Depressie en cognitie

bij type 2 diabetes

Miranda Schram

afdeling Interne Geneeskunde MUMC+

Disclosure potential conflicts of interest

Geen (potentiële) belangenverstrengeling

Voor bijeenkomst mogelijk relevante relaties:

Bedrijfsnamen

•  Sponsoring of onderzoeksgeld •  -

•  Honorarium of andere (financiële) vergoeding

•  -

•  Aandeelhouder

•  -

•  Andere relatie, namelijk …

•  -

Eén derde van de volwassen Limburgers heeft (pre)diabetes

… 2 van 6 vakken met publiek

• Risk of depression in type 2 diabetes is doubled

• QoL ↓, societal costs ↑

• Mortality risk ↑: OR for mortality 1.46 * OR for cvd mortality 1.39 *

Type 2 diabetes and depression

* F. van Dooren et al, Plos One 2013; 8(3):e57058

Course of depression in type 2 diabetes

•  Paucity of data

•  Probably a chronic course

• Under reported, under recognised, under

treatment

•  Treatment resistance, ineffective treatment?

• Different etiology than early life depression

• Biology largely unknown

Course of depression in type 2 diabetes

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Mechanisms

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Mechanisms

Endothelial dysfunction

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Inflammation

Mechanisms

We investigated the associations between markers of -  Hyperglycemia (glucose, AGEs) -  Inflammation, and -  Endothelial dysfunction with depressive symptoms and depressive disorder in a population-based study

Research questions

Endothelial dysfunction

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Inflammation

Mechanisms

The Maastricht Study

§  10,000 participants, 40-75 years

§  From the Maastricht area

§  Oversampling of type 2 diabetes

§  Advanced ‘deep’ phenotyping

§  Survey I: 2010-2018

§  Dataset n~3400 (Nov’10-Sept’13)

Eur J Epidemiology (2014) 29:439-451

Extremely detailed phenotyping

Depression PHQ-9, MINI diagnostic interview (gold standard) Diabetes Oral glucose tolerance test Glycemic control (fasting gluc, HbA1c, AGEs: SAF, Pentosidine, CEL, CML) Inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) Endothelial function (sVCAM-1, sICAM-1, sE-selectin, vWF) MRI (brain atrophy and cerebral small vessel disease) Lifestyle (physical activity, sedentary time, nutrition)

Methods

General characteristics

    No type 2 diabetes

(n=2349)

Type 2 diabetes

(n=918)

Age, years 58.7 ± 8.2 62.6 ± 7.6

Female sex, n (%) 1291 (55%) 298 (33%)

Partner, n (%) 1972 (85%) 731 (82%)

Educational level, % low/middle/high 28/28/44 46/28/26

HbA1c, % 5.5 ± 0.4 6.9 ± 1.0

Smoking, % never/former/current 37/50/12 28/56/16

Body mass index, kg/m2 26.0 ± 3.9 29.9 ± 5.0

Blood pressure, mmHg 132 ± 17 / 76 ± 10 142 ± 18 / 77 ± 10

Total cholesterol, mmol/l 5.5 ± 1.1 4.5 ± 1.0

HDL cholesterol, mmol/l 1.61 ± 0.47 1.27 ± 0.37

N= 3267

Prevalence of depression

3,4

1,4

2,7

4,0

6,2

2,7

6,3

9,0

0

1

2

3

4

5

6

7

8

9

10

PHQ-9 score > 10 Minor depression Major depression Major and minor depression

prev

alen

ce in

%

Non-DM

DM2

*

* *

*

Association of depression with T2DM

Odds ratio 95% CI p-value

Depressive symptoms      

PHQ-9 score (continuous) 1.06 (1.02-1.09) < 0.001

PHQ-9 ≥ 10 1.94 (1.20-3.13) 0.007

Depressive disorder

Minor depressive disorder (MINI) 1.81 (0.90-3.64) 0.097

Major depressive disorder (MINI) 1.99 (1.24-3.19) 0.005

Adjusted for age, sex, educational level, bmi, smoking, partner status, systolic blood pressure, prior CVD, total cholesterol and HDL cholesterol

Independent variables Major depression OR (95%CI) P-value

Fasting glucose per SD 1.30 (1.09-1.55)

0.003

HbA1c per SD

1.37 (1.15-1.63)

0.001

Skin Autofluoresence per SD 1.28 (1.02-1.62)

0.036

Hyperglycemia sum score per SD 1.54 (1.22-1.96)

<0.001

adjusted for age, sex, smoking, alcohol consumption, hypertension, cholesterol ratio, physical activity, and BMI

Hyperglycemia and depression

Advanced Glycation Endproducts (AGEs)

Van Dooren et al, Depression and Anxiety, 2016 Jun 6

*

Adjusted for age, sex, type 2 diabetes, bmi, smoking, eGFR

Independent variables Major depression OR (95%CI) P-value

Fasting insulin per SD

0.97 (0.8-1.18) 0.740

HOMA per SD 1.04 (0.83-1.29)

0.756

Insulin resistance markers sum score per SD

1.01 (0.78-1.13)

0.923

Insuline resistance and depression

adjusted for age, sex, smoking, alcohol consumption, hypertension, cholesterol ratio, physical activity, and BMI

Hyperglycemia, IR and depression

§  Type 2 diabetes is geassocieerd met meer depressie

§  Verschillende maten van hyperglycemie zijn geassocieerd met depressie

§  Insuline resistentie is niet geassocieerd met depressie

Conclusie

Endothelial dysfunction

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Inflammation

Mechanisms

Depression PHQ-9, MINI diagnostic interview (gold standard) Diabetes Oral glucose tolerance test Glycemic control (fasting gluc, HbA1c, AGEs: SAF, Pentosidine, CEL, CML) Inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) Endothelial function (sVCAM-1, sICAM-1, sE-selectin, vWF) MRI (brain atrophy and cerebral small vessel disease) Lifestyle (physical activity, sedentary time, nutrition)

Methods

Low grade inflammation

OR was 1,54 (1,18-2,02) for LGI sumscore after adjustment for age, sex, DM2, eGFR, prior CVD

Van Dooren et al, Brain Behaviour and Immunity, 2016 Aug;56:390-6.

