Transcript Diabetes-Cognitive-I..

Diabetes, Cognitive Impairment
and dementia
Professor Tony Bayer
School of Medicine, Cardiff University
Diabetes, cognitive impairment and
dementia
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Epidemiology – impact of diabetes on
cognition
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Possible pathophysiological
mechanisms linking diabetes with
cognitive impairment and dementia
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Recognising cognitive impairment
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Implications for managing diabetes
Cognitive function in adults with type 1
diabetes
• Meta-analysis of 33 case-control
studies of individuals aged 18-50y
• Magnitude of cognitive dysfunction is
moderate
• Most tests examine ability to respond
rapidly and cognitive slowing is
fundamental deficit – not memory
• Differences emerge early, within 2y of
diagnosis and children’s brain more
susceptible than adults (those with
onset age <7y have higher risk than
those older
Diabetes Control and Complications Trial Research Group.
Diabetes 1997; 46: 771-86
McCrimmon RJ et al. Lancet 2012; 379:2291-9
Cognitive function in adults with type 1
diabetes
New Engl J Med 2007;356:1842-52.
CONCLUSIONS
No evidence of substantial long-term declines in cognitive function was found in a
large group of patients with type 1 diabetes who were carefully followed for an
average of 18 years, despite relatively high rates of recurrent severe hypoglycaemia.
Cognitive function and decline
in type 2 diabetes
Visual attention
Verbal memory
Facial recognition
Attention
Psychomotor speed
Visual memory
Logical reasoning
Auditory attention
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Prospective cohort (EVA) study of 961 community dwelling people aged 5971 (mean 64; 55 with diabetes), with MMSE>26 at baseline
After 4 years, compared to those who had normal glucose or impaired
fasting glucose, people with diabetes had lower scores on tests of
psychomotor speed, attention and verbal memory
Fontbonne et al. Diab Care 2001; 24: 366-70
Cognitive function and decline
in type 2 diabetes
A
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Diabetes duration and adjusted odds (95% CI) of
A. cognitive impairment at baseline and B. cognitive
decline over 4 - 6 years on DSST, Trails B & m-MMSE
Prospective cohort
study of 9679
B
women aged 65-99y (mean 72y; 682
with diabetes)
Women with diabetes had lower
baseline scores on 3 tests of
cognitive function and experienced
an accelerated cognitive decline
Women who had diabetes for >15y
had more cognitive impairment at
baseline and 57-114% greater risk of
major decline than women without
diabetes
Gregg et al. Arch Intern Med.
2000;160(2):174-180.
Blood glucose and cognitive performance
in type 2 diabetes
• Cross-sectional study of 2,205 men,
aged 55–69y, from Caerphilly, South
Wales & adjacent villages; 165 with
type 2 diabetes
• After adjusting for stroke & vascular risk
factors, those with diabetes had
cognitive deficits for verbal fluency,
NART (crystallised IQ), AH4 (fluid IQ)
and CAMCOG.
(AH4= -66+80 loge glucose-18 loge glucose2; 95% CI -29 to -6, p=0.002)
• AH4 score in men with diabetes had a
curvilinear relationship with blood
glucose; both high and low glucose had
worse performance
Gallacher JEJ et al. Eur J Epidemiol 2005; 20: 761-768
Risk of dementia in Type 2 Diabetes:
the Rotterdam Study, 1999
• 6,370 subjects aged 55+, dementia-free
at baseline, followed up for an average
2.1.y
Age & sex
adjusted
RR (95% CI)
• Data obtained using a 3-step screening
and comprehensive diagnostic work-up
and examination of medical files
Total dementia
1.9 (1.3-2.8)
VaD
2.0 (0.7-5.6)
• Mean age of cohort 69y, n = 692 with
diabetes
AD
1.9 (1.2-3.1)
AD without CVD 1.8 (1.1-3.0)
• Patients on insulin were at highest risk
for dementia (RR of 4.3 95%CI 1.7-10.5)
• Population attributable risk of diabetes
to incident dementia was 8.8%
Ott et al. Neurology 1999; 58: 1937-41
Accelerated progression of mild cognitive impairment
(MCI) to dementia in people with diabetes
• 302 subjects, age >75y, with MCI
followed for 9y in the Kungsholmen
Project: 155 subjects progressed to
dementia.
