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