Presentation by Carol Greenwood (PhD) at the Diabetes Perspectives... Ages and Stages Symposium (September 29, 2014)

1. Type 2 Diabetes and Dementia: What’s the link? A Review of the Metabolic and Vascular Contributors
Carol Greenwood
Professor, Dept Nutritional Sciences
University of Toronto
Senior Scientist, Rotman Research Institute
Baycrest

2. THANK YOU!
Nicole Anderson
Brad MacIntosh
Michael Chui
Jyotika Desai
Liesel-Ann Meusel
Yanni Papanikolaou
Ekaterina Tchistiakova
William Yuen
Noah Koblinsky
Andrea Maione
Malcolm Binns
Jon Ween
Simon Graham
Jeremy Gilbert
David Jenkins
Sid Feldman
RESEARCH PARTICIPANTS!!!

3. Goals of the Presentation

To understand the impact of T2DM on cognitive function and dementia risk

To explore metabolic and vascular mechanisms which contribute to this risk

To look at the impact of CHO intake on cognitive function

4. Cognition in Type 2 Diabetes

T2DM associated with modest cognitive decrements that evolve slowly over time (Reijmer et al., 2010, 2011)

Middle aged adults – decrements are modest and reasonably confined to specific cognitive functions (Ryan & Geckle, 2000; Ruis et al., 2009)

Older adults – decrements more predominant and widespread, impacting more cognitive functions

Primarily occurring in areas of processing speed, attention, executive function (van den Berg et al., 2010; Yueng et al., 2009)
Meusel LC, et al. Frontiers in Aging Neuroscience 6, article 148. 2014. doi: 10.3389/fnagi.2014.00148.; Meusel LC, et al. J Curr Clin Care 2012; 2(1):6-16.

5. Risk Factors for Decrements on Measures of Information Processing Speed in T2DM
Taken from: Reijmer et al, Diabetes/Metab Res Rev. 26:507-519, 2010
In pooled analyses, across three studies, both higher HbA1c and presence of macrovascular disease are associated with increased risk for poorer information processing speed

6. Decrements Are More Predominant and Widespread in Older Adults with T2DM
Taken from: Reijmer et al, Diabetes/Metab Res Rev. 26:507-519, 2010

7. Translates Into Increased Dementia Risk

Beyond the age of 65 years, T2DM conveys the highest risk for progression to dementia: a 6-8% increased risk relative to those who do not have T2DM

This is over and above that associated with hypertension, dyslipidaemia, and obesity

Associates with both vascular dementia and Alzheimer Disease

8. Vascular Factors Increase Both Stroke and Dementia Risk
Hypertension
Diabetes
High Cholesterol
Smoking
Adopted from Goldestein et. al, Stroke 2006

9. Is the increased dementia risk with T2DM SOLELY explained by its contribution to vascular dysfunction, or are there other contributing T2DM- associated factors?

10. Type 2 Diabetes and Vascular Complications

In addition to hypertension and dyslipidemia, hyperglycemia seems to be an important factor resulting in:

Global decreases in cerebral blood flow

Decreased blood vessel dilation in response to vasodilatory stimuli

Structural changes in the vessel wall that result in atherosclerotic plaque formation.

Presence of cerebrovascular disease associated with a 2-5 fold increase in stroke occurrence, implicated in dementia

11. Hyperglycemia and Vascular Complications
Hyperglycemic-induced reductions in the vasodilator nitric oxide (NO) and increases in the vasoconstrictor endothelin-1 impair dilation of blood vessels. Over time, this results in structural changes in the vessel wall that result in atherosclerotic plaque formation.
adapted from: Meusel et al., J Curr Clin Care 2012; 2(1):6-16.

12. But…..
It is now acknowledged that other metabolic disturbances in T2DM are equally harmful to brain health and function.

