cognitive dysfunction in type 2 diabetes mellitus patients

Not yet recruiting

• Conditions: Type 2 diabetes mellitus with other specified complications,

• Registration Number: CTRI/2019/01/016877
• Lead Sponsor: Kasturba Medical College Manipal

Brief Summary

**Introduction**

Magnitudeof type 2 diabetes mellitus (T2DM) is ever increasing in India and at present ~69 million people are living with diabetes [1]  and another ~ 77 million people are pre-diabeticsubjects, having high potential for the development of T2DM [2]. Uncontrolledserum glucose levels for extended durations are associated with retinopathy,nephropathy, neuropathy as well as cardiovascular, cerebrovascular andperipheral vascular diseases. Recently cognitive dysfunction (CD) in T2DM isgaining much attention due to their co-occurrence.  Major cognitive dysfunctions associated withT2DM are psychomotor speed, executive function, verbal memory and processingspeed, working memory, immediate and delayed recall, verbal fluency, visualretention and attention [3].

Morethan half of the brain is constituted by lipids. They play critical roles in maintainingthe brain’s structural and functional components [4,5,6].Sphingolipids areclass of lipids that are present in higher concentration in the brain comparedto that in the plasma. Sphingolipids constitutes ~22% dry weight of the humanbrain white matter where as it constitutes only 5% dry weight of plasma[7,8,9]. Certain sphingolipid species are enriched highly in brain while theirlevels are relatively low abundance in all other tissues and some of theirlevels are 20-90 fold higher in brain than in plasma [10].Presence of certainspecific classes of brain lipids in the serum makes it an ideal marker to studythe possible abnormalities occurring in its composition during diseaseconditions.

Thusperforming a targeted lipidomics of the serum samples from T2DM patients withcognitive dysfunction and its comparison to T2DM patients without CD canprovide us an insight into the role of these molecules in management of suchpatients.

 **Literature survey**

In a French population study with 59-71 age group diabeticpatients’ cognitive decline was higher compared to non-diabetic individuals [11].A study in older than 60 years of Latinos indicated that diabetes was asignificant predictor for major cognitive decline [12] with 4.8% diabeticpatients showing severe CD known as dementia at this age group while prevalenceof CD was 31% in diabetic people aged more than 85 years [13].Asystematic review of the cognitive decline in diabetes showed 1.2 to 1.5 foldincrease in rate of decline in cognitive ability in diabetes compared tonon-diabetic population [14]. In a Japanese elderly population study, comparedto non-diabetic groups, diabetics had a significant cognitive decline, whichwas well correlated with hippocampal atrophy but not whole brain atrophy [15]. In a Croatian study on adult population diabetics hadhigher cognitive dysfunction compared to controls [16]. In an US study,diabetes was associated with cognitive decline (1.39 fold) in elderly personabove 70 years of age [17]. In a Polish study, 31.5% diabetics had CD,the age group was above 65 years [18]. In a Taiwanesestudy with an age group of 65 or above, 11.5% of the diabetic population had CDcompared to control population [19]. In a Chinese large cross sectional study13.5% of the diabetic population above 65 years of age had mild cognitivedysfunction [20].In an Australian adult population study, cognitive decline wasassociated with impaired cerebrovascular responsiveness in T2D [21]. In aGreece population study of diabetic patients above 65 years of age, 2 foldhigher chances of CD was observed compared to control population [22].

 The relationshipbetween T2DM and dysfunction of lipids have led to many lipidomics studies. Large number of studiesshowed variations in lipidomics in T2DM patients which is not a surprise basedon the fact that alterations  in lipidmetabolism is a well-known fact in T2DM. Additionally, both targeted and untargetedlipidomics studies have been performed in cognitive dysfunction. Non-targeted lipidomics offrontal cortex grey and white matter in control and mild cognitive impairmentsubjects revealed that phosphatidylethanolamines were reduced in white matterwhere as diacyl glycerol levels were elevated in grey matter [23]. Targeted fattyacid lipidomics of plasma in mild cognitive impairment revealed higher levelsof arachidic, erucic, mead and vaccenic acid andlower levels of cerotic and linoleic acid compared to healthy controls [24].In another study, targeted lipidomics of plasma and frontal cortexdiacylglycerols in mild cognitive impairment revealed elevated levels of diacylglyerols with saturated, unsaturated,and polyunsaturated fatty acid substituents compared to healthy controls [23].

