and would guide therapy approach. In addition, there is also conflicting data on the relation between apolipoproteinE (ApoE) genetic status and susceptibility to multiple sclerosis and its activity.
The aim of this study was to characterize the profile of cognitive dysfunction in a Bulgarian cohort of multiple sclerosis patients as a function of disease duration and to correlate this data with key neuroimaging indicators, as well as with biomarkers in the serum and cerebrospinal fluid (CSF) –amyloid beta and tau in CSF and ApoE genetic status.
Materials and methods: 100 multiple sclerosis patients underwent detailed neuropsychological assessment with a battery comprising tests for general cognitive functioning, episodic verbal and visuo-spatial memory, verbal fluency, attention, executive function, depression and fatigue and their reults were compared to those of 57 healthy controls. 37 patients underwent MRI examination; the results of 22 patients were assessed using the Pasquier and Scheltens visual scales for general cortical atrophy and medial temporal atrophy respectively; 3D double inversion recovery (DIR) sequence was added to the standard protocol for 15 patients and their results were assessed by two radiologists including cortical lesions, cortical atrophy and white matter lesion load. 43 patients underwent genetic testing for ApoE status and the results were compared to those of 108 healthy controls. 15 patients underwent lumbar puncture and were tested for amyloid-beta and tau quantities inCSF, these results were compared to those of 15 patients with Alzheimer’s disease.
Results and discussion: Cognitive dysfunction in multiple sclerosis was detected even during the first year of disease course. The cognitive profile was not static and changed with disease progression–during the first years of disease, when the neuroinflammatory component was the leading cause of damage, patients demonstrated predominantly dysexecutive features, information processing disturbance and deficits in attention,verbal fluency and memory retrieval, while in the more advanced stages of disease, when the neurodegenerative component was the leading cause of damage, this specific cognitive profile was lost and universal deficits in almost all cognitive domains were observed.Tests for executive functioning were observed to be best for clinical practice due to their abilities for early detection of cognitive dysfunction and its adequate tracing in disease progression –Symbol Digit Modalities Test (SDMT), Digit Symbol Modalities Test (DSMT), Trail Making Test (TMT), verbal fluency tests, Stroop Color Word Test (SCWT). The Montreal Cognitive Assessment (MoCA) scale for global cognitive functioning turned out to be much more sensitive than the Mini-Mental State Examination (MMSE) scale in its ability to trace cognitive dysfunction in disease progression.
Depression scores were strictly individual in each patient and did not correlate with disease duration, but strongly correlated with the presence of cognitive dysfunction.
Fatigue scores showed a greater, although weak, correlation with disease duration and also strongly correlated with the presence of cognitive dysfunction.
Brain atrophy markers were much more sensitive to the degree of cognitive dysfunction than white matter lesion load markers. Specific cognitive domains correlated with specific patterns of brain atrophy –medial temporal lobe atrophy correlated with results in verbal and non-verbal episodic memory tests and verbal fluency, while general cortical atrophyunspecifically correlated with the results of most tests. Cortical lesion load correlated with the degree of cortical atrophy as a possible factor in its genesis; cortical atrophy also correlated with the number of periventricular lesions as a possible marker for a still unknown inflammatory factor in the CSF driving greater damage in these compartments.
The patients’ levels of tau in the CSF were above the reference range and the levels of amyloid-beta were lower than the reference range of the used method. The levels of amyloid-beta decreased with disease progression and the patients’ age and correlated with the results for episodic verbal memory, indicating their ability to trace neurodegeneration and possibly hippocampal damage in multiple sclerosis. Still, and unsurprisingly, tau levels were significantly lower and amyloid-beta levels significantly higher than those of the patients with Alzheimer’s disease.
ApoE genetic status failed to show significant correlations with multiple sclerosis susceptibility and disease activity.
Описание
Дисертационен труд за присъжданена ОНС „Доктор“; Научна специалност: Неврология. Научни ръководители: Чл. кор. проф. д-р Лъчезар Динчов Трайков, дмн, Доц. Маргарита Радославова Райчева, дп. София
2018
Ключови думи
множествена склероза; когнитивни нарушения; времеви фактори; образна диагностика; изследване на серум; ApoE генетична характеристика , multiple sclerosis; cognitive disturbances; time factors; neuroimaging; blood serum examinations; ApoE genetic status=