• Multi-adjusted hazard ratio (95% CI)
of dementia was 2.87 (1.30-6.34) for
baseline diabetes, and 4.96 (2.2710.84) for pre-diabetes.
Cumulative hazard for the progression from
MCI to dementia by diabetes status in MCI
cohort (adjusted for age, sex, and education).
• In a Kaplan-Meier survival analysis,
diabetes and pre-diabetes
accelerated the progression from
MCI to dementia by 3.18 y.
Xu W et al. Diabetes, 2010; 59: 2928-35
Possible pathophysiological mechanisms linking
diabetes with changes in the brain
Macrovascular disease
•Cerebral infarcts
Genetic
predisposition
Microvascular disease
•Insidious ischaemia
Hyperglycaemia
•Advanced protein glycation
•Oxidative stress
•Mitochondrial dysfunction
DIABETES
Recurrent hypoglycaemia
Comorbidity
Medications
Vascular
pathology
Hyperinsulinaemia &
insulin resistance
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Increased Aβ secretion
Increased Aβ breakdown
Inflammation
Tau phosphorylation
‘Ageing’
pathology
DEMENTIA
Alzheimer
pathology
Adapted from Biessels GJ et al.
Lancet Neurology 2006; 5: 64-74
Benefits of timely detection
Best Clinical Practice 2012
Potential benefits of
timely detection of
dementia and/or
diabetes
Mini–Cog : a quick screen for significant
cognitive impairment in people with diabetes
Mini-Cog
Step 1: ask patient to repeat 3 unrelated words – apple,
• In a GP study of older
table, penny – and remember them
people with type 2 diabetes,
Step 2: ask patient to draw a clock face – so draw a large
Mini-Cog had sensitivity of
circle, put in the numbers so it looks like a clock and then
86%, specificity of 91%,
set time to 5 to 3. (Score clock as normal if patient sets the
positive predictive value of
correct time and all numbers in roughly correct positions)
54% and negative predictive
Step 3: ask patient to recall the 3 words from Step 1.
value of 98% for dementia.
(Score 1 point for each recalled word)
Scoring:
• Not influenced by
education, culture or
language; performance
comparable to MMSE.
Sinclair AJ et al. Diab Res Clin Pract 2013
Impact of glycaemic control on cognition
ACCORD-MIND - Memory in Diabetes Sub-study of the Action
to Control Cardiovascular Risk in Diabetes (ACCORD) Trial
2977 patients aged 55-80 (mean 62y) with type 2 diabetes, treated with
standard care or intensive glycaemic control.
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20% of patients found to have
undetected cognitive impairment
at baseline
No difference in DSST score (or any
other cognitive tests) at 40 mths.
Greater mean total brain volume
on MRI on intensive than standard
treatment (p=0.0007)
Launer et al. Lancet Neurol 2011;10:969-77
• Baseline cognitive function (DSST
score) significantly associated with risk
of severe hypoglycemia (p<0.0001)
Punthakee et al.
Diab Care 2012;
35:787-793
Hypoglycaemic episodes and risk of dementia in older
patients with type 2 diabetes
No. of antecedent
severe hypoglycaemic
episodes
Adjusted Hazard Ratio (95% Cl) for
Incident Dementia (compared with
patients with no hypoglycaemia)
Excess Attributable Risk
Per Year (95% CI)
1 or more
1.44 (1.25–1.66)
2.39 (1.72-3.01)
1
1.26 (1.10–1.49)
1.64 (0.91-2.36)
2
1.80 (1.37–2.36)
4.34 (2.36-6.32)
≥3
1.94 (1.42–2.64)
4.28 (2.10-6.44)
Longitudinal cohort study (1980– 2007) of 16,667 patients with type 2 diabetes
(mean age 65y): at least one episode of severe hypoglycaemia in 1465 (8.8%)
Dementia risk adjusted for age, sex, race, BMI, education, comorbidities,
diabetes duration, 7-year mean HbA1c, and duration of insulin use
Whitmer RA et al. JAMA. 2009;301(15):1565–1572
Individualising HbA1c Goals
Review glycaemic targets if:
Usual HbA1c
targets if
dementia
HbA1c 8.1–9%
(65–75
mmol/mol)
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Significant cognitive impairment
Hypoglycaemia unawareness
History of falls
Evidence of advanced/poorly
controlled cardiovascular and/or
microvascular complications
• Life expectancy <3 years
• End of life/palliative care
Based on Triplitt C. Consult Pharm. 2010;25(Suppl B):19–27;
Sinclair AJ, Diabetes Metab. 2011;37(Suppl 3):S27–38.
