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

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!!!

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

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.

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

Decrements Are More Predominant and Widespread in Older Adults with T2DM

Taken from: Reijmer et al, Diabetes/Metab Res Rev. 26:507-519, 2010

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

Vascular Factors Increase Both Stroke and Dementia Risk

Hypertension Diabetes High Cholesterol Smoking

Adopted from Goldestein et. al, Stroke 2006

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

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

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.

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

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

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

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

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.

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

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

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)

Tremendous Heterogeneity Within T2DM Population

Diabetic age 71

Diabetic age 76

No Difference in Hippocampal Volumes in Older Adults with Hypertension (HO)

vs. Hypertension and T2DM (DO)

Right Hippocampus Left Hippocampus

Volu

me

(mm

3 )

0

500

1000

1500

2000

2500

3000

HO HO DO DO

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

Cerebrovascular Reactivity (Breath-Hold Task)

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.

Decreased cortical thickness was associated with poor performance on executive function tasks

Tchistiakova et al, NeuroImage: Clinical, 5:36-41, 2014.

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.

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

Brain Regions Activated During Task Performance

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

Preliminary Results Changes to the default mode network

Ability to activate regions associated with task performance

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

Glucose and Cognition in Adults

4

6

8

10

12

Young Seniors

PlaceboGlucose

Hall et al, 1989 Neuropsychologia: 27: 1129

(18-23 y) (58-77 y)

# S

corin

g U

nits

Rec

alle

d

Paragraph Recall

*

Consumption of Simple CHO Foods Impairs Delayed Recall in Adults With T2DM

0 2 4 6 8

# of

Sco

ring

Uni

ts R

ecal

led

Paragraph Recall

0

2

4

6

Word List Recall

# of

Wor

ds R

ecal

led

Water Food

Greenwood et al, 2003 Diabetes Care 26:1961

*

Low- Versus High- Glycemic Index CHOs In Adults With Type 2 Diabetes

IMM-1 IMM-2 IMM-3 DEL-1 DEL-2

No.

of w

ords

reca

lled

2

4

6

8

10

12

14

16Water Bread Pasta

ab

a

gAUC0 200 400 600 800

No.

of w

ords

reca

lled

0

2

4

6

8

10

12

Word List Recall

Papanikolaou et al, 2006 Diabetologia 49:855

Would have anticipated comparable differences in insulin responses to food ingestion

Time (min)0 20 40 60 80 100 120 140

Bloo

d G

luco

se (m

mol

/L)

6

7

8

9

10

11

12Water Bread Pasta

a

c

bb

a

c

a

b

c

Plasma Glucose, Insulin and Salivary Cortisol Following Macronutrient Drinks in Adults with Type 2 Diabetes

Glucose

Time (mins)

0 20 40 60 80 100

Pla

sma

Glu

cose

(mm

ol/L

)

8

10

12

14

16

18Glucose Protein Fat Water

Insulin

Time (mins)

0 20 40 60 80 100

Pla

sma

Insu

lin

10

15

20

25

30

35

Cortisol

Time (mins)

0 20 40 60 80 100

Cor

tisol

ug/

dL

0.004

0.005

0.006

0.007

Desai & Greenwood, in preparation

Postprandial Cortisol Predicts Decrements in Paragraph Recall Performance in Adults with Type 2 Diabetes

Desai & Greenwood, in preparation

Paragraph Recall

Paragraph 1 RecallImmediate Delay 1 Delay 2

Uni

ts o

f Inf

orm

atio

n R

ecal

led

4

8

12

16

20

24Glucose Protein Fat Water

aa

bb

aa,b

a a

b ba,b a,b

Cortisol Results in Verbal Memory Decrements

Change in Cortisol

-0.2 -0.1 0.0 0.1 0.2

Cha

nge

in U

nits

Rec

alle

d on

Par

a 1

Del

ay 2

-10

-5

0

5

10

15 p=0.04

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

# W

ords

Rec

alle

d

Digit Span

a b

a

Chui & Greenwood, 2008 Nutrition Research 28:423

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

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