**Research gaps identified**

We have magnitude data about cognitive dysfunctionin type 2 diabetes mellitus from several parts of the world although with muchvariations in sample size and age groups. However, we do not have the detaileddata of magnitude of T2DM patients with CD from the Indian population which weassume to be different due to significant dietary variations as well as lifestyle factors which are well associated with cognitive functions. Further, we didnot find any studies that were performed to link T2DM with CD through lipidomicsapproach.

**Objectives**

·        To measure the magnitude of cognitive dysfunctionin T2DM patients

·        To compare serum targeted lipidomics in T2DMpatients with and without cognitive dysfunction

·        Identifying key lipid molecules altered incognitive dysfunction in type 2 diabetes mellitus for future studies

**Detailed methodology**

Followingapproval from the IEC and obtaining informed consent from the previouslyidentified T2DM patients, digital symbol Substitution and Montreal cognitivetests will be performed to measure the magnitude of cognitive dysfunction inT2DM patients. Anticipating 8% of diabetes to report of cognitive dysfunctionwith a 20% relative precision at 95% confidence level accounting for 20%non-response minimum of 1278 T2DM patients will be recruited for this study. Fortargeted lipidomic studies, 2ml of fasting blood will be collected from 20 T2DMpatients each with and without cognitive dysfunction. If the patient alreadygives the serum sample for biochemical analysis the residual serum samples willbe collected from the Biochemistry lab, KMC Manipal. The serum samples will bestored in -80 degree centigrade freezer. The samples will then be transported toCCAMP- NCBS Mass spectrometry Facility in Bangalore in a box of liquid nitrogenmaintaining -80 degree centigrade temperature .Less than 100 μl serum will beused for lipidomic studies. Lipidomics analysis will be done by LiquidChromatography – Mass Spectrometry (LC-MS) technology at CCAMP- NCBS Massspectrometry Facility, Bangalore.

**Inclusionand exclusion criteria**

—  **Inclusioncriteria for the 1st objective:** All T2DM patients above 20 years  of age with informed consent  visiting the hospital of various age groupsready to volunteer

—  Minimum of 5 years of formal education

—  Patients having all the co-morbidities includinghypo and hyperthyroidism, hypertension, CAD, kidney and liver diseases, HIV,Vitamin B12 deficiency and any other infectious diseases

·        **Exclusion criteria for 1stobjective:**T2DM patientswho are severely sick and un co-operative for performing the cognitive tests

·        Patients withvisual impairment, confusion and delirium

·        **Inclusion criteria for the 2ndobjective**-  T2DM patients above 60 years of age with morethan 10 years of diabetes without any complications who are ready to volunteerwith informed consent

·        **Exclusion criteria for the 2ndobjective** - T2DM patients suffering from hypo and hyper thyroidism, hypertension,HIV, Vitamin B12 deficiency, kidney, liver and other infectious diseases

**MontrealCognitive Assessment (MoCA)**

The instrument which can be used for screening mildcognitive impairment is Montreal Cognitive Assessment (MoCA). Thescreening instrument which was designed for detecting mild cognitive impairmentis Montreal Cognitive Assessment (MoCA). Ziad Nasreddinefrom Montreal, Quebec developed the MoCA scoring system. This is a worldwide used screening assessment. The MoCA test is a paper and pencil test. It isa single page 30-point test which approximately takes 10 minutes to beadministered. The availability of the full test and the instructions to befollowed in administering the MoCA are accessible in online for clinicians and educational purposes. The availability of the test is in 56 languages anddialects. A validation study done by Nasreddine inthe year 2005 proved MoCA to be more useful tool than MMSE in detecting mildcognitive impairment.

