Preventing Dementia: The Depression-Diabetes Nexus
Toronto Dementia Research Alliance
Roger S McIntyreAssoc. Professor of Psychiatry and Pharmacology, University of Toronto
Head, Mood Disorders Psychopharmacology Unit,University Health Network
University of Toronto Psychiatry
14 Academic divisions/programs across 7 fully affiliated hospitals 17 endowed chairs and 2 endowed professorships 682 Active Faculty members, 183 full-time and 499
part-time 79 members hold appointments in the Institute of
Medical Science. 155 Residents 60 Fellows
Mood Disorder Psychopharmacology Unit (MDPU)/ UHN
Lead Centre: International Mood Disorders Collaborative Project. UHN- Cleveland Clinic (University of Texas, SA) n=1250 patients
Lead Centre: International Centre of Excellence in Mood Disorder Research UHN-Gulf Region ( Kuwait and Saudi Arabia)
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MDPU Capabilities
Biomarkers (neuroimaging, biofluids, genetics) Endophenotypes Predictors (i.e. illness, treatment) Transdisciplinary intervention
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MDPU-Research Mission Statement and Synergism with TDRA
To identify avenues that cause, prevent and modify disease course in mood disorders
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To identify ultra-high risk individuals for dementing disorders and initiate primary and secondary prevention
Major Depression Associated with Decreased Brain Volume
3-year prospective study comparing 38 patients with 30 healthy controls Significant decline in gray matter density was noted in hippocampus, amygdala, anterior
cingulate cortex, and dorsomedial prefrontal cortex Threshold was set at P<.001
Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165. Copyright © 2008 American Medical Association. All rights reserved.
Multiple Episodes/Longer Illness Duration Associated with Greater Hippocampal Volume Loss
Years of illness
Left
HC
vol
umes
(mm
3)
Years of illness
Rig
ht H
C v
olum
es (m
m3)
403020100
3400
3200
3000
2800
2600
2400
2200
2000
1800 403020100
3400
3200
3000
2800
2600
2400
2200
2000
1800
MacQueen et al. PNAS Feb. 2003; Vol. 100 no.3:1387-1392.
Left Hippocampus Right Hippocampus
Greater Decline in Gray Matter Volume in Unremitted Compared with Remitted MDD Patients
Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165. Copyright @ 2008 American Medical Association. All rights reserved.
3-year prospective study comparing 38 patients with 30 healthy controls
Significantly greater decline in gray matter density was noted in non-remitted versus remitted major depressive disorder patients in: Hippocampus Anterior cingulate cortex Dorsomedial prefrontal cortex Dorsolateral prefrontal cortex
Threshold was set at P<0.01
Mood Disorder Episode Frequency Increases Risk for Dementia
0
1
2
3
4
5
6
7
1 2 3 4 >5
Haz
ard
Rat
io
Number of Episodes
MDD
Bipolar Disorder
Kessing LV Anderson PKJ Neurol Neurosug Psychiatry 2004; 75:1662-1666
Rapp, M. A. et al. Arch Gen Psychiatry 2006;63:161-167.
Major Depression Increases AD Neuropathology in the Hippocampus
Insulin: Critical for Normal CNS Function
Neurotrophic
Synaptic plasticity (i.e. memory formation)
Neurodevelopment
Neuroprotection
Neuromodulation (e.g. acetylcholine)
Feeding and behaviorMcIntyre RS, et al. Expert Opin Pharmacother. 2007;8(11):1615-1628.
Insulin: A Mediator of AD Neuropathology?
Central Nervous System
Synaptic plasticity
Ca2+
AMPA-R
NMDA-R P13K
Insulin
Pancreas
Glucose
Periphery
PKB BAD
Caspase-9Survival
FoxO
Ref
Disease
Aβ
IDE GSK3
Tau
Alzheimer’s
Cell death
Cell death
Cell death
P13KInsulin Insulin Cell death
ERK1/2
Synaptic plasticity
Learning memory
?
Blood-brain barrier
NMDA-R=N-methyl-D-aspartate receptor.van der HeideLP, et al. Prog Neurobiol. 2006;79(4):205-221.
McIntyre RS, et al. Exp Opin In Pharmacother. 2006;7(10):1305-1321.
Insulin-Degrading Enzyme and Alzheimer’s Disease
Aβ=amyloid β. IDE=insulin-degrading enzyme. Qiu WQ, et al. Neurobio of Aging. 2006;27(2):190-198.
Greater Suppression of Neurogenesis with Concurrent Diabetes Mellitus and Depression
Wang SH et al. Toxicol Sci 2009 June 5
C: control rats injected with vehicle alone; DM: streptozotocin-induced diabetic rats without depressive-like behaviour; DM+D: streptozotocin-induced diabetic rats with depressive-like behaviour; DM+D+AG: aminoguanidine (AG, 10 mg/kg) administrated in DM+D rats for 4 weeksap<0.001 DM+N, DM+D vs CON value; bp<0.001 DM+N vs DM+D; cp<0.001 DM+D+AG vs DM+D value. Values are means SD.
a
ab
c
Num
bers
of B
rdU
+ ce
lls80.00
60.00
40.00
20.00
0.00 C DM DM+D DM+D+AG
Survival
Diabetes Mellitus and Dementia
DM increases risk of both AD and VaD, regardless of age of onset Type 2 DM/Abnormal FBG present in up to
80% of AD Altered brain metabolism noted prior to
cognitive deterioration “Type 3 Diabetes Mellitus”
Hippocampal Volume Changes in Diabetes Mellitus
MRI=magnetic resonance imaging. Hippocampal volumes (+SE) on brain MRI in participants with diabetes (n=41) and without diabetes (n=465). Volumes are adjusted for age and sex and normalized to
average head size.
6.0
6.1
6.2
6.3
6.4
6.5
No Diabetes Diabetes
Hip
poca
mpa
l Vol
ume
(ml)
p=.042
Den Heijer T, et al. Diabetologia. 2003;46(12):1604-1610.
Diabetes Medication is Associated with less AD Neuropathology
Beeri MS et al., Neurology 71, September 2008, 750-757
The Depression-Diabetes Nexus
McIntyre RS, et al. An Clin Psych.2007;19(4):257-264.
Insulin
Insulin-Growth Factor
Pro-inflammatory Cytokines
Reactive Oxygen Species
Glucocorticoids
Mood Disorders
Diabetes Mellitus
Preventing Dementia: The Opportunity of the TDRA
Identifying ultra-high risk individuals (latent, prodrome)
Biomarkers Multi modal probabilistic modeling Sample size Specificity Primary/secondary prevention
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