13. tau pathology
inflammation
neurovascular dysfunction
microglial activation & reactive gliosis
demyelination & hypermetabolism
oxidative
stress
type 2 diabetes
adapted from: Meusel et al., J Curr Clin Care 2012; 2(1):6-16.
Type 2 Diabetes: A Compromised Brain
increased production of Aβ
Aβ aggregation
neuronal dysfunction
white matter damage
atrophy
cognitive impairment, dementia risk including Alzheimer’s disease
vascular damage
metabolic disruption
•
hyperglycemia
•
insulin resistance
•
altered insulin signalling
•
AGE production
•
HPA axis dysfunction

14. Our Recent Study: Neurocognitive Correlates of Hypertension and Type 2 Diabetes
GOAL: to understand how brain structure and function is impacted in individuals with T2DM and how these changes impact neuropsychological test performance
Participants:
control group: older adults with hypertension
patient group: older adults with hypertension AND T2DM
Exploring the ADDED effect of T2DM, over and above that associated with hypertension

15. Participant Demographics

17 cognitively intact older adults with hypertension versus 13 older adults with hypertension and T2DM
•
age: 72.2 (5.7)
•
education: 15.6 (2.9)
•
duration of hypertension (years): 10.2 (6.7)
•
duration of T2DM (years; n = 13): 11.2 (6.8)

Health status of participants:
•
insulin levels, triglycerides, HDL cholesterol, BMI, waist circumference, and diastolic blood pressure did not differ based on T2DM status

16. T2DM Group Had Higher HbA1c, But Lower Systolic Blood Pressure and Plasma LDL Levels Relative to Hypertension Only Group
Hypertension Only
Hypertension and T2DM
HbA1c (%)
5.7 ± 0.3
6.9 ± 0.5*
Systolic Blood Pressure
139 ± 16
126 ± 16*
LDL Cholesterol
2.9 ± 0.9
1.8 ± 0.6*
* Significantly different from the hypertension only group.

17. Study Design

behavioural

neuropsychological test battery
structural imaging
cortical thickness **
functional imaging
breath-hold task **
episodic memory task
working memory task
** work conducted by:
Ekaterina Tchistiakova, PhD. candidate
Supervisor: Dr. Brad MacIntosh, Sunnybrook Research Institute

18. Previous Structural Imaging Work in T2DM

greater whole brain atrophy (Kamiyama et al., 2010)

smaller total brain volume, larger peripheral CSF volume, increased lateral ventricle volume over time (deBresser et al., 2010)

increased progression of brain atrophy over 3 years (van Elderen et al., 2010)

prefrontal atrophy associated with poorer glycemic control (Bruehl et al., 2009)

Regional and whole brain atrophy associated with poorer performance on measures of global cognitive function and a variety of specific cognitive tasks (van Elderen et al., 2010; Bruehl et al., 2009; Hayashi et al., 2011)
diabetic old
healthy old

19. T2DM Effects on Cerebrovascular Health Which Are Independent of Hypertension

reduced cerebral autoregulation (Brown et al., 2008; Kim et al., 2008) and brain vasodilation response (Last et al., 2007)
reduced regional cerebral blood flow and reactivity (Last et al., 2007)
decreased blood flow velocity, increased cerebrovascular resistance, impaired reactivity (Novak et al., 2006)

20. Tremendous Heterogeneity Within T2DM Population
Diabetic age 71
Diabetic age 76

21. No Difference in Hippocampal Volumes in Older Adults with Hypertension (HO) vs. Hypertension and T2DM (DO)
Right Hippocampus Left Hippocampus
Volume (mm3)
0
500
1000
1500
2000
2500
3000
HO
HO
DO
DO

22. Structural MRI: Cortical Thickness
Dale et al., 1998
= distance between the white matter surface and pial surface
white matter-grey matter border (WM/GM border)
grey matter-CSF border (pial surface)
pial surface
WM/GM border

23. Cerebrovascular Reactivity (Breath-Hold Task)

24. Relative to older adults with hypertension, those with hypertension and T2DM have decreased cortical thickness and reduced cerebrovascular reactivity
Tchistiakova et al,
NeuroImage: Clinical,
5:36-41, 2014.

25. Decreased cortical thickness was associated with poor performance on executive function tasks
Tchistiakova et al,
NeuroImage: Clinical,
5:36-41, 2014.