Adverse effect of dementia diagnosis on
management of diabetes
Receipt in past
year…
HbA1c
LDL Cholesterol
Eye examination
All three tests
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Adjusted predicted
probability,
% (95%CI)
Adjusted risk ratio
(95%CI)
Dementia
77.4 (76.9-77.8)
0.96 (0.96-0.97)
No dementia
80.4 (80.2-80.5)
Dementia
70.3 (69.9-70.8)
No dementia
77.5 (77.3-77.7)
Dementia
54.0 (53.4-54.5)
No dementia
63.1 (62.9-63.3)
Dementia
36.9 (36.4-37.4)
No dementia
46.2 (46.0-46.4)
0.91 (0.90-0.91)
0.85 (0.85-0.86)
0.80 (0.79-0.81)
Retrospective cohort study of 288,805 Medicare beneficiaries with
diabetes; 44,717 (15%) with comorbid dementia
Thorpe et al. JAGS 2012; 60: 644-51
Achieving best clinical practice (2013)
In a dementia care setting
Early stage Dementia
STEP 1: Symptom awareness and active screening:
•Proactive screening (at diagnosis of dementia and annually).
STEP 2: Symptom alleviation & complication screen:
•Consult with diabetes team or GP to start diabetes treatment to alleviate
physical symptoms.
Aim to for fasting BG 7-9 range (HbA1c 7-8%, 53-64 mmol/mol)
Screen for complications (eyes, feet, kidney , CVD) – repeat bi-annually.
Eliminate diabetes symptoms and or con-current infection that may
exacerbate confusional state.
STEP 3: Risk minimisation:
•Prevent complications that will reduce QoL (eye and feet).
Reduce falls and hypoglycaemia risk –medicines review (consult diabetes
team or GP).
Prevent hyperglycaemic symptoms
In a diabetes care setting
STEP 1: Awareness and screening for dementia
•Screen for cognitive impairment dementia if risk factors present or
patient/carer concern- MMSE or Mini-cog.
Assess for acute confusional state and treat (could be related to
diabetes and/or infection/pain).
Assessment of cognition/capacity to understand and retain information.
STEP 2: Manage cognitive deficit
•Ensure self-management deficits are addressed in context of cognitive
impairment in partnership with carers.
Eliminate diabetes symptoms and or con-current infection that may
exacerbate confusional state.
Promote good nutrition
STEP 3: Minimise therapy risk
•Avoid overly intensive management use therapies that reduce risk of
hypoglycaemia.
Focus education and support on carers as well as patient.
Aim to achieve fasting BG 6-9 range (A1c 7 -8%, 53-64 mmol/mol)
STEP 4: Palliation and therapy minimisation (advanced dementia):
•Reduce diabetes therapy to minimum – focus on preventing acute
symptoms.
STEP 4: Palliation and therapy minimisation (advanced dementia):
•Reduce diabetes therapy to min to prevent acute symptoms.
•Involve/patient carers in discussion
Advanced Dementia
A diagnosis of diabetes in a person with
dementia indicates …
– a need to reconsider aims of care and glucose
targets
– an indicator to review adherence to diabetes
treatment and assess nutritional status
– a reminder to undertake a cardiovascular risk
assessment
– a prompt to review hypoglycaemia risk