The MoCA is an instrumentwhich is used for screening cognitive dysfunction. This is basically a paperand pencil test and the time administered for this test is 10 minutes. Variouscognitive domains such as language, memory, executive functions, visuospatialskills, calculation, abstraction, attention, concentration and orientation areassessed from this test. The validation of the test has been established indetection of mild cognitive impairment suffering from Alzheimer’s disease andother pathological conditions in subjects with mild cognitive impairment whoscored in the normal range of MMSE According to a study in 2015 the sensitivityand specificity of the MoCA for detecting MCI were found to be 90% and 87%respectively, compared with 18% and 100% respectively for the MMSE. Variousfeatures in the MoCA designing explain its sensitivity to a superior level formild cognitive impairment detection. More number of words, fewer trials oflearning and a longer delay before recall are there in the MoCA test ratherthan the MMSE. MoCA can also assess executive functions, language abilities,processing of complex visuospatial abilities in a higher level than MMSE. Thegeneral MoCA was basically normed for a highly educated population because itwas developed in a setting of memory clinic. Later a basic MoCA which is wellknown as MoCA B was developed for the less educated and literate people tofulfill the limitation of the general MoCA test. The scoring system of MoCAranges in between 0 and 30. A person is said to have proper cognitivefunction when he/she scores 26 or above. A study in the past showed normalpeople scoring an average of 27.4 and people with [mild cognitive impairment](https://en.wikipedia.org/wiki/Mild_cognitive_impairment "Mild cognitive impairment") (MCI)scoring an average of 22.1 in the MoCA test.

**Digital Symbol Substitution test**

A frequent consequence of brain disordersslowed mental processing and impaired ability for focused behavior (Duncan andMirsky 2004, Leclercq and Zimmermann 2002). Damage to the brain stem or diffusedamage involving the cerebral hemispheres, especially the white matterinterconnections can produce a variety of attentional deficits. Attentionaldeficits are very common in neuropsychiatric disorders. Most neuropsychologicaldeficits are very common in neuropsychiatric disorders. The Wechsler’s part ofintelligence test contains several such relevant tests among which Digit Symbolsubstitution test is one of them. Digit Symbol Substitution test is anexcellent measure of focused attentional capacity. This test requiresconcentration plus motor and mental speed for successful performance andrequires rapid processing of symbolic informations and coding of symbol numberpairs. The patient must accurately and rapidly code numbers into symbols.Performance is determined by the number of correct numbers transcribed in 90seconds. Copyright versions of Montreal Cognitive test will be used for thisstudy after taking permission from the respective website. The DSST test is apart of Weschler’s Adult Intelligence Skill which assessed mental speed. It isa test which is procured by the Clinical Psychology department, KMC Manipal.This test can be administered from patients within age groups 16-85 years. Thetime limit for the subtest is a maximum of 120 seconds [25].

 **Expected Outcome**

There is a possibility of getting certainclass of sphingolipids which may be up-regulated and down-regulated in T2DMpatients suffering from CD. This information may be helpful for therapeuticintervention studies in future.

**Importance of theproposed research**

The data generated may give critical inputs for the role of sphingolipidssubclasses in the occurrence of CD in T2DM patients.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-01-15
• Last Update Posted: 2019-02-01

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 1278

Inclusion Criteria

1st objective:1) All T2DM patients above 20 years of age with informed consent visiting the hospital of various age groups ready to volunteer 2)Minimum of 5 years of formal education 3)Patients having all the co-morbidities including hypo and hyperthyroidism, hypertension, CAD, kidney and liver diseases, HIV, Vitamin B12 deficiency and any other infectious diseases 2nd objective- 1)T2DM patients above 60 years of age with more than 10 years of diabetes without any complications who are ready to volunteer with informed consent.

Exclusion Criteria

1st objective: 1)T2DM patients who are severely sick and unco-operative for performing the cognitive tests 2)Patients with visual impairment, confusion and delirium 3)Exclusion criteria for the 2ndobjective -T2DM patients suffering from hypo and hyper thyroidism, hypertension, HIV, Vitamin B12 deficiency, kidney, liver and other infectious diseases.

Study & Design

• Study Type: Observational
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Assessing cognitive dysfunction in type 2 diabetes mellitus patients and to find out whether there is a possibility of getting certain class of sphingolipids which may be up-regulated and down-regulated in T2DM patients suffering from CD. This information may be helpful for therapeutic intervention studies in future.	one time

Secondary Outcome Measures

Name	Time	Method
to find out whether there is a possibility of getting certain class of sphingolipids which may be up-regulated and down-regulated in T2DM patients suffering from CD. This information may be helpful for therapeutic intervention studies in future.	one time

Trial Locations

Locations (1)

Kasturba Hospital Manipal; 🇮🇳 Udupi, KARNATAKA, India

Kasturba Hospital Manipal

🇮🇳Udupi, KARNATAKA, India

Arpita Chakraborty

Principal investigator

6290941523

arpita.chakraborty2013@gmail.com