*

* * *

*

1,25

1,35 1,36

1,19

1,64

1

1,1

1,2

1,3

1,4

1,5

1,6

1,7

1,8

sVCAM-1 sICAM-1 E-selectine vWF EDsumscore

Endothelialfunctionisassociatedwithdepressivedisorder

Odd

sratio

Odd

sratio

Endothelial dysfunction

OR was 1,40 (1,10-1,77) for ED sumscore after adjustment for age, sex, DM2, eGFR, prior CVD

Van Dooren et al, Brain Behaviour and Immunity, 2016 Aug;56:390-6.

* * *

*

Longitudinal associations of low-grade inflammation sum

score with incident depression

Odds ratio 95% CI p value

     

Model 1: crude + demographics 1.81 1.37 - 2.38 <0.001

Model 2: model 1 +

cardiovascular risk factors 1.44 1.05 - 1.97 0.022

Model 3: model 2 + lifestyle risk

factors 1.34 0.95 - 1.88 0.096

Inflammation and incident depression

Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.

Longitudinal associations of endothelial dysfunction sum

score with incident depression

Odds ratio 95% CI p value

     

Model 1: crude + demographics 1.80 1.43 - 2.26 <0.001

Model 2: model 1 +

cardiovascular risk factors 1.48 1.14 - 1.92 0.004

Model 3: model 2 + lifestyle risk

factors 1.40 1.07 - 1.84 0.014

Endothelial dysfunction and incident depression

Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.

55%

45%

LGI, ED and incident depression

Inflammation, endothelial dysfunction and chronic depression

Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.

  Remission   Resistant or recurrent Odds

ratio 95% CI p value

Odds

ratio 95% CI p value

LGI            

Model 1: demographics 1.75 1.17; 2.62 0.007 2.72 1.89; 3.93 0.000

Model 2: model 1 +

cardiovascular risk factors 1.82 1.17; 2.83 0.008 1.86 1.21; 2.86 0.005

Model 3: model 2 + lifestyle risk

factors 1.62 0.99; 2.69 0.057 1.69 1.03; 2.77 0.039

              ED             

Model 1: demographics 1.06 0.67; 1.68 0.818 2.18 1.59; 3.00 0.000

Model 2: model 1 +

cardiovascular risk factors 1.01 0.61; 1.67 0.967 1.51 1.04; 2.21 0.032

Model 3: model 2 + lifestyle risk

factors 0.74 0.42; 1.31 0.302 1.37 0.89; 2.09 0.150

Depressie als gevolg van vaatschade

ORs = 1.14 – 1.58

Agtmaal et al JAMA Psychiatry 2017 Jul 1;74(7):729-739.

§  Inflammatie en endotheel dysfunctie zijn geassocieerd met incidente depressie, mogelijk causaal verband

§  Inflammatie en endotheel dysfunctie samen kunnen chronische depressie voorspellen

Conclusie

Endothelial dysfunction

§  Psychosocial variables

§  Lifestyle factors

§  Biological mechanisms

Inflammation

Mechanisms

Type 2 diabetes and dementia

2x greater risk of dementia in type 2 diabetes

•  Via hyperglycaemia?

•  Via vascular brain damage?

Type 2 diabetes and cognitieve functie

White matter hyperintensities

Brain tissue volumes

Vaatschade in het brein

Vaatschade op MRI

Geen diabetes Pre-diabetes Diabetes

Van Agtmaal et al, submitted

White matter volume

Van Agtmaal et al, submitted

Geen diabetes Pre-diabetes Diabetes

Grey matter volume

Geen diabetes Pre-diabetes Diabetes

Van Agtmaal et al, submitted

Cerebrospinal fluid

Van Agtmaal et al, submitted

Geen diabetes Pre-diabetes Diabetes

•  Prediabetes is associated with

•  White matter hyperintensities

•  Lower white matter volume

•  4 years of aging

•  T2DM is associated with

•  White matter hyperintensities

•  Lower white matter volume

•  Higher CSF volume

•  8.5 years of aging

Conclusion

•  Depressie en dementie komen 2x zo veel voor bij type 2 diabetes

•  Verklarende mechanismen hiervoor zijn: •  Hyperglycemie •  Inflammatie •  Endotheel dysfunctie •  Vasculaire brein schade

•  Zowel prediabetes als type 2 diabetes zijn geassocieerd met versnelde veroudering van het brein weefsel vergelijkbaar met 4 vs 8 jaar veroudering

Take home message

Eén derde van de volwassen Limburgers heeft (pre)diabetes

… 2 van 6 vakken met publiek

17 PhD theses on The Maastricht Study

A further 20 PhD

theses in preparation