Diabetes, Cognitive Impairment and dementia Professor Tony Bayer

School of Medicine, Cardiff University

Diabetes, cognitive impairment and dementia

• Epidemiology – impact of diabetes on

cognition

• Possible pathophysiological

mechanisms linking diabetes with

cognitive impairment and dementia

• Recognising cognitive impairment

• 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.

CONCLUSIONSNo 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.

• Prospective cohort (EVA) study of 961 community dwelling people aged 59-71 (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

Cognitive function and decline in type 2 diabetes

Fontbonne et al. Diab Care 2001; 24: 366-70

Visual attentionVerbal memoryFacial recognitionAttentionPsychomotor speedVisual memoryLogical reasoningAuditory attention

• Prospective cohort study of 9679 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

Cognitive function and decline in type 2 diabetes

Gregg et al. Arch Intern Med. 2000;160(2):174-180.

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

A B

• 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 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

(AH4= -66+80 loge glucose-18 loge glucose2; 95% CI -29 to -6, p=0.002)

Blood glucose and cognitive performance in type 2 diabetes

Risk of dementia in Type 2 Diabetes: the Rotterdam Study, 1999

Age & sex adjusted

RR (95% CI)

Total dementia 1.9 (1.3-2.8)

VaD 2.0 (0.7-5.6)

AD 1.9 (1.2-3.1)

AD without CVD 1.8 (1.1-3.0)

• 6,370 subjects aged 55+, dementia-free at baseline, followed up for an average 2.1.y

• Data obtained using a 3-step screening and comprehensive diagnostic work-up and examination of medical files

• Mean age of cohort 69y, n = 692 with diabetes

• 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

Xu W et al. Diabetes, 2010; 59: 2928-35

Cumulative hazard for the progression from MCI to dementia by diabetes status in MCI cohort (adjusted for age, sex, and education).

• 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 (2.27-10.84) for pre-diabetes.

• In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 y.

DIABETESDIABETES DEMENTIADEMENTIA

Possible pathophysiological mechanisms linking diabetes with changes in the brain

Vascular pathology

‘Ageing’ pathology

Alzheimer pathology

Macrovascular disease•Cerebral infarcts

Microvascular disease•Insidious ischaemia

Hyperglycaemia•Advanced protein glycation•Oxidative stress•Mitochondrial dysfunctionRecurrent hypoglycaemia

Hyperinsulinaemia & insulin resistance• Increased Aβ secretion• Increased Aβ breakdown• Inflammation• Tau phosphorylation

Genetic predisposition

ComorbidityMedications

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

• In a GP study of older people with type 2 diabetes, Mini-Cog had sensitivity of 86%, specificity of 91%, positive predictive value of 54% and negative predictive value of 98% for dementia.

• Not influenced by education, culture or language; performance comparable to MMSE.

Sinclair AJ et al. Diab Res Clin Pract 2013

Mini-CogStep 1: ask patient to repeat 3 unrelated words – apple, table, penny – and remember themStep 2: ask patient to draw a clock face – so draw a large circle, put in the numbers so it looks like a clock and then set time to 5 to 3. (Score clock as normal if patient sets the correct time and all numbers in roughly correct positions)Step 3: ask patient to recall the 3 words from Step 1. (Score 1 point for each recalled word)Scoring:

• Baseline cognitive function (DSST score) significantly associated with risk of severe hypoglycemia (p<0.0001)

Punthakee et al. Diab Care 2012;

35:787-793

Impact of glycaemic control on cognition

• 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

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.

Hypoglycaemic episodes and risk of dementia in older patients with type 2 diabetes

Whitmer RA et al. JAMA. 2009;301(15):1565–1572

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

No. of antecedent severe hypoglycaemic

episodes

Adjusted Hazard Ratio (95% Cl) for Incident Dementia (compared with patients with no hypoglycaemia)

Excess Attributable RiskPer 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)

Individualising HbA1c Goals

Review glycaemic targets if:

•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

HbA1c 8.1–9% (65–75 mmol/mol)

Based on Triplitt C. Consult Pharm. 2010;25(Suppl B):19–27;Sinclair AJ, Diabetes Metab. 2011;37(Suppl 3):S27–38.

Usual HbA1c targets if dementia

Usual HbA1c targets if dementia

Adverse effect of dementia diagnosis on management of diabetes

• Retrospective cohort study of 288,805 Medicare beneficiaries with diabetes; 44,717 (15%) with comorbid dementia

Receipt in past year…

Adjusted predicted probability,% (95%CI)

Adjusted risk ratio(95%CI)

HbA1c Dementia 77.4 (76.9-77.8) 0.96 (0.96-0.97)

No dementia 80.4 (80.2-80.5)

LDL Cholesterol Dementia 70.3 (69.9-70.8) 0.91 (0.90-0.91)

No dementia 77.5 (77.3-77.7)

Eye examination Dementia 54.0 (53.4-54.5) 0.85 (0.85-0.86)

No dementia 63.1 (62.9-63.3)

All three tests Dementia 36.9 (36.4-37.4) 0.80 (0.79-0.81)

No dementia 46.2 (46.0-46.4)

Thorpe et al. JAGS 2012; 60: 644-51

Achieving best clinical practice (2013)

In a dementia care setting In a dementia care setting In a diabetes care setting In a diabetes care setting STEP 1: Symptom awareness and active screening:•Proactive screening (at diagnosis of dementia and annually).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 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 symptomsPromote good nutrition

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 symptomsPromote good nutrition

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 minimum – focus on preventing acute symptoms.

Early stage DementiaEarly stage Dementia

Advanced DementiaAdvanced Dementia

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 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.

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.

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 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 min to prevent acute symptoms.•Involve/patient carers in discussion

STEP 4: Palliation and therapy minimisation (advanced dementia):•Reduce diabetes therapy to min to prevent acute symptoms.•Involve/patient carers in discussion

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