26. Study Design

behavioural

neuropsychological test battery
structural imaging
cortical thickness
functional imaging
breath-hold task
episodic memory task
working memory task **
** work conducted by:
Dr. Liesel-Ann Meusel, PDF and William Yuen, M.Sc.

27. Previous Functional Imaging Work in T2DM

resting-state fMRI (Zhou et al., 2010): reduced functional connectivity between hippocampus and:

posterior cingulate

precuneus

medial frontal cortex

anterior cingulate

inferior parietal lobule

28. Brain Regions Activated During Task Performance
Brain Regions Which Are Deactivated During Task Performance (Default Mode)

29. Preliminary Results

Changes to the default mode network

Ability to activate regions associated with task performance

30. Practice Considerations

Need to help individuals manage both their glycemic control as well as other common co-morbid conditions, including hypertension and dyslipidemia

While cognitive deficits will not be highly prevalent in younger adults, with aging, they could become more apparent

Susceptibilities to metabolic dysregulation can even be seen at the meal-to-meal level

31. Glucose and Cognition in Adults
4681012YoungSeniorsPlaceboGlucose
Hall et al, 1989
Neuropsychologia: 27: 1129
(18-23 y)
(58-77 y)
# Scoring Units Recalled
Paragraph Recall
*

32. Consumption of Simple CHO Foods Impairs Delayed Recall in Adults With T2DM
0
2
4
6
8
# of Scoring Units Recalled
Paragraph Recall
0
2
4
6
Word List Recall
# of Words Recalled
Water
Food
Greenwood et al, 2003
Diabetes Care 26:1961
*

33. Low- Versus High- Glycemic Index CHOs In Adults With Type 2 Diabetes
IMM-1IMM-2IMM-3DEL-1DEL-2 No. of words recalled 246810121416Water Bread Pasta abagAUC0200400600800 No. of words recalled 024681012
Word List Recall
Papanikolaou et al, 2006
Diabetologia 49:855
Would have anticipated comparable differences in insulin responses to food ingestion
Time (min) 020406080100120140 Blood Glucose (mmol/L) 6789101112Water Bread Pasta acbbacabc

34. Plasma Glucose, Insulin and Salivary Cortisol Following Macronutrient Drinks in Adults with Type 2 Diabetes
GlucoseTime (mins) 020406080100 Plasma Glucose (mmol/L) 81012141618Glucose Protein Fat Water InsulinTime (mins) 020406080100 Plasma Insulin 101520253035CortisolTime (mins) 020406080100 Cortisol ug/dL 0.0040.0050.0060.007
Desai & Greenwood, in preparation

35. Postprandial Cortisol Predicts Decrements in Paragraph Recall Performance in Adults with Type 2 Diabetes
Desai & Greenwood, in preparation
Paragraph RecallParagraph 1 RecallImmediate Delay 1Delay 2 Units of Information Recalled 4812162024Glucose Protein Fat Water aabbaa,baabba,ba,bCortisol Results in Verbal Memory DecrementsChange in Cortisol-0.2-0.10.00.10.2 Change in Units Recalled on Para 1 Delay 2 -10-5051015p=0.04

36. Improved Performance Following Antioxidant Vitamins in Adults with Type 2 Diabetes
0
2
4
6
8
10
Treatment
Water
Food
Food + Vitamins
0
2
4
6
8
10
12
14
Treatment
Water
Food
Food + Vitamins
Word List Recall
ab
b
a
# Words Recalled
Digit Span
a
b
a
Chui & Greenwood, 2008
Nutrition Research 28:423

37. Memory Deficits in Type 2 Diabetes Associated with Meal Ingestion
Food Ingestion
Insulin Levels
Glucose Levels
Cortisol Levels
Decrements in Hippocampal Function
Oxidative Stress
Inflammatory
Cytokines

38. Conclusions

T2DM is associated with increased risk for cognitive decline and dementia

Both vascular and metabolic complications of T2DM and other common co-morbid disorders are involved

T2DM-associated changes can be observed in brain structure, cerebrovascular health and blood perfusion, and neural activity

Treatment needs to focus across all co-morbid conditions as they all appear to contribute in their own right

Minimizing glucose excursions and metabolic stress may help in sustaining cognitive